Prevention and management of chronic kidney disease in type 2 diabetes

Prevention and management of chronic kidney disease intype 2 diabetes

Date written: April 2009nep_1240 162..194

Final submission: April 2009Author: Chadban S, Howell M, Twigg S, Thomas M, Jerums G, Cass A, Campbell D, Nicholls K, Tong A, Mangos G,Stack A, MacIsaac RJ, Girgis S, Colagiuri R, Colagiuri S, Craig J

GUIDELINES

Blood glucose control should be optimized aiming for a general HbA1c target 27%. (Grade A*).In people with type 2 diabetes and microalbuminuria or macroalbuminuria, angiotensin receptor blocker (ARB) orangiotensin-converting enzyme inhibitor ACEi antihypertensives should be used to protect against progression ofkidney disease. (Grade A*).The blood pressure (BP) of people with type 2 diabetes should be maintained within the target range. ARB or ACEishould be considered as antihypertensive agents of first choice. Multi-drug therapy should be implemented as requiredto achieve target blood pressure. (Grade A*)People with type 2 diabetes should be informed that smoking increases the risk of chronic kidney disease (CKD) (GradeB*).

*Refer to Table A1: Definition of NHMRC grades of recommendation. Also refer to NHMRC ‘National Evidence Based Guidelines forDiagnosis, Prevention and Management of CKD in Type 2 Diabetes’ (see http://www.cari.org.au) for Levels of Evidence and EvidenceGrading which were undertaken in accordance with the NHMRC Hierarchy of Evidence procedure.

SUGGESTIONS FOR CLINICAL CARE

• The HbA1c target may need to be individualized tak-ing in to account history of hypoglycaemia andco-morbidities. (refer to NHMRC Evidence Based Guide-line for Blood Glucose Control in Type 2 Diabetes athttp://www.nhmrc.gov.au).• Systolic blood pressure (SBP) appears to be the bestindicator of the risk of CKD in type 2 diabetes. However,an optimum and safest lower limit of SBP has not beenclearly defined.• In people with type 2 diabetes antihypertensive therapywith ARB or ACEi decreases the rate of progression ofalbuminuria, promotes regression to normoalbuminuria,and may reduce the risk of decline in renal function.• Due to potential renoprotective effects, the use ofACEi or ARB should be considered for the small sub-group of people with normal BP who have type 2 diabetesand microalbuminuria.• The extent to which interventions with lipid loweringtherapy reduces the development of CKD in people withtype 2 diabetes is unclear. As there is limited evidencerelating to effects of lipid treatment on the progression ofCKD in people with type 2 diabetes, blood lipid profilesshould be managed in accordance with guidelines for pre-vention and management of cardiovascular disease (CVD).• Lifestyle modification (diet and physical activity) is anintegral component of diabetes care (refer to the NHMRC

Evidence Based Guidelines for Blood Glucose Control inType 2 Diabetes), however, there are insufficient studiesof suitable quality to enable dietary recommendations tobe made with respect to prevention and/or management ofCKD in people with type 2 diabetes.

BACKGROUND

Aim of the guideline

This guideline topic has been taken from the NHMRC‘National Evidence Based Guidelines for Diagnosis, Preven-tion and Management of CKD in Type 2 Diabetes’ whichcan be found in full at the CARI website (http://www.cari.org.au). The NHMRC guideline covers issuesrelated to the assessment and prevention of CKD in indi-viduals with established type 2 diabetes. The NHMRCguidelines do not address the care of people with diabeteswho have end-stage kidney disease or those who have afunctional renal transplant. In addition, the present guide-line does not provide recommendations regarding the man-agement of individuals with established CKD, with respectto the prevention of other (non-renal) adverse outcomes,including retinopathy, hypoglycaemia, bone disease and car-diovascular disease. It is important to note however, that inan individual with type 2 diabetes, the prevention of thesecomplications may be a more important determinant fortheir clinical care. Consequently, the recommendations

NEPHROLOGY 2010; 15, S162–S194 doi:10.1111/j.1440-1797.2010.01240.x

© 2010 The AuthorsJournal compilation © 2010 Asian Pacific Society of Nephrology

made must be balanced against the overall managementneeds of each individual patient.

Prevention and management of CKD in type 2 diabetes

It should be noted that the best way to prevent CKDin individuals with diabetes is to prevent diabetes.NHMRC recommendations for the primary prevention oftype 2 diabetes are available elsewhere (http://www.diabetesaustralia.com.au). These guidelines specificallytarget the management of individuals with established type 2diabetes.

A risk factor analysis for kidney dysfunction in type 2diabetes following 15 years of follow up from the UKPDSstudy,1 identified systolic blood pressure; urinary albuminexcretion and plasma creatinine as common risk factors foralbuminuria and kidney impairment (creatinine clearanceand doubling of plasma creatinine). Additional independentrisk factors for kidney impairment were female gender,decreased waist circumference, age, increased insulin sensi-tivity and sensory neuropathy. A cross-sectional study of1003 Japanese hospital patients with type 2 diabetes2 identi-fied large waste circumference and elevated BP as risk factorsfor microalbuminuria while dyslipidaemia was identified as arisk factor for decreased glomerular Filtration Rate (GFR).

In contrast to type 1 diabetes, only 20% of newly diag-nosed people with type 2 diabetes are normotensive andhave a normal circadian blood pressure profile. Thereforehypertension usually precedes the onset of microalbumin-uria.3 BP control modulates the progression not only ofmicroangiopathy (diabetic kidney disease and retinopathy)but also of macroangiopathy (Coronary heart disease(CHD) and stroke).

In microalbuminuric people with type 2 diabetes, obser-vational studies have shown an association between poorglycaemic control and progression of albuminuria. Anumber of studies have identified a strong independentassociation between hyperglycaemia and the rate ofdevelopment of microvascular complications.4 The largeobservational WESDR study5 indicated an exponentialrelationship between worsening glycaemic control andthe incidence of nephropathy as well as retinopathy andneuropathy.

The UKPDS has clearly shown the importance of target-ing glycosylated haemoglobin (HbA1c) levels close tonormal (HbA1c < 7.0%) in people with type 2 diabetes. Amodest decrease in HbA1c over 10 years from 7.9 to 7.0%lowered the risk of microvascular endpoints with the onsetof microalbuminuria being reduced by 25%.6 These findingsare supported by a study of intensified glycaemic control innon-obese Japanese subjects with type 2 diabetes.7 In theUKPDS, there was no significant reduction in the risk ofprogression from microalbuminuria to proteinuria withintensive blood glucose control.8

The AusDiab study collected information on albumin-uria, measured as a spot albumin: creatinine ratio (ACR)(mg/mmol) with microalbuminuria being between 3.4 and34 mg/mmol and macroalbuminuria at >34 mg/mol.9 The

prevalence of albuminuria increased with increasing glycae-mia. People with diabetes and impaired glucose tolerancehad an increased risk for albuminuria compared with thosewith normal glucose tolerance, independent of other knownrisk factors for albuminuria (including age and sex).

Hyperglycaemia is an important determinant of the pro-gression of normoalbuminuria to microalbuminuria in diabe-tes. Strict blood glucose control has been shown to delay theprogression from normoalbuminuria to microalbuminuria orovert kidney disease6 and from normo- or microalbuminuriato overt kidney disease.7 The influence of intensive glycae-mic control is greatest in the early stages of CKD althoughsome observational studies suggest an association of glycae-mic control with the rate of progression of overt kidneydisease and even end-stage kidney disease (ESKD).10

The American Heart Association (AHA) has under-taken a review of the DCCT, UKPDS, ACCORD,ADVANCE and VA Diabetes trials and on the basis of thereview issued a Scientific Statement addressing intensiveglycaemic control in relation to cardiovascular events.11

While the AHA review is focused on cardiovascular events,the statement is relevant to the consideration of the man-agement of CKD given the strong association between CKDand CVD in people with type 2 diabetes. Consistent withthe evidence reviewed in these guidelines (refer to followingsections), the AHA note that a small but incrementalbenefit in microvascular outcomes (principally renal out-comes) is indicated with HbA1c values approachingnormal. As a consequence the AHA statement notes thaton the basis of findings from the DCCT, UKPDS andADVANCE trials some patients may benefit (in terms ofmicrovascular outcomes) from HbA1c goals lower than thegeneral goal of <7%. However, the AHA also state that lessstringent goals may be appropriate for patients with . . . ‘ahistory of hypoglycaemia, limited life expectancy, advancedmicrovascular or macrovascular complications, or extensivecomorbid conditions . . .’. Thus individualized glycaemicgoals other than the general goal of <7% HbA1c may beappropriate for some patients.11

Several studies suggest that a reduction in albuminuria aswell as treatment of elevated blood pressure by the prefer-ential use of an ACEi may lower the risk of CVD to a greaterextent than with equihypotensive doses of dihydropyridinecalcium channel blockade.12,13 One long-term study fromIsrael has shown that ACE inhibition exerts a renoprotec-tive effect in normotensive middle-aged people with type 2diabetes and microalbuminuria. In this 7-year study, GFRremained stable in the ACEi (enalapril) treated group,while both albuminuria and GFR deteriorated rapidly in theplacebo group.12,14,15 However, the study did not include athird arm treated with conventional antihypertensiveagents, and therefore it is not clear if the renoprotectiveeffect was mediated by lowering of systemic BP as opposed toan intrarenal effect of the ACEi.

Antihypertensive therapy, especially with ARB’s andACEi, has been clearly shown to reduce albumin excretionrate (AER).16,17 There are trials indicating that ACEi exertcardioprotective effects in addition to lowering of BP, evenin normotensive people.18 Renoprotection has been demon-

Type 2 Diabetes: Kidney Disease S163

strated for ARB’s in two large studies.19,20 The existence of aspecific renoprotective effect of ACE inhibition in peoplewith type 2 diabetes was not confirmed in the UKPDS8

although it is possible that both captopril and atenololexerted an equal renal protective effect, over and abovelowering of systemic BP.

The term ‘renoprotection’ is considered to denote atleast three criteria:1. Antiproteinuric effect, which has been used as a surro-gate for the subsequent rate of decline in kidney function.2. Attenuation of the rate of decline in GFR.3. Attenuation of the rate of decline of GFR when com-pared with a control group treated with other antihyperten-sive agents in equihypotensive doses.

Proteinuria is a weaker basis for identifying renoprotec-tive treatments than a reduction in the rate of decline ofGFR.21

Several studies have documented the efficacy ofantihypertensive therapy in lowering AER in bothhypertensive22–24 and normotensive25 people with type 2 dia-betes and microalbuminuria.

People with type 2 diabetes and kidney disease show abroad range of lipid abnormalities, characterized by a switchto a more atherogenic lipid profile. This becomes morepronounced with increasing proteinuria, although severalfactors such as glycaemic control, insulin administration,obesity and genetic factors may alter the degree ofdyslipidaemia.

Increased levels of triglycerides are consistently seen inpeople with type 2 diabetes and microalbuminuria or overtproteinuria.26–28 The high triglyceride levels are associatedwith an increased proportion of atherogenic small denseLDL cholesterol particles.29 The implication is that serumtriglycerides should be as low as possible to prevent athero-genic changes in LDL-cholesterol particles.30 HDL choles-terol levels in people with type 2 diabetes have beenreported to be normal in association with overt diabetickidney disease28 whereas decreased HDL-cholesterol levelshave been reported in association with microalbuminuria.27

Higher apolipoprotein (a) levels have been reported inpeople with type 2 diabetes and micro- and macroalbumin-uria than in control subjects, and also in people withmacroalbuminuria than with normoalbuminuria.31 Apolipo-protein (a) levels have been related to the rates of progres-sion of albuminuria,32 however, others have not confirmedthese findings in people with diabetes and CKD.28

There is evidence to support the hypothesis that changesin lipid profiles may play a causal role in the initiation andprogression of kidney disease, based on the finding of lipiddeposits and foam cells in the glomeruli of humans withkidney disease.33

Primary or secondary intervention with statins in hyper-cholesterolaemic people has shown similar cardioprotectiveeffects in diabetic and non-diabetic subjects.34–36 The abso-lute clinical benefit achieved by cholesterol lowering may begreater in people with CHD and diabetes than with CHDand without diabetes because people with diabetes have ahigher absolute risk of recurrent CHD events and otheratherosclerotic events.34

Observational studies have shown that dyslipidaemiainteracts with other risk factors to increase cardiovascularrisk.37,38 Microalbuminuria is a risk factor for CVD as well asovert kidney disease in people with type 2 diabetes,39,40 anddyslipidaemia is more common in microalbuminuric thannormoalbuminuric people with type 2 diabetes.27 In peoplewith type 1 or type 2 diabetes and increased AER, elevatedLDL-cholesterol and triglycerides are common, whereasHDL-cholesterol may be high, low or normal. Nearly allstudies have shown a correlation between serum cholesterolconcentration and progression of CKD.41,42 Since increasedAER and dyslipidaemia are each associated with anincreased risk of CHD, it is logical to treat dyslipidaemiaaggressively in people with increased AER. Subgroups withdiabetes in large intervention studies have confirmed thatcorrection of dyslipidaemia results in a decrease in CHD.43

However, few trials have examined the effects of treatingdyslipidaemia on kidney end-points in people with type 2diabetes and increased AER. Further studies are thereforerequired in people with microalbuminuria and macroalbu-minuria in order to assess the effects of statins and fibrateson albuminuria and kidney function. Until the results of thistype of study are known, it will not be possible to determineif correction of dyslipidaemia alone exerts renoprotectiveeffects. Furthermore, it is not known if intervention withspecific agents such as statins or fibrates exerts effectson kidney end-points over and above protection fromcardiovascular events.

Dyslipidaemia is a common finding in individuals withtype 2 diabetes, particularly those with CKD, in whom it isa significant risk factor for adverse cardiovascular out-comes27,37,38 (refer also to the NHMRC guidelines for theprevention of cardiovascular disease in type 2 diabetes).Moreover, the lowering of LDL cholesterol in individualswith type 2 diabetes leads to primary and secondary preven-tion of cardiovascular events and mortality.44 The absoluterisk benefit of lipid lowering is much larger reflecting theincreased absolute risk of adverse cardiovascular outcomes.

SEARCH STRATEGY

Databases searched: The search strategies were designed toreduce bias and ensure that most of the relevant data avail-able on type 2 diabetes were included in the present reviewand were similar to those detailed in the Cochrane Collabo-ration Reviews Handbook (Higgins JPT et al.).45 Theelectronic databases searched were Medline, EMBASE,Cochrane Library, CINAHL, HTA and DARE. Thedetailed search strategy, research terms and yields are pro-vided in Appendix 3 of the complete guideline documentthat can be found on the CARI website (http://www.cari.org.au).Date of searches:Blood Glucose – April 3, 2008BP – March 18, 2008Blood Lipids – March 27, 2008Dietary Factors – March 28, 2008Smoking Cessation – April 1, 2008.

The CARI GuidelinesS164

WHAT IS THE EVIDENCE?

Role of blood glucose control

Improving glycaemic control reduces the development andprogression of kidney disease in people with type 2 diabetes(Evidence Level I – Intervention).

The issue of the role of blood glucose control in thedevelopment and progression of kidney disease in individu-als with type 2 diabetes has been addressed by a number ofsystematic reviews and RCTs. A summary of relevant studiesis presented in Table A2 with key studies discussed in thetext below. While a number of these studies have examinedthe use of specific antihyperglycaemic agents, it is not pos-sible on the basis of the current evidence to provide recom-mendations of the use of specific agents in relation to theprogression of CKD.

The systematic review by Newman et al.4 addressed thequestion of whether improved glycaemic control reducesthe rate of development of secondary diabetic complicationsin people with either type 1 or type 2 diabetes and microal-buminuria. Five RCTs were identified in people with type 2diabetes. The review considered ESKD, estimation of theGlomerular Filtration Rate (eGFR) and clinical proteinuriawith the following outcomes:• No RCT evidence was identified to show that improvedglycaemic control has any effect on the development ofESKD. The most relevant study is the UKPDS from whichfurther information may come from long-term follow up.• Evidence from the VA Cooperative study46 indicate thatintensified glycaemic control has little if any effect on therate of GFR decline.• Three studies were identified in relation to improvedglycaemic control and the development of clinical pro-teinuria and microalbuminuria, namely the Kumamotostudy,47 UKPDS6 and the VA Cooperative study.46 Thesestudies provide some evidence that intensive treatment ofhyperglycaemia in normoalbuminuric people with type 2diabetes will, in a proportion of people, prevent developmentof microalbuminuria and provide some evidence of a reduc-tion in the rate of clinical proteinuria. However, the studiesonly included a proportion of people with microalbuminuria.The VA study examined as a sub group the effect of glycaemiccontrol in those with microalbuminuria, however, the studywas relatively small and of limited duration.

The systematic review by Richter et al.48 assessed theeffects of pioglitazone in the treatment of type 2 diabetes.The relevant outcomes for these guidelines are mortality(kidney disease) and morbidity (nephropathy). Overall theevidence for a positive patient-oriented outcome for the useof pioglitazone was considered not to be convincing. Threestudies were identified that included endpoints relevant tothe assessment of kidney disease namely, Hanefeld et al.,49

Matthews et al.50 and Schernthaner et al.51 The Hanefeldet al.49 study compared pioglitazone plus sulfonyl urea withmetformin plus sulphonyl urea over 12 months in 649people with type 2 diabetes with a history of poorly con-trolled diabetes. The pioglitazone treatment resulted in a15% reduction in the urinary ACR compared with a 2%

increase in the metformin group with both treatmentsgiving clinically equivalent glycaemic control. The Mat-thews et al.50 study compared pioglitazone plus metforminwith glicazide plus metformin in 630 people with poorlymanaged type 2 diabetes over 12 months. The pioglitazonetreatment gave a 10% reduction in the ACR compared witha 6% increase in the glicazide group with no significantdifference in HbA1c.

The Schernthaner et al.51 study included 1199 peoplewith type 2 diabetes inadequately treated by diet alone(HbA between 7.5% and 11%) and aged between35–75 years from 167 centres located across 12 Europeancountries. Pioglitazone treatment resulted in a 19% decreasein ACR compared with 1% in the metformin group. Bloodpressure was not statistically different between groups. Theresults were considered to be consistent with previousstudies that troglitazone but not metformin or glibencla-mide reduced urinary albumin excretion rate.

The systematic review by Richter et al.52 assessed theeffects of rosiglitazone in the treatment of type 2 diabetes.The study by Lebovitz et al.53 was identified as including anoutcome measure relevant to kidney disease. The studyexamined the use of rosiglitazone as a monotherapy in 493people with type 2 diabetes over a 7 month period. Urinaryalbumin excretion was decreased significantly comparedwith the placebo. For the subgroup of people with microal-buminuria, both doses of rosiglitazone gave a reduction inACR from baseline of around 40%. Only a small percentageof patients were receiving antihypertensive therapy whichthe authors suggested indicates the effect to be a result ofimproved glycaemic control or a different effect of rosiglita-zone. The measurement of urinary ACR was a secondaryprospective outcome of the study of 203 people with type 2diabetes by Bakris et al.54 comparing rosiglitazone with gly-buride in a randomized controlled trial. RSG significantlyreduced ACR from baseline and strongly correlated withchanges in blood pressure and little relation to changes inFPG or HbA1c. Given similar levels of glucose control, themean reduction in ACR was greater for rosiglitazone thanglyburide and a greater proportion of participants in theRSG treatment group with baseline microalbuminuriaachieved normalization of the ACR by the 12 months.However, the power of the study in relation to the secondaryoutcome ACR was low and the differences in between thegroups was not statistically significant, thus the suggestedpotential benefit of RSG cannot be determined from thisstudy.

The objectives of the systematic review by Saenz et al.55

were to assess the effects of metformin monotherapy onmortality, morbidity, quality of life, glycaemic control, bodyweight, lipid levels, blood pressure, insulinaemia and albu-minuria in people with type 2 diabetes. The review identi-fied only one small trial of 51 people with type 2 diabeteswith incipient nephropathy with 3 month follow up,56

which reported some benefit for microalbuminuria withmetformin treatment. The authors concluded that microal-buminuria should be incorporated into the research out-comes and no overall conclusion has been made withrespect to effects of metformin on diabetic kidney disease.


In addition to the studies identified by Saenz et al.,55 theHOME trial57 examined the efficacy of metformin in 345people with type 2 diabetes over a 4 month period. Met-formin was associated with a 21% increase in the UAEcompared with the placebo, the authors considered this tobe a short-term anomaly given the association of UAE withHbAc1, however, they were unable to identify the reasonfor the anomaly.

The ADVANCE trial58 was designed to assess the effectson major vascular outcomes of lowering the HbAc1 to atarget of 6.5% or less in a broad cross-section of people withtype 2 diabetes with CVD or high risk of CVD. The primaryendpoints were a composite of both macrovascular andmicrovascular events. Endpoints relevant to kidney diseaseincluded development of macroalbuminuria, doubling ofserum creatinine, and the need for renal replacementtherapy or death due to kidney disease. At baseline approxi-mately 27% of the participants had a history of microalbu-minuria and 3–4% had macroalbuminuria. At the end of thefollow up period the mean HbAc1 was significantly lower inthe intensive group (6.5%) than the standard group (7.3%).The mean SBP was on average 1.6 mm Hg lower than thestandard group.

A significant reduction (hazard ratio 0.86 CI: 0.77–0.97)in the incidence of major microvascular events occurred,while macrovascular events were not significantly differentbetween the groups. Intensive glucose control was associ-ated with a significant reduction in renal events includingnew or worsening of nephropathy (HR 0.79; CI: 0.66–0.93)predominantly due to a reduction in the development ofmacroalbuminuria and new onset microalbuminuria (0.91CI: 0.85–0.98). A trend towards a reduction in the need forrenal replacement therapy was also noted. The study con-cluded that the lack of a significant effect on major macro-vascular events may be due to inadequate power to detectsuch an effect given a lower than expected rate of macrovas-cular events. Some but not all of the overall effect on majorevents could be attributed to the small but significant1.6 mm Hg lower SBP in the intensive group.58

A significantly higher number of severe hypoglycaemicepisodes were recorded in the intensive group comparedwith the standard group (2.7% vs 1.5%). The rates were 0.7severe events per 100 people in the intensively controlledgroup and 0.4 severe events per 100 people in the stand-ard control group. The rates for minor hypoglycaemicevents were 120 per 100 people in the intensively controlledgroup compared with 90 per 100 people in the stand-ard control group. Overall the main benefit identifiedby the ADVANCE study was a one fifth reduction inkidney complications in particular the development ofmacroalbuminuria.58

A US study of Hispanic and African Americans assessedthe efficacy of rosiglitazone in a high risk (based on ethnic-ity) type 2 diabetes group.59 The urinary ACR was collectedas a secondary outcome under the general grouping of CVDmarkers. The study included 245 people with type 2 diabeteswith FPG greater than or equal to 140 mg/dL and HbA1cgreater than or equal to 7.5% who had been on a sulphonylurea monotherapy for a minimum of 2 months and were

randomized to receive glyburide (GLY) plus rosiglitazone(RSG) or glyburide (GLY) plus placebo for 6 months.The urinary ACR was reduced by 26.7% in the treatmentgroup (GLY + RSG) compared with control group(GLY + placebo). Improved insulin sensitivity and b-cellfunction with thiazolidinedione treatments was also noted.

US studies on the long-term effectiveness of miglitolhave been conducted by Johnston et al. for 385 HispanicAmericans with type 2 diabetes and 345 African Americanswith type 2 diabetes.60,61 ACR was included as an ‘efficacyparameter’ in both studies. The duration of the studies was12 months. Miglotol treatment was associated with a minorreduction in ACR in both studies.

The short-term trial of 223 mixed type 1 and type 2diabetes by,62 reported significant improvement in albumin-uria in those with micro or macroalbuminuria following a4 month high dose treatment with sulodexide. The effectwas considered to be additive to the ACE inhibitory effect.The sub analysis by diabetes type produced similar results.

The multifactorial intensive treatment of the STENO2study63 reduced the risk of nephropathy by 50%. This long-term study (mean 7.8 years) of 160 people with type 2diabetes and microalbuminuria, utilized multifactorial inter-ventions for modifiable risk factors for cardiovascular diseasewhich included intensive treatment of blood glucose. Whilea the intensive treatment group achieved a significantlylower blood glucose concentration, given the multifactorialnature of the study it is not possible to determine the rela-tive contribution that intensive blood glucose control mayhave had on the renal outcomes.

ROLE OF BP CONTROL

(a) BP as a risk factor for CKD

Arterial hypertension is a key risk factor for kidney damagein people with type 2 diabetes Evidence (Level I –Aetiology).

Several trials have clearly shown that intensive treat-ment of elevated BP lowers the risk of microvascular disease,CVD and mortality in type 2 diabetes (refer to systematicreviews of.4,16,17,64

The UKPDS has been the largest long-term study tocompare the effects of intensive versus less intensive BPcontrol in hypertensive people with type 2 diabetes. In this9-year study of 1148 people, allocated to tight BP control(n = 758) or less tight control (n = 390), mean BP wassignificantly reduced in the tight control group (144/82 mm Hg), compared with the group assigned to less tightcontrol (154/87 mm Hg) (P < 0.0001). The study showedthat microvascular endpoints, including the development ofmicroalbuminuria or overt diabetic kidney disease, werereduced by 37% in the intensive control group (P < 0.01).8

In this study, captopril and atenolol were used in equihy-potensive doses and each drug attenuated the developmentof microvascular complications to a similar degree over10 years.65

Elevated BP was identified as one of the major risk factorsassociated with a decline in kidney function and increase in


albuminuria in a long-term non-interventional prospectivestudy of 574 people with type 2 diabetes who were normo-tensive and normoalbuminuric (based on dipstick) at thestart of the study.66 Those with elevated BP (>95 mm Hg)had an almost 10 fold increased risk of developing microal-buminuria compared with those with lower BP over theaverage 8 year follow-up period. Recent analysis of the BParm data of the ADVANCE Trial67 by Galan et al.68 hasindicated that lower achieved follow-up (median 4.3 years)systolic blood pressure levels were associated with progres-sively lower renal event rates to below 110 mm Hg.

These studies support the concept that arterial hyperten-sion plays a pivotal role in contributing to kidney damage intype 2 diabetes, across the range of albumin excretion fromnormal to micro- to macroalbuminuria. The studies alsoshow that the rate of GFR decline can be successfullylowered in people with type 2 diabetes by effective antihy-pertensive therapy, however, the systematic review by4 con-sidered that a 72% drop in clinical proteinuria noted inrelevant trials was unlikely to be caused by the small differ-ence in the BP between treatment groups and is consistentwith renoprotective effects of ACEi.

(b) BP control for prevention and management of CKD

In people with type 2 diabetes antihypertensive therapywith ARB or ACEi decreases the rate of progression ofalbuminuria, promotes regression to normoalbuminuria, andmay reduce the risk of decline in renal function (EvidenceLevel I – Intervention).

A large number of systematic reviews and trials haveexamined antihypertensive therapy using ACEi and ARBsin people with type 2 diabetes. A summary of relevantstudies is shown in Table A3 with findings of key studiesdescribed in the text below.

Systematic reviews and meta-analyses:The systematic review of RCTs up until 2002 reported by

Newman et al.4 examined three areas relevant to consider-ation of the use of antihypertensive therapy that are sum-marized below:

1. Antihypertensive therapy and development ofESKD in people with type 2 diabetes and microalbumin-uria.

Only three RCTs were identified as being of sufficient sizeand length of follow up namely ABCD, UKPDS and HOPE.Of these ABCD did not include ESKD as an endpoint.

In the UKPDS study the prevalence of ESKD was lessthan 2% with a relative risk for tight control of 0.58 (95%CI: 0.015–2.21) with similar results for death from kidneyfailure.8

The HOPE Study demonstrated that there was a non-significant relative risk reduction for the requirement forrenal dialysis among people treated with ramipril.18

As a consequence of the above two trials, Newman et al.4

concluded that there was no evidence of a beneficial effectof antihypertensive therapy on the development of ESKD.

2. Antihypertensive therapy and change in GFR inpeople with type 2 diabetes and microalbuminuria.

Three placebo controlled trials in normotensive peoplewere identified.14,25,69 Newman et al.4 considers the data areinconclusive. No appropriate trials comparing differentantihypertensive agents and intensive versus moderate BPcontrol were identified. However, later analysis of theABCD trial70 indicated a significant effect of intensivetherapy on the progression from microalbuminuria to clini-cal proteinuria, however, there was no change in creatinineclearance and no difference between ACEi and CCB.

Two placebo controlled trials in hypertensive peoplewere identified.71,72 Newman et al.4 concludes that thelimited evidence indicates kidney function to remain stablein hypertensive people with type 2 diabetes with microal-buminuria treated with ACEi compared with a decline inthe placebo group (36 month follow up). The Parvinget al.72 study also indicated a significant reduction in the rateof progression to clinical proteinuria with ARB treatmenthowever, this was not associated with a significant decline increatinine clearance.

Two trials were identified that compared intensive andmoderate BP control in hypertensive people with type 2diabetes with microalbuminuria.8,73 However, the UKPDSstudy was unable to differentiate between normoalbuminu-ric and microalbuminuric subgroups. In the large ABCDstudy no significant difference in creatinine clearance wasfound in either normoalbuminuric or microalbuminuricsubgroups.

Three appropriate trials were identified comparing differ-ent antihypertensive agents in hypertensive people withtype 2 diabetes with microalbuminuria.73–75 None of thesetrials showed significant differences in GFR or creatinineclearance.

3. Antihypertensive therapy and development ofclinical proteinuria in people with type 2 diabetes andmicroalbuminuria.

Three randomized placebo-controlled trials in normo-tensive people with type 2 diabetes with microalbuminuriawere identified.14,25,69 These three trials all used the ACEienalapril as the treatment. The overall relative risk for thedevelopment of proteinuria for the three trials was 0.28(95% CI: 0.15–0.53) with no significant heterogeneitybetween studies. No study provided information to allowassessment of regression to normoalbuminuria. The overallrisk reduction was 4.5% giving a NNT of 22 patients peryear to prevent one case of clinical proteinuria. The differ-ences in BP between treatment and placebo were small andas such consider that a 72% drop in clinical proteinuria wasunlikely to be caused by such a small difference and morelikely that ACEi have a specific renoprotective effect.4

No appropriate trials were identified comparing antihy-pertensive agents and intensive versus moderate BP controlother than the later analysis of the ABCD trial. Intensivetherapy with either enalapril or nisoldipine resulted in alower percentage of people who progressed from normoal-buminuria and microalbuminuria to clinical proteinuriawith no difference between the ACEi and CCB.73

Only one available placebo controlled study was identi-fied for hypertensive people with type 2 diabetes withmicroalbuminuria.71 The treatment involved two dose levels


of the ARB antagonist irbesartan for 2 years. A combinedrelative risk for clinical proteinuria for the ARB treatmentswas 0.50 (95% CI: 0.0.31–0.81). This reduction in therate of progression to clinical proteinuria was independentof BP.

Only the ABCD trial was identified as being relevant forcomparing intensive versus moderate BP control in hyper-tensive people with type 2 diabetes with microalbumin-uria.73 Individuals were randomized to either ACEi enalaprilor the CCB antagonist nisoldipine. The percentage ofpeople who progressed from microalbuminuria to clinicalproteinuria was not significantly different between the treat-ment groups. Newman et al.4 noted that the results sup-ported the observations from the UKPDS of progression toclinical proteinuria among microalbuminuric and normoal-buminuric people with type 2 diabetes was not affected bythe level of BP control, however, separation of the twogroups is not possible.

Four trials were identified comparing different hyperten-sive agents in hypertensive people with type 2 diabetes withmicroalbuminuria.12,74–76 The trials all included an ACEitreatment compared with either a CCB antagonist or bblocker. The overall relative risk of development of clinicalproteinuria for ACEi versus other hypertensive therapy was0.74 (95% CI: 0.44–1.24) with no significant heterogeneity.Thus the ACEi reduced progression to clinical proteinuriaas effectively as the other therapies. These findingswere considered to be comparable with the UKPDSfindings which could not separate normoalbuminuria frommicroalbuminuria.

The two systematic reviews addressed the use of antihy-pertensive agents in people with diabetes with respect torenal outcomes.16,17 The objectives of the review by Strippoliet al.16 were to evaluate the effects of antihypertensiveagents in people with diabetes and normoalbuminuria.While the objectives of the review by Strippoli et al.17 wereto evaluate the benefits and harms of ACEi and ARBs inpreventing the progression of CKD. Both reviews includedstudies of both type 1 and type 2 diabetes and Strippoliet al.17 people with either microalbuminuria or macroalbu-minuria. While the reviews included both type 1 and type 2diabetes the majority of selected trials enrolled only peoplewith type 2 diabetes.

The overall conclusions of the two systematic reviews aresummarized below:• A significant reduction in the risk of developing microal-buminuria in normoalbuminuric patients has been demon-strated for ACEi only. This effect appears to be independentof BP and, kidney function and type of diabetes. However,there is insufficient data to be confident that these factorsare not important effects modifiers.16

• There is randomized trial evidence that ACEi versusplacebo/no treatment used at the maximum tolerable doseprevent death in people with diabetic kidney disease but notso for ARB versus placebo/no treatment. Both agentsprevent progression of nephropathy and promote regressionto a more favorable clinical pattern of normoalbuminuria.The relative effects of ACEi and ARBs are uncertain due toa lack of head to head trials.17

In relation to type 2 diabetes the following outcomes areof note:16,17

• All-cause mortality– non-significant effect of ACEi versus placebo.– comparison between ACEi and CCB – no significantdifference, however, only two studies were availablewhere relative risk could be estimated.– at less than the maximum tolerable dose for ACEiversus placebo/no treatment – no significant effect.– at the maximum tolerable dose for ACEi versusplacebo/no treatment – no significant effect in the tworelevant studies both of which were mixed type 1 andtype 2 diabetes populations.– for ARB versus placebo/no treatment – all of thestudies included people with type 2 diabetes and no sig-nificant effect was noted.

• Doubling of serum creatinine– non-significant effect of ACEi versus placebo.– comparison of ACEi and CCB – no available suitablestudies where relative risk was able to be estimated.– for ACEi versus placebo/no treatment – overall effectof marginal significance in favour of ACEi.– for ARB versus placebo/no treatment – the two studiesselected both included people with type 2 diabetes withan overall significant reduction for ARB compared withplacebo/no treatment.

• Progression to ESKD– non-significant effect of ACEi versus placebo in theone mixed type 1/type 2 diabetes study only.18

– comparison between ACEi and CCB – no availablesuitable studies where relative risk was able to beestimated.– for ACEi versus placebo/no treatment – non-significant relative risk in the two studies that includedpeople with type 2 diabetes.– for ARB versus placebo/no treatment – the two studiesselected both included people with type 2 diabetes withan overall significant reduction in progression to ESKDfor ARB compared with placebo/no treatment.

• Progression from normoalbuminuria to microalbuminuriaor macroalbuminuria

– overall significant effect of ACEi versus placebo inreducing the rate of progression.– ACEi compared with other hypertensive agents –limited to the UKPDS study which showed no significanteffect of ACEi in reducing the rate of progression.– normotensive patients – ACEi versus placebo – notrials identified with people with type 2 diabetes.– hypertensive patients – ACEi versus placebo – evi-dence for significant reduction in rate of progression withACEi treatment.– ACEi compared with CCB – significant effect of ACEiin reducing the rate of progression.

• Progression of microalbuminuria to macroalbuminuria– ACEi versus placebo/no treatment – the type 2 diabe-tes studies are weighted to a relative risk less than one(i.e. favoring ACEi) consistent with the overall assess-ment with type 2 diabetes studies accounting for approxi-mately 70% of the total number in all selected studies.


– ARB versus placebo/no treatment – all selected studiesincluded people with type 2 diabetes and show an overallreduction in the rate of progression in favour of ARBtreatment.

• Regression from microalbuminuria to normoalbuminuria– ACEi versus placebo/no treatment – the type 2 diabe-tes studies are weighted to a relative risk greater than 1(i.e. favors ACEi) consistent with the overall assessmentof studies with type 2 diabetes being approximately 65%of the total number in all of the included studies.– ARB versus placebo/no treatment – the two trialsincluded people with type 2 diabetes and show an overallmarginal increase in the rate of regression in favor ofARB treatment.

• Comparison of effect on BP– ACEi versus placebo no trials identified that includedpeople with type 2 diabetes.– ACEi and CCB on BP – no significant effect, however,limited to one mixed type 1/type 2 diabetes study.The relevant trials comparing ACEi treatment with

ARB treatment all included people with type 2 diabetes andno significant differences on all cause mortality, progressionof microalbuminuria to macroalbuminuria or regressionfrom microalbuminuria to normoalbuminuria were noted.17

However, as noted in the overall conclusion by the authorsthe trials were limited and provide insufficient evidence forcomparison of effects.

The objectives of the systematic review was to assess theRCT evidence for the effects of different therapeutic BPgoals and interventions in the normotensive range on thedecline of glomerular function.64 The search strategy waslimited to studies of people with 2 years duration of type 1 ortype 2 diabetes with incipient or overt nephropathy with orwithout elevated BP. The intervention was required to betreatment with one or more hypertensive agents. Thereview identified 5 RCTs meeting the search criteria. All ofthese studies have been identified and assessed.4,16,17 Onlytwo studies that considered the effect of BP targets withinthe normotensive range in people with type 2 diabetes wereidentified.70,73

Kaiser et al.64 considered GFR as surrogate endpoint inthe absence of a renal failure endpoint such as need fordialysis and/or transplantation. The authors noted that notrial demonstrated any beneficial effect of lower target BPvalues on the progression of kidney failure. In shortdecreases in albuminuria were not accompanied by adecrease in the rate of decline in GFR. They conclude thatthe available evidence does not support a beneficial effect ofBP lowering within the normotensive range on progressionof diabetic nephropathy as assessed by the change in GFR.

The systematic review and meta analysis pooled analysesfrom the number of small studies comparing combinationtreatment of ACEi + ARB with ACEi alone.77 A total of tenstudies covering both type 1 and type 2 diabetes wereincluded in the meta-analysis. The majority of the studieswere of people with type 2 diabetes. The authors concludedthat the meta-analysis suggests that combined ACEi + ARBreduces 24 h proteinuria to a greater extent than ACEialone and that this benefit is associated with small effects on

GFR. However, analysis also concludes that the availablestudies were heterogeneous and mostly of short duration(only one study greater than 12 weeks) and the few longerterm studies have not demonstrated a benefit.

Hamilton et al.78 conducted a meta-analysis of RCTsevaluating the efficacy of ACEi in the treatment of nephr-opathy in individuals with type 2 diabetes. Specifically themeta-analysis addressed the reduction in albuminuria orproteinuria and thus included only those studies that pro-vided either geometric or arithmetic means of albuminuria.Studies reporting geometric means and arithmetic meanswere analysed separately. The results of the meta-analysisindicated that treatment with ACEi produced significantreductions in albuminuria in people with type 2 diabetes instudies where geometric means were used to normalize databut less clear where data is reported as arithmetic means(presumed to reflect the skewing of the albuminuria data).While studies were stratified on the basis of the degree ofalbuminuria and study duration, no distinction betweennormotensive or hypertensive patients have been made.

Studies with ARB’s in people with type 2 diabetes andovert kidney disease have shown that angiotensin receptorblockade with irbesartan attenuates the rate of doubling ofserum creatinine by 20–30% over 2.7 years when comparedwith placebo or amlodipine, used in equihypotensivedoses.19 A study of angiotensin receptor blockade with irbe-sartan in hypertensive, microalbuminuric people with type 2diabetes showed a 70% decrease in AER over 2 years.72

However, preservation of GFR over and above the effects ofBP lowering was not demonstrated in this relatively short-term study.

Studies not covered by Systematic Reviews

The ADVANCE study is a multinational randomizedcontrol trial undertaken by 215 centres across 20 countrieswhich, in addition to intensive blood glucose treatment,included a BP treatment study arm.67 Participants were ran-domized to either fixed combined perindopril indapamide orplacebo. Additional antihypertensive agents were allowedfor both groups as required with the exception that thiazidediuretics were not allowed and the only open labelled ACEiallowed was perindopril to a maximum dose of 4 mg a daythereby ensuring that the active treatment group did notexceed the maximum recommended dose. The active treat-ment resulted in a mean reduction after 4.3 years (median)in SBP and DBP of 5.6 and 2.2 mm Hg, respectively, com-pared with placebo. The relative risk of a major micro-vascular event was 7.9% in the active treatment groupcompared with 8.6% in the placebo group, however, this wasnot significant. Active treatment was associated with a bor-derline significant reduction in macroalbuminuria and a sig-nificant reduction in the development of microalbuminuriawith a relative risk reduction of 21% (95% CI: 15–30).Further detailed analysis of the ADVANCE trial data hasindicated that lower achieved follow-up systolic BP levelswere associated with progressively lower renal event rates tobelow 110 mm Hg.68 Renoprotective effects of blood pres-


suring lowering with perindopril indapamide treated werenoted even among the sub group with baseline BP below120/70 mm Hg.

An open label parallel prospective randomized trial pro-vides a comparison of the effects of a ARB (losartan) and aCCB (amlidopine) on the UAE and ACR of 87 hyperten-sive type 2 diabetes Japanese patients with persistent mac-roalbuminuria.79 The ARB and CCB treatments providedsimilar BP control (no significant difference). The ARBtreatment resulted in a 30% drop in the UAE after 6 monthstreatment and a 16% drop in the ACR. There was nosignificant change in both the UAE and the ACR in theCCB treatment.

In relation to ACEi, a number of additional trials havebeen identified, the details and findings of which are sum-marized in Table A3.80–83 While the study summarized inTable A10 has examined both ACEi and ARBs either aloneof in combination.84 A number of studies have specificallyassessed the ARB valsartan.85–90 The details and findings ofthese studies are summarized in Table A3 below. Overall,the studies are consistent with the renoprotective effect ofARBs, however, they do not provide additional data allow-ing a direct comparison with ACEi.

The BENDICT Trial was a long-term (median43 months) prospective multicentre RCT of 1204 peoplewith type 2 diabetes, elevated BP and normoalbumin-uria.91,92 The trial was aimed at assessing the efficacy of ACEiand CCB alone and in combination. Additional agents werepermitted to achieve appropriate BP control. Trandolaprilplus verapamil and trandolapril alone decreased the inci-dence of microalbuminuria to similar extent. Verapamilalone was found to be no different to the placebo.

The comparative effects of HCT, ACEi and ARB onUAE (as a secondary outcome) were assessed in 70 peoplewith type 2 diabetes in the Netherlands.93 The people withtype 2 diabetes were Caucasian with an average age inthe randomized treatment groups of 60–63, hypertensiveand either normoalbuminuric or early microalbuminuric(UAE < 100 mg/day). The trial was of 12 months durationafter a 1 month run in and a 4–6 month BP titration period.All three agents achieved the aggressive BP goals equallywell in the three treatment groups. The UAE was reducedby around 35% over 12 months and there was no significantdifference between the three treatments. The authors notethat this outcome may reflect the relatively small samplesize. This additional ACEi/ARB comparative study fromthose reported does not provide additional evidence for theefficacy of ARB compared with ACEi in achieving regres-sion of microalbuminuria.17

The multicentric CENTRO trial of 129 Italians withtype 2 diabetes compared the ARB candesartan with theACEi enalapril with albumin excretion rate as a secondaryoutcome. After 6 months treatment the ARB treatmentgroup had a reduced albumin excretion rate and ACR, whilethe ACEi was higher.94 However, the baseline conditionsdiffered between treatment groups and the majority ofindividuals were normoalbuminuric thus the relevance ofthe outcomes for individuals with microalbuminuria isquestionable.

The GEMINI trial involved 1235 people with type 2diabetes with elevated BP under either an ACEi or ARBhypertension treatment randomized for treatment with twodifferent b-blockers (carvedilol and metoprolol).95 A posthoc analysis of differential effects of the b-blockers on theprogression of albuminuria indicated a greater reduction inmicroalbuminuria for carvedilol compared with metoprolol.In those with normoalbuminuria fewer progressed tomicroalbuminuria on carvedilol. These effects were notrelated to BP. Multivariate analysis demonstrated only base-line urine ACR and treatment were significant predictors ofchanges in albuminuria. In a separate analysis the presenceof metabolic syndrome at baseline corresponded with an ORof 2.68 (95% CI: 1.36–5.30) over the duration of the study.

The DETAIL study involved 250 people with type 2diabetes with mild to moderate hypertension andeGFR 3 70 mL/min per 1.73 m2 from 6 European coun-tries.96 The study compared an ARB and an ACEi treatmentover 5-years. After 5 years the difference in eGFR betweenthe ARB and the ACEi was -3.1 mL/min per 1.73 m2 andwas insignificant. The mean annual declines in eGFR were3.7 mL/min per 1.73 m2 for the ARB and 3.3 mL/min per1.73 m2 for the ACEi. These results were considered by theauthors to be similar to eGFR decline reported in the IRMA2, IDNT, and RENAAL studies and compare to an expecteduntreated type 2 diabetes annual decline in the order of10 mL/min per 1.73 m2. Telmisartan was concluded to benot inferior to enalapril in providing long-term renoprotec-tion. However, the results do not necessarily apply to moreadvanced nephropathy but support clinical equivalence ofARB and ACEi in persons with conditions that place themat high risk for CV events.

The large ONTARGET trial comparing ARB and ACEiof in excess of 25 000 participants included a large propor-tion with diabetes and microalbuminuria.97 Relevant sec-ondary outcomes are kidney impairment and kidney failurerequiring dialysis. The only significant differences betweentreatments (ACEi, ARB and ACEi + ARB) were forincreased kidney impairment in the combination therapycompared with the ACEi. Further analysis of renal out-comes,98 indicated a significantly higher increase in ACR inthe ACEi treatment group compared with the ARB andACEi + ARB (31% vs 24% and 21%). The risk of develop-ing new microalbuminuria was not different between ACEiand ARB treatment groups, but was significantly lower inthe combination treatment group. However, in contrast toalbuminuria a greater rate of decline in eGFR was noted forthe combination treatment group, thus the authorsconcluded that there was no evidence for a renal benefitwith combination therapy even though proteinuria wasimproved. No subgroup analysis has been undertaken withrespect to diabetes or albuminuria.

The short-term (6 month) study examined the renopro-tective effects in people with type 2 diabetes with albumin-uria of treatment with a direct renin inhibitor (aliskiren) inaddition to maximal treatment with an ARB (losartan).99

Treatment with 300 mg of aliskiren was demonstrated toreduce the ACR by 18% compared with the placebo groupand to increase the number of people with an albuminuria


reduction of greater than 50% over the treatment period.These effects were independent of changes in BP and there-fore considered to indicate renoprotective effects of thetreatment. The rationale behind the trial was provision offurther benefit by use of a direct renin inhibitor in additionto maximal use of a angiotensin II receptor antagonist.

Table A3 provides a summary of studies that provideevidence in relation to use of antihypertensive agents inpeople with type 2 diabetes and the progression of CKD.Included are details of a number of studies conducted priorto 2000 that have not been discussed above that are pro-vided as an overview of the collective evidence in relationto the role of BP control in the progression of CKD.100–103

(iii) Role of blood lipid modification

The extent to which interventions with lipid loweringtherapy reduces the development of CKD is unclear (Evi-dence Level I – Intervention).

As detailed below there are some trials that show that,over and above the cardio-protective actions, lipid-loweringmay also exert beneficial effects on the development andprogression of kidney disease in individuals with type 2diabetes, as determined by albuminuria and/or GFR.However, there are no RCT studies in which renal outcomesincluding ESKD or doubling of serum creatinine have beenused. It is unlikely that these studies will ever be performedgiven the overwhelming benefit of lipid lowering in terms ofcardio-protection. Clinical trials in cardiovascular diseasestudying agents targeting dyslipidaemia have commonlyexcluded subjects with late stage CKD. Moreover, the sig-nificant cardiovascular benefits of these agents could con-found associations between lipid effects and renal functionoutcomes. Consequently, conclusions regarding their poten-tial as reno-protective agents must be limited by relianceon early, surrogate markers of kidney disease and itsprogression.

An overall summary of relevant studies is provided inTable A4 with findings from key studies described in thetext below.

Systematic reviews and meta-analyses

Sandhu et al.104 conducted a systematic review and meta-analysis to determine the effect of statins on the rate ofkidney function loss and proteinuria in individuals withCKD (with and without diabetes). They included 27 eli-gible studies with 39 704 participants (21 with data foreGFR and 20 for proteinuria or albuminuria). Overall, thechange in the eGFR was slower in statin recipients (byapproximately 1.2 mL/min per year). In addition, treatmentwith statins resulted in a significant reduction in baselinealbuminuria and/or proteinuria. However, the magnitude ofcholesterol reduction from baseline was not significantlyassociated with the described renal benefit of statins inmeta-regression. In the smaller studies specifically per-formed in people with type 2 diabetes and kidney disease(n = 3) the change in eGFR was unaffected by statins,

although the modest magnitude of the effect observed in theother (larger) trials, if translated to these smaller studies,would mean the latter were underpowered to detect aneGFR difference.

Keating & Croom105 specifically addressed the pharma-cological properties and efficacy of the fibric acid derivative,fenofibrate, in the treatment of dyslipidaemia in individualswith type 2 diabetes. The review included consideration ofeffects on albuminuria in the two major RCTs (FIELD andDAIS, see below). In both trials fenofibrate, reduced therate of progression from normoalbuminuria to microalbu-minuria and microalbuminuria to macroalbuminuria andincreased the rate of regression, when compared with treat-ment with placebo. This effect was modest in size. Forexample, the proportion of people developing microalbu-minuria was significantly reduced in the FIELD trial (10%compared with 11%) and in the DAIS trial (8% comparedwith 18%).

Strippoli et al.106 examined data on 50 trials (30 144people), 15 of which evaluated the potential renoprotectiveeffect of statins. Most of these studies enrolled people withearly or late stages of CKD and with a history of coronaryheart disease. These studies did not include people withmoderate CKD but without known cardiovascular disease.In the small number of studies reporting urinary proteinexcretion (g/24 h) in individuals with CKD (6 randomizedcontrolled trials, 311 people), statins modestly reducedalbuminuria and/or proteinuria. However, in contrast tofindings of other meta-analyses, no significant effect wasobserved on creatinine clearance (11 randomized controlledtrials, 548 people). This review was unable to distinguish aspecific response in individuals with diabetes.

Fried et al.107 conducted a meta-analysis of trials of effectsof lipid lowering therapy on nephropathy. A total 12 trialswere included following systematic review, with all but onebeing a RCT. Of the 12 trials, the cause of kidney diseasewas stated as being due to diabetes (no distinction betweentype 1 or type 2 diabetes) in 7 of the 12 trials. Meta-analysisindicated that lipid reduction had a beneficial effect on thedecline in GFR. The reduction in GFR from lipid-loweringtherapy was 1.9 mL/min per year. There was no significantheterogeneity and no indication of publication bias. Regres-sion analysis showed no relationship between effect of treat-ment and age, gender, cause of kidney disease and the typeof lipid lowering therapy. No clear conclusions were possiblewith respect to the effect of lipid lowering therapy on pro-teinuria due to significant heterogeneity. Overall theauthors concluded that meta-analysis suggests that lipidlowering therapy may help slow the rate of kidney diseaseprogression. However, the applicability to type 2 diabetes isless clear as no sub group analysis was conducted.

Randomized clinical trials using statins

Statins are the most widely used class of drug for lipid low-ering in individuals with type 2 diabetes. Currently in Aus-tralian practice at least two thirds of patients seeing theirGP are receiving a statin. This reflects the clear and incon-


trovertible evidence that lowering of LDL cholesterol inindividuals with type 2 diabetes is associated with reducedcardiovascular events and mortality.44 Moreover, whenresults were adjusted for baseline risk, people with diabetesbenefited more in both primary and secondary prevention.In addition, a number of studies have looked at the effects ofstatins on renal parameters, including GFR, creatinineclearance and urinary albumin excretion. However, notrials report endpoints such as end stage kidney diseaseor doubling of creatinine as an outcome. The followingtrials provide evidence in relation to the use of statins inpeople with type 2 diabetes and that also include renaloutcomes.

A number of major statin trials have been conducted,which have included individuals with type 2 diabetes. Inpost hoc analyses of these large studies, beneficial effects onrenal functional parameters have been examined in thesubgroup of participants with diabetes.• In the MRC/BHF heart protection study108 subgroupanalysis for participants with diabetes, allocation to simvas-tatin (40 mg/day) significantly decreased the rise in SCrvalues. Subjects were excluded from entering the trial iftheir serum creatinine was above 200 mmol/L, reflectingthat those with late stage CKD were not studied.• In the Greek atorvastatin and coronary heart diseaseevaluation (GREACE) treatment with atorvastatin wasassociated with a significant decrease in urinary albuminexcretion, however, the study did not include separateanalysis for type 2 diabetes.109

• The Aggressive Lipid-Lowering Initiation Abates NewCardiac Events (ALLIANCE) showed beneficial effects onGFR in individuals with type diabetes, however, the studydid not separately identify or assess type 2 diabetes.110

There have also been a number of studies examining theeffects of statins on albuminuria and or creatinine clearancein individuals with type 2 diabetes, however, most of theseare small (i.e. less than 50). The following two studies havebeen identified:• A multicentric double blind parallel group RCT of type 2diabetes Swedish patients with dyslipidaemia (fasting LDL-C > 3.3 mmol/L) compared two statin treatments (rosuvas-tatin and atorvastatin) over a 16 week treatment period.111

The primary endpoints were UAE and GFR which weremeasured/calculated at baseline and at 8 and 16 weeks intothe treatment period. The treatment goal (achieved bytitration) was an LDL-C <3.0 mmol/L. As noted by theauthors, the short duration of the study allows only conclu-sions to be made with respect to ‘acute or subacute changes’in UAE and estimated GFR. The overall conclusion of thetrial was that both drugs were well tolerated and ‘show noevidence of short-term detriment on the renal endpoints ofUAE and GFR over a 4 month treatment period.’ Anabsence of clinically important changes in albuminuria wasnoted for both treatments.• Nakamura et al.112 studied the effect of cerivastatin onurinary albumin excretion in people with type 2 diabetes,microalbuminuria and dyslipidaemia. Sixty participantswere enrolled in a double-blind study for 6 months, receiv-ing either cerivastatin (0.15 mg/day) or placebo. At the

endpoint, cerivastatin treatment resulted in a significantdecrease in UAE (P < 0.01).

Randomized clinical trials using fibrates

Fibrates are effective in raising HDL cholesterol levels inindividuals with type 2 diabetes and in improving LDLcholesterol quality. Two recent large studies have examinedthe effect of fenofibrate on renal outcomes in individualswith type 2 diabetes. The efficacy of this drug class has notbeen tested in individuals with renal impairment. There isalso an increased potential for side-effects in this subgroup.• A subgroup analysis of the Diabetes AtherosclerosisIntervention Study (DAIS), examined the effects of fenofi-brate treatment (vs placebo) in 314 people with type 2diabetes (Canada and Europe) with mild to moderate lipidabnormalities and normo to microalbuminuria.113 The studylength was a minimum of 3 years. Regression of albuminuria(defined as micro to normoalbuminuria or macro to microal-buminuria) was significantly higher in the treatment group(13%) compared with the placebo group (11%), while pro-gression of albuminuria was significantly lower in the treat-ment group (8%) compared with the placebo group (18%).Significantly more people showed no change in albuminuriain the treatment group (79%) compared with the placebogroup (71%). The use of ACEi and ARBs increased duringthe course of the study; however, the use at the end of thetrial was not significantly different between the groups atthe end of the trial. The differences between groups in theprogression and regression of albuminuria remained signifi-cant after controlling for baseline BP and HbA1c. The finalurinary albumin was significantly correlated with eitherHbA1c level or BP. A significant correlation was observedbetween urinary albumin and baseline fasting triglyceride(TG) levels. After fenofibrate treatment urinary albuminlevels correlated significantly with HDL-C levels but notwith changes in TG. The study was not able to assess thepersistence of the reduction to microalbuminuria after ces-sation of treatment.

Keech et al.114 and Radermecker & Scheen115 report thelarge (9795) multinational Fenofibrate Intervention andevent Lowering in Diabetes (FIELD) study, which includedassessment of progression and regression of albuminuria.Fenofibrate was associated with a significantly lower pro-gression and significantly higher regression of albuminuria,however, the overall differences were relatively small (in theorder of 2%). Albuminuria was a secondary outcome of thestudy.

In the only study to compare statins and fibrates, head tohead, in 71 individuals with type 2 diabetes both benzafi-brate and pravastatin prevented increase in the urinaryalbumin excretion rate over 4 years, with no differenceobserved between drug classes.116

Randomized clinical trials using other lipidlowering agents

A number of other agents have clinically useful effects ondyslipidaemia in individuals with type 2 diabetes, including


probucol and glitazones. However, their other primaryactions, on oxidative stress and glucose lowering make itimpossible to gauge the contribution of lipid lowering totheir efficacy. Currently available glitazones do vary in theirimpact on lipid profiles, indicating sub-class variations ineffect. Nonetheless, both agents appear to have effects onthe development and progression of kidney disease in indi-viduals with type 2 diabetes.

The effects of probucol treatment on the progression ofdiabetic nephropathy was evaluated in a randomized openstudy of 102 people with type 2 diabetes with clinical albu-minuria (UAE > 300 mg/g Cr).117 The mean follow upperiod was 28.5 months for all patients and 18.6 monthsfor advanced patients (defined as those having serumCr > 2.0 mg/dL). The mean interval to initiation of haemo-dialysis was significantly longer in probucol patients. Inadvanced cases treated with probucol, increases in serumcreatinine and urinary protein were significantly suppressedand the haemodialysis-free rate was significantly higher. Thestudy concluded that probucol may suppress the progressionof diabetic nephropathy as a consequence of the anti-oxidative effect of the drug.

The multifactorial intensive treatment of the STENO2reduced the risk of nephropathy by 50%.63 This long-termstudy (mean 7.8 years) of 160 people with type 2 diabetesand microalbuminuria, utilized multifactorial interventionsfor modifiable risk factors for cardiovascular disease whichincluded blood lipid control with statins and fibrates. Whilethe intensive treatment group achieved a significantly lowerblood glucose concentration, given the multifactorialnature of the study it is not possible to determine the rela-tive contribution of the intensive lipid treatment may havehad.

(iv) Role of diet modification

There are insufficient studies of suitable quality to enabledietary recommendations to be made with respect toCKD in people with type 2 diabetes (Evidence Level II –Intervention).

Lifestyle modification (diet and physical activity) is anintegral component of diabetes care (refer to the guidelinesfor Blood Glucose Control in type 2 diabetes). However,there are few studies that have specifically addressed kidneyrelated outcomes in type 2 diabetes and as such it is notpossible to currently make recommendations specific to themanagement of CKD. The following sections summarize thecurrent evidence in relation to alternate diets, proteinrestriction, and salt.

Role of dietary fats

The Diabetes and Nutrition Clinical Trial (DCNT) is apopulation based prospective, observational multicentrestudy designed to evaluate the nutritional pattern of peoplewith diabetes in Spain and associations with diabetic com-plications.118 The study (total 192) included a mix of peoplewith type 2 diabetes (99) and type 1 diabetes (93). Nephr-

opathy progression was indicated by change from normoal-buminuria to microalbuminuria and microalbuminuria tomacroalbuminuria. Regression was indicated by changefrom microalbuminuria to normoalbuminuria. The nutri-tional pattern of people with nephropathy regression wascharacterized by greater polyunsaturated fatty acid (PUFA)and smaller saturated fatty acid (SFA) than those withnephropathy, whereas the PUFA to SFA and monounsat-urated fatty acid (MUFA) to SFA ratios were greater.An opposite pattern was observed for progression ofnephropathy.

The authors note that the findings of the study are con-sistent with CVD studies and the role that SFAs may play ininsulin sensitivity and other factors affecting diabetescontrol. Nonetheless, the authors consider that control ofBP and blood glucose and cessation of smoking shouldremain the therapeutic objectives for modifiable risk factors.When these objectives are obtained, other measures such asencouraging PUFA and MIFA over SFA may help preventmicro and macroalbuminuria.118

Table A5 presents a summary of the relevant studiesfound by the search strategy in relation to dietary fat. Withthe exception of the study by Cardenas et al.118 discussedabove, the studies are either of short duration and thusprovide little useful evidence for the role of dietary fat in theprogression of CKD. Relevant details of the studies are pro-vided in Table A12. In summary, there are insufficient reli-able studies to support a recommendation in relation to theprevention and management of CKD in people with type 2diabetes.

Protein restriction

Intake of protein in the usual range does not appear to beassociated with the development of CKD. However, long-term effects of consuming >20% of energy as protein ondevelopment of CKD has not been determined. Althoughdiets high in protein and low in carbohydrate may produceshort-term weight loss and improved glycaemic control, ithas not been established that weight loss is maintained inthe long term. There have been few prospective controlledstudies of low protein diets in people with type 2 diabetesand kidney disease. The studies that have been performedhave generally been deficient in experimental design, inmethods for measuring kidney function and/or in durationof follow-up. Furthermore, the level of compliance with alow protein diet has not always been assessed objectively byurinary urea nitrogen excretion. A particular criticism isthat changes in the creatinine pool and creatinine intakeseen in low protein diet studies render measurements ofcreatinine clearance or the reciprocal of serum creatinineunreliable for the assessment of GFR.119

The objective of the systematic review was to assess theeffects of dietary protein restriction on the progression ofdiabetic nephropathy in people with diabetes (type 1 andtype 2 diabetes).120 The review identified 11 studies (9 RCTsand 2 before and after trials) where diet modifications werefollowed for at least 4 months. Before and after trials were


included as it was considered that people could act as theirown controls. Of these studies 8 were of people with type 1diabetes, one type 2 diabetes and two included both type 1and type 2 diabetes. Overall the total number of participantsin the trials was 585 with 263 being people with type 2diabetes. Protein modified diets of all types lasting aminimum of 4 months were considered with protein intakeranging from 0.3 to 0.8 g/kg per day.

Overall protein restriction appeared to slow progressionof CKD, but not by much on average. Individual variabilitysuggests some may benefit more than others. Results of metaanalysis imply that patients can delay dialysis by, on averagearound one or 2 months. Positive but non-significant corre-lation between improvement in GFR and level of proteinrestriction is evident. There were insufficient studies to rec-ommend a level of protein intake. Furthermore, problems ofnon-compliance remain a significant issue. The review alsoconsidered different sources of protein (e.g. red meat,chicken, fish, vegetarian); however, relevant studies are ofshort duration only. The authors consider that the availableinformation supports further research in this area. Thenumber of studies that include people with type 2 diabetesare limited.

The study by Dussol et al.121 was the only other RCTidentified that was not reviewed by Robertson et al.120 This2 year single centre RCT of type 1 and type 2 diabetesindicated that the low-protein diet did not alter the courseof GFR or of AER in people with diabetes with incipient orovert nephropathy.

Table A6 includes a summary of studies identified by thesearch strategy. The studies are characterized by being smalland of short duration. Relevant details are provided below;however, as for dietary fat, there are insufficient reliablestudies that provide evidence to support a recommendationin relation protein restriction in the prevention and man-agement of CKD in people with type 2 diabetes.

Restricted salt intake

When considering the evidence related to salt intake andCKD in people with type 2 diabetes, the following pointsmade based on a literature review for preparation of aCochrane Protocol are noteworthy:122

• Dietary salt is important in BP control in both hyperten-sives and normotensives (supported by meta-analyses) andtherefore expect that this could be protective in the devel-opment and progression of CKD.• High dietary salt suppresses the renin-angiotensin system(RAS). Salt sensitivity in people with diabetes may beincreased due to less responsive RAS. Low salt intakeenhances and high salt intake reduces the antiproteinuriceffect of ACE inhibition.• Urinary albumin excretion is reduced by lowering dietarysalt.• Changes in dietary salt may have a beneficial influenceon TGF b production, affecting the progression of CKD.

Table A7 presents a summary of studies identified by thesearch strategy in relation to the assessment of the role of

restricted salt intake. As for protein restriction the studiesare small and of short duration. Details of the studies areincluded in Table A7; however, it is concluded that thereare insufficient reliable studies that provide evidence tosupport a recommendation in relation to restriction ofdietary salt and the prevention and management of CKD inpeople with type 2 diabetes.

(v) Role of smoking cessation

Smoking increases the risk of the development and progres-sion of CKD in people with type 2 diabetes (Evidence LevelII – Aetiology).

Interventional studies to assess the effects of smokingcessation have not been performed, but it has been calcu-lated from the cause-specific 10-year mortality data of thesubjects screened for the Multiple Risk Factor InterventionTrial (MRFIT), that stopping smoking is the most (cost-)effective risk factor intervention in people with diabetes.Smoking cessation would prolong life by a mean of 4 yearsin a 45-year old man and by 3 years in a diabetic man,whereas aspirin and antihypertensive treatment wouldprovide approximately 1 year of additional life expect-ancy.123,124 The following cohort studies summarized in thetext below and in Table A15 have included assessment ofrenal outcomes.

Smoking has been found to be an independent risk factorfor progression of AER in people with type 2 diabetes. In aprospective 9-year follow-up study of 108 people with type 2diabetes and normal AER after a duration of diabetes of9 years, there was an over-representation of smokers (55% vs27%; P = 0.01) in people who progressed to micro- or mac-roalbuminuria versus those who did not progress.125

A number of prospective cohort studies were identifiedby the search strategy that have considered smoking inpeople with type 2 diabetes in relation to kidney function.Relevant details of these studies are summarized inTable A15. All of these studies showed an associationbetween smoking and albuminuria. Only one cohort studywas found which included an assessment of smoking as a riskfactor for eGFR.126 Of the 7 prospective cohort studies iden-tified only one small study reported no significant associa-tion between smoking and the progress of albuminuria.127

Chuahirun & Wesson128 prospectively sought predictorsof renal function decline in 33 people with type 2 dia-betes, successfully targeting a mean BP goal of 92 mm Hg(about 125/75 mm Hg) with antihypertensives includingACEi. Initial plasma creatinine was <1.4 mg/dL, follow-up 64.0 1 1.1 months. Regression analysis showed thatsmoking was the only examined parameter that signifi-cantly predicted renal function decline. In the 13 smokers,serum Cr increased from 1.05 +/ to 0.08 mg/dL to1.78 1 0.20 mg/dL although MAP was the same. The 20non-smokers had a lesser Cr rise at 1.08 1 0.03 mg/dL to1.32 1 0.04 mg/dL.

The 6 month prospective cohort studies concluded thatcigarette smoking exacerbates renal injury despite adequateBP control with ACEi.129 Smoking cessation by those with


microalbuminuria was associated with amelioration of theprogressive renal injury caused by continual smoking. Thesmaller but long-term study concluded that smoking andincreased UAE are interrelated predictors of nephropathyprogression and that smoking increases UAE in patientsdespite improved BP control and ACE inhibition.130

The prospective cohort study included 6513 people withtype 2 diabetes with 5 year follow up period.131 Smoking wasidentified as an independent risk factor for establishedmicroalbuminuria and for the development of microalbu-minuria. Similarly the retrospective cohort study,126 usedlogistic to show that smoking was the most important riskfactor for progression of nephropathy. The authors con-cluded that quitting smoking should be part of the preven-tion therapy. The OR for smoking and development ofmicroalbuminuria in a prospective cohort study of 930people with type 2 diabetes and high cholesterol was 3.19(95% CI: 1.02–9.96).132

The large cohort study of people with type 2 diabetesreceiving dialysis treatment, concluded that dialysis pati-ents with a history of smoking had the highest all causemortality.133

In addition to the prospective cohort studies, a numberof cross sectional studies were identified by the search strat-egy. These provide a lower level of evidence for the assess-ment of smoking as a risk factor for CKD. A total of 11 crosssectional studies have been identified the details of whichare summarized in Table A8. All of the studies identifiedsmoking to be associated with or to be an independent riskfactor indicators of CKD.

SUMMARY OF THE EVIDENCE

• Given the strong association between type 2 diabetes andESKD, strategies aimed at prevention of type 2 diabetes arealso relevant to the prevention of CKD.• Effective control of blood glucose has been shown toreduce the progression of CKD in people with type 2 diabe-tes. There is some evidence to suggest that HbA1c targetsbelow that recommended for the management of type 2diabetes may have beneficial outcomes with respect toCKD. However, the same evidence suggests that lowertargets may have adverse outcomes or at best no effect oncardiovascular events, which are a key focus in the manage-ment of type 2 diabetes. Furthermore, lower blood glucosetargets are also associated with an increase in serioushypoglycaemic events.• Elevated BP is strongly associated with the developmentof albuminuria in people with type 2 diabetes. Managementof elevated BP has been shown to influence the rate ofprogression of CKD as well as CVD and is thus a major focusof both prevention and management.• There is evidence to indicate that antihypertensiveagents that act on the renin-angiotensin system (i.e. ACEiand ARB) have a renoprotective effect over and above thatresulting from the effect on BP. As a consequence use ofthese agents is favored in the treatment of elevated BP intype 2 diabetes and has also lead to their use in normoten-sive people with type 2 diabetes.

• Abnormal blood lipid profiles are strongly associated withthe progression and severity of CKD in people with type 2diabetes. Given the strong association between dyslipi-daemia and CVD, management of blood lipid in type 2diabetes is recommended irrespective of the presence ofindicators of CKD. There is no evidence to suggest alternatemanagement strategies are required for management ofCKD. Nor is there evidence to show that lipid loweringprevents development or rate of progression of CKD inindividuals with type 2 diabetes.• There is limited evidence demonstrating a long-termeffect of dietary interventions on the progress of CKD intype 2 diabetes. There is some evidence to suggest thatprotein restriction may affect the rate of progress of CKD,however, the clinical application of these interventions arequestionable. Diet and lifestyle are, however, important forthe management of type 2 diabetes and CVD risk and thuslikely to form a component of the overall management of anindividuals risk profile irrespective of CKD.• In observational studies, smoking has been identified as aindependent risk factor in the progression of CKD, andgiven the role of smoking as a strong risk factor in a range ofother outcomes, including CVD, an individuals smokingcessation is an important recommendation irrespective ofCKD.

WHAT DO THE OTHER GUIDELINES SAY?

KDOQI: Clinical Practice Guidelines and Clinical PracticeRecommendations for Diabetes and Chronic KidneyDisease, AJKD, Suppl 2. 49(2):S46, February 2007. (Notecovers both type 1 and type 2 diabetes)• Hyperglycemia, the defining feature of diabetes, is a fun-damental cause of vascular target-organ complications,including kidney disease. Intensive treatment of hypergly-cemia prevents DKD and may slow progression of estab-lished kidney disease.• Target HbA1c for people with diabetes should be <7.0%,irrespective of the presence or absence of CKD.• Clinicians should encourage the adoption of a healthylifestyle in their patients; this includes sound nutrition,weight control, exercise and smoking cessation.• In patients with type 2 diabetes, therapeutic lifestylechanges (diet, exercise, and weight loss, when appropriate)should be the initial interventions for hyperglycemia.• Most people with diabetes and CKD have hypertension.Treatment of hypertension slows the progression of CKD.• Hypertensive people with diabetes and CKD stages 1–4should be treated with an ACE inhibitor or an ARB, usuallyin combination with a diuretic.• Target BP in diabetes and CKD stages 1–4 should be<130/80 mm Hg.• Normotensive people with diabetes and macroalbumin-uria should be treated with an ACE inhibitor or an ARB.• Treatment with an ACE inhibitor or an ARB may beconsidered in normotensive people with diabetes andmicroalbuminuria.• Albuminuria reduction may be considered a treatmenttarget in DKD.


• Dyslipidemia is common in people with diabetes andCKD. The risk of CVD is greatly increased in this popula-tion. People with diabetes and CKD should be treatedaccording to current guidelines for high-risk groups.• Target low-density lipoprotein cholesterol (LDL-C) inpeople with diabetes and CKD stages 1–4 should be<100 mg/dL; <70 mg/dL is a therapeutic option.• People with diabetes, CKD stages 1–4, and LDL-C>100 mg/dL should be treated with a statin.• Target dietary protein intake for people with diabetes andCKD stages 1–4 should be the recommended daily allow-ance (RDA) of 0.8 g/kg body weight per day.UK Renal Association: No recommendation.Canadian Society of Nephrology: No recommendation.European Best Practice Guidelines: No recommendation.NICE Guidelines: National Collaborating Centre forChronic Conditions. type 2 diabetes: national clinicalguideline for management in primary and secondary care(update). London: Royal College of Physicians, 2008.• Start ACE inhibitors with the usual precautions andtitrate to full dose in all individuals with confirmed raisedalbumin excretion rate (>2.5 mg/mmol for men, >3.5 mg/mmol for women).• Substitute an angiotensin II-receptor antagonist for anACE inhibitor for a person with an abnormal albumin-: creatinine ratio if an ACE inhibitor is poorly tolerated.• For a person with an abnormal albumin : creatinine ratio,maintain BP below 130/80 mm Hg.American Diabetes Association: Standards of MedicalCare in Diabetes – 2008. Diabetes Care: 31, S1 JANUARY2008. (Note covers both type 1 and type 2 diabetes)• To reduce the risk or slow the progression of nephropathy,optimize glucose control.• To reduce the risk or slow the progression of nephropathy,optimize BP control.• In the treatment of the nonpregnant patient with micro-or macroalbuminuria, either ACE inhibitors or ARBsshould be used.• In patients with type 2 diabetes, hypertension, andmicroalbuminuria, both ACE inhibitors and ARBs havebeen shown to delay the progression to macroalbuminuria.• In patients with type 2 diabetes, hypertension, macro-albuminuria, and renal insufficiency (serum creatinine –1.5 mg/dL), ARBs have been shown to delay the progressionof nephropathy.• If one class is not tolerated, the other should besubstituted.

IMPLEMENTATION AND AUDIT

No recommendation.

SUGGESTIONS FOR FUTURE RESEARCH

No recommendation.

CONFLICT OF INTEREST

Non-identified.

ACKNOWLEDGEMENT

The Type 2 Diabetes Guidelines project was funded by theDepartment of Health and Ageing under a contract withDiabetes Australia. The development of the ‘National Evi-dence Based Guidelines for Diagnosis, Prevention and Man-agement of Chronic Kidney Disease in Type 2 Diabetes’ wasundertaken by CARI in collaboration with The DiabetesUnit, Menzies Centre for Health Policy at the University ofSydney.

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APPENDIX

Table A1 Definition of NHMRC grades of recommendation

Grade ofrecommendation Description

A Body of evidence can be trusted to guide practice.B Body of evidence can be trusted to guide practice in most situations.C Body of evidence provides some support for recommendations(s) but care should be taken in its application.D Body of evidence is weak and recommendation must be applied with caution


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ropa

thy

byab

out

50%

.


Gam

baro

etal

.(2

002)

62R

CT,

doub

lebl

ind,

plac

ebo

Mul

tice

ntre

Type

1di

abet

esan

dty

pe2

diab

etes

,m

icro

orm

acro

albu

min

uric

n=

223

Sulo

exid

evs

Plac

ebo

UA

E4

Sign

ifica

ntly

redu

ced

albu

min

uria

inpe

ople

wit

hbo

thty

pe1

and

type

2di

abet

es.

Han

efel

det

al.

(200

4)49

RC

T,do

uble

blin

dM

ulti

cent

reTy

pe2

diab

etes

,ina

dequ

atel

ym

anag

edn

=64

9

Piog

litaz

one

plus

SUvs

Met

form

inpl

usSU

AC

R12

Clin

ical

lyeq

uiva

lent

impr

ovem

ents

ingl

ycae

mic

cont

rol.

Piog

litaz

one

plus

SUre

sult

edin

are

duct

ion

ofA

CR

.Ove

rall

diffe

renc

esfr

omba

selin

eA

CR

smal

l(i.e

.<15

%).

John

ston

etal

.(1

998)

60R

CT

Type

2di

abet

es,H

ispa

nic

n=

385

Mig

litol

vsPl

aceb

oA

CR

.12

Mig

litol

had

‘just

non-

sign

ifica

nt’r

educ

tion

ofA

CR

.

John

ston

etal

.(1

998)

61R

CT

Type

2di

abet

es,A

fric

an-A

mer

ican

n=

345

Mig

litol

vsPl

aceb

oA

CR

12M

inor

redu

ctio

nin

AC

Rw

ith

mig

litol

.

Lebo

vitz

etal

.(2

001)

53R

CT

Mul

tice

ntre

(42)

,US,

mix

edra

ce.

Type

2di

abet

es,3

6–81

year

s,FP

G(7

.8–1

6.7

mm

ol/L

),B

MI

betw

een

22–3

8kg

/m2 ,n

ore

nali

mpa

irm

ent

orD

N.

n=

493

Ros

igla

tzon

e(2

or4

mg/

day)

vsPl

aceb

oU

AE,

AC

R7

AC

Rde

crea

sed

sign

ifica

ntly

inbo

th2

and

4m

g/da

yR

SG.C

ompa

red

wit

han

insi

gnifi

cant

incr

ease

from

base

line

ofth

epl

aceb

o.Fo

rsu

bgro

upw

ith

mic

roal

bum

inur

ia,b

oth

dose

sof

RSG

gave

redu

ctio

nin

AC

Rfr

omba

selin

eof

arou

nd40

%.

Onl

ya

smal

lper

cent

age

ofpa

tien

tsw

ere

rece

ivin

gan

tihy

pert

ensi

veth

erap

y–

sugg

ests

effe

ctis

are

sult

ofim

prov

edgl

ycae

mic

cont

rolo

ra

diffe

rent

effe

ctof

RSG

.

Levi

net

al.

(200

0)46

RC

TTy

pe2

diab

etes

(mea

nag

e60

,mea

ndu

rati

onof

diab

etes

8ye

ars)

n=

153

Inte

nsiv

e(H

bA1c

goal

7.1%

)vs

Stan

dard

(HbA

1cgo

al9.

1%)

UA

E,A

CR

24In

tens

ive

glyc

aem

icco

ntro

lret

arde

dm

icro

albu

min

uria

,but

may

not

less

enth

epr

ogre

ssiv

ede

teri

orat

ion

ofgl

omer

ular

func

tion

.

Mat

thew

set

al.

(200

5)50

RC

T,do

uble

blin

dTy

pe2

diab

etes

,poo

rly

man

aged

n=

630

Met

form

inpl

uspi

oglit

azon

evs

Met

form

inpl

usgl

icla

zide

AC

R12

Mea

nA

CR

redu

ced

by10

%in

met

plus

piog

grou

p.Po

tent

ialb

enefi

tsar

ein

dica

ted.

Ohk

ubo

etal

.(1

995)

7R

CT

Japa

nTy

pe2

diab

etes

,div

ided

into

prim

ary

prev

enti

onan

dse

cond

ary

inte

rven

tion

coho

rts

onth

eba

sis

ofal

bum

inur

iaan

dre

tino

path

y.n

=11

0

Mul

tipl

eIn

sulin

Trea

tmen

t(M

IT)

vsC

onve

ntio

nalI

nsul

inTr

eatm

ent

(CIT

)

UA

E60

Inte

nsiv

egl

ycae

mic

cont

rolc

ande

lay

the

onse

tan

dpr

ogre

ssio

nof

neph

ropa

thy.

The

cum

ulat

ive

perc

enta

ges

ofth

ede

velo

pmen

tan

dth

epr

ogre

ssio

nin

neph

ropa

thy

afte

r6

year

sw

ere

7.7%

for

the

MIT

grou

pan

d28

.0%

for

the

CIT

grou

pin

the

prim

ary-

prev

enti

onco

hort

(P=

0.03

2).

Sche

rnth

aner

etal

.(2

004)

51R

CT,

doub

le-b

lind

Mul

tice

ntre

,167

cent

res

acro

ss12

Euro

pean

coun

trie

sTy

pe2

diab

etes

inad

equa

tely

trea

ted

bydi

etal

one

(HbA

betw

een

7.5%

and

11%

),35

–75

year

sn

=11

99

Piog

litaz

one

vsM

etfo

rmin

AC

R12

Piog

litaz

one

–19

%de

crea

sein

AC

Rco

mpa

red

wit

h1%

inm

etfo

rmin

grou

p.B

Pno

tst

atis

tica

llydi

ffere

ntbe

twee

ngr

oups

.Con

sist

ent

wit

hpr

evio

usst

udie

sth

attr

oglit

azon

ebu

tno

tm

etfo

rmin

orgl

iben

clam

ide

redu

ced

urin

ary

albu

min

excr

etio

nra

te.

Shic

hiri

etal

.(2

000)

47

Kun

amot

oSt

udy

RC

Tn

=11

0M

ITvs

CIT

Alb

umin

uria

96In

tens

ive

glyc

aem

icco

ntro

l(M

IT)

–cu

mul

ativ

epe

rcen

tage

sof

wor

seni

ngin

neph

ropa

thy

wer

esi

gnifi

cant

lylo

wer

.


Tab

leA

3Su

mm

ary

ofst

udie

sre

leva

ntto

the

asse

ssm

ent

ofth

ero

leof

bloo

dpr

essu

reco

ntro

land

anti

hype

rten

sive

agen

tsin

CK

Dan

din

divi

dual

sw

ith

type

2di

abet

es.

Stud

yID

Stud

yde

scri

ptio

nIn

terv

enti

onO

utco

me

rele

vant

toC

KD

Follo

wup

(mon

ths)

Com

men

ts

AD

VA

NC

E(2

007)

67

and

deG

alan

(200

9)68

RC

TM

ulti

cent

re(2

15ac

ross

20co

untr

ies)

Type

2di

abet

esdi

agno

sed

at30

year

sor

olde

r.A

ge3

55ye

ars

atth

est

art

ofth

est

udy.

His

tory

ofm

ajor

vasc

ular

orm

icro

vasc

ular

dise

ase

orat

leas

ton

eot

her

risk

fact

orfo

rva

scul

ardi

seas

e.n

=11

000

Peri

ndop

rilp

lus

inda

pam

ide

vspl

aceb

o

Wor

seni

ngne

phro

path

yi.e

.dev

elop

men

tof

mac

roal

bum

inur

ia,d

oubl

ing

ofse

rum

crea

tini

ne,n

eed

for

rena

lrep

lace

men

tth

erap

yor

deat

hdu

eto

kidn

eydi

seas

e.

52(m

edia

n)A

ctiv

etr

eatm

ent

mea

nre

duct

ion

inSB

Pan

dD

BP

of5.

6an

d2.

2m

mH

gre

spec

tive

ly,c

ompa

red

wit

hpl

aceb

o.T

here

lati

veri

skof

am

ajor

mic

rova

scul

arev

ent

was

7.9%

inth

eac

tive

trea

tmen

tgr

oup

com

pare

dw

ith

8.6%

inth

epl

aceb

ogr

oup

(non

-sig

nific

ant)

.A

ctiv

etr

eatm

ent

was

asso

ciat

edw

ith

abo

rder

line

sign

ifica

ntre

duct

ion

inm

acro

albu

min

uria

and

asi

gnifi

cant

redu

ctio

nin

the

deve

lopm

ent

ofm

icro

albu

min

uria

wit

ha

rela

tive

risk

redu

ctio

nof

21%

(95%

CI:

15–3

0).

Aga

rdh

etal

.(1

996)

74R

CT,

doub

lebl

ind

Mul

tice

ntre

,mul

tina

tion

alTy

pe2

diab

etes

,mic

roal

bum

inur

ia,

earl

ydi

abet

icne

urop

athy

,hy

pert

ensi

ve23

9m

ales

96fe

mal

es

Lisi

nopr

ilvs

Nife

dipi

neU

AE,

crea

tini

necl

eara

nce

12Si

gnifi

cant

lym

ore

bene

ficia

leffe

cton

UA

E,ho

wev

ercr

eati

nine

clea

ranc

edi

dno

tch

ange

sign

ifica

ntly

wit

hei

ther

trea

tmen

t.

Ahm

adet

al.

(199

7)25

RC

Tsi

ngle

blin

dIn

dia

Type

2di

abet

esN

orm

oten

sive

n=

103

AC

Eivs

Plac

ebo

AER

60A

fter

5ye

ars

AC

Eitr

eate

dpa

tien

tsex

peri

ence

dsi

gnifi

cant

lyle

sspr

ogre

ssio

nof

mic

roal

bum

inur

iato

clin

ical

albu

min

uria

.

Bab

a&

MIN

DSt

udy

Gro

up(2

001)

82R

CT

–in

tent

totr

eat

anal

ysis

Mul

tice

ntre

Japa

nTy

pe2

diab

etes

Nor

moa

lbum

inur

iaM

icro

albu

min

uria

n=

486

AC

Eivs

CC

BU

AE

24C

CB

and

AC

Eiha

da

sim

ilar

effe

cton

neph

ropa

thy

inhy

pert

ensi

vepe

ople

wit

hty

pe2

diab

etes

wit

hout

over

tpr

otei

nuri

a.

Bak

ris

etal

.(2

005)

95R

CT

Type

2di

abet

es,h

yper

tens

ion,

AC

Eior

AR

Bas

part

ofth

etr

eatm

ent

regi

me

prio

rto

com

men

cem

ent

ofth

est

udy.

n=

1235

Met

opro

lol(

mai

ntai

nA

CEi

/AR

B)

vsC

arve

dilo

l(m

aint

ain

AC

Ei/A

RB

)

Alb

umin

uria

(spo

tA

CR

)5

afte

rre

achi

ngta

rget

BP

Pre

spec

ified

and

post

hoc

anal

yses

ofth

eG

EMIN

Itr

ial.

Gre

ater

redu

ctio

nin

mic

roal

bum

inur

iaw

asob

serv

edfo

rca

rved

ilol.

Tho

sew

ith

norm

oalb

umin

uria

few

erpr

ogre

ssed

tom

icro

onca

rved

ilol.

Thi

sef

fect

was

not

rela

ted

toB

P.M

ulti

vari

ate

anal

ysis

inal

bum

inur

iach

ange

dem

onst

rate

don

lyba

selin

eur

ine

AC

Ran

dtr

eatm

ent

wer

esi

gnifi

cant

pred

icto

rs.I

na

sepa

rate

anal

ysis

–th

epr

esen

ceof

met

abol

icsy

ndro

me

atba

selin

eco

rres

pond

edw

ith

anO

Rof

2.68

(95%

CI:

1.36

–5.3

0)ov

erth

edu

rati

onof

the

stud

y.

Bar

nett

etal

.(2

004)

96R

CT,

doub

lebl

ind.

Mul

tice

ntre

(39)

,6Eu

rope

anco

untr

ies

Type

2di

abet

es,m

ildto

mod

erat

ehy

pert

ensi

on,a

llha

dto

have

been

trea

ted

byan

AC

Eito

elim

inat

ein

tole

ranc

e,G

FR>7

0m

L/m

inpe

r1.

73m

2 ,m

ostl

yw

hite

and

mal

e.n

=25

0

AR

B(t

elis

arta

n–

40m

g/da

yup

to80

mg/

day

for

BP

cont

rol)

AC

Ei(e

nala

pril

–10

mg/

day

upto

20m

g/da

yfo

rB

Pco

ntro

l)(A

ddit

iona

lhyp

erte

nsiv

eal

low

edas

requ

ired

)

GFR

(cal

cula

ted

from

seru

mcr

eati

nine

),U

AE

60T

hedi

ffere

nce

inG

FRbe

twee

nth

eA

RB

and

the

AC

Eiw

as-3

.1m

L/m

inpe

r1.

73m

2an

dw

asin

sign

ifica

nt.T

hem

ean

annu

alde

clin

esin

GFR

wer

e3.

7m

L/m

inpe

r1.

73m

2fo

rth

eA

RB

and

3.3

mL/

min

per

1.73

m2

for

the

AC

Ei.T

hese

resu

lts

sim

ilar

toG

FRde

clin

ere

port

edin

IRM

A2,

IDN

T,an

dR

ENA

AL

stud

ies.

Com

pare

toun

trea

ted

type

2di

abet

esan

nual

decl

ine

of10

mL/

min

per

1.73

m2 .

Telm

isar

tan

isno

tin

feri

orto

enal

apri

lin

prov

idin

glo

ng-t

erm

reno

prot

ecti

on.D

oes

not

nece

ssar

ilyap

ply

tom

ore

adva

nced

neph

ropa

thy

–bu

tsu

ppor

tcl

inic

aleq

uiva

lenc

eof

AR

Ban

dA

CEi

inpe

rson

sw

ith

cond

itio

nsth

atpl

ace

them

athi

ghri

skfo

rC

Vev

ents

.


Cha

net

al.

(200

0)76

RC

TTy

pe2

diab

etes

Hyp

erte

nsiv

en

=10

2

AC

Eivs

CC

BU

AE,

CC

rIn

itia

lly12

then

54(m

ean)

Trea

tmen

tw

ith

AC

Eias

soci

ated

wit

hgr

eate

rre

duct

ion

inal

bum

inur

iath

anw

ith

CC

Bin

the

enti

repa

tien

tgr

oup

and

espe

cial

lyin

thos

ew

ith

mic

roal

bum

inur

ia.I

nm

acro

albu

min

uria

,rat

eof

dete

rior

atio

nin

rena

lfun

ctio

nw

asal

soat

tenu

ated

wit

hA

CEi

.

Esta

cio

(200

6)85

RC

Tty

pe2

diab

etes

norm

oten

sive

n=

129

Inte

nsiv

eB

Pco

ntro

l(v

alsa

rtan

+ot

her

asre

quir

ed)

vsM

oder

ate

BP

cont

rol(

plac

ebo

plus

othe

rsas

requ

ired

)

UA

E,se

rum

crea

tini

ne,

crea

tini

necl

eara

nce

23(m

edia

n)In

tB

P–

1181

10.9

/751

5.7

Mod

BP

–12

41

109/

801

6.5

UA

E–

sign

ifica

nttr

eatm

ent

diffe

renc

eat

2ye

ars.

AB

CD

Esta

cio

etal

.(2

000)

73

Esta

cio

&Sc

hrie

r(1

998)

12

Schr

ier

etal

.(2

002)

70

RC

Tpr

ospe

ctiv

eTy

pe2

diab

etes

Nor

mot

ensi

ve(D

BP

betw

een

80an

d89

mm

/Hg,

not

rece

ivin

gan

tihy

pert

ensi

ves)

n=

470

AC

Ei,e

nalp

ril

vsC

CB

,nis

oldi

pine

vsPl

aceb

o

Cre

atin

ine

clea

ranc

e,U

AE

64B

lood

pres

sure

cont

rolo

f138

/86

or13

8/78

mm

/Hg

wit

hei

ther

AC

Eior

CC

Bas

the

init

ialh

yper

tens

ive

agen

tap

pear

edto

stab

ilize

rena

lfun

ctio

nin

hype

rten

sive

peop

lew

ith

type

2di

abet

esw

itho

utov

ert

albu

min

uria

over

a5

year

peri

od.M

ore

inte

nsiv

eB

Pco

ntro

ldec

reas

edal

lcau

sem

orta

lity.

Inte

nsiv

eB

Pco

ntro

lin

norm

oten

sive

type

2di

abet

essl

owed

prog

ress

ion

toin

cipi

ent

and

over

tne

phro

path

y,de

crea

sed

prog

ress

ion

ofre

tino

path

yan

ddi

min

ishe

dth

ein

cide

nce

ofst

roke

.Stu

dyin

dica

tes

BP

cont

rola

sbe

ing

the

impo

rtan

tfa

ctor

rath

erth

anA

CEi

vsC

CB

.

Foga

riet

al.

(200

0)83

RC

TTy

pe2

diab

etes

(wel

lcon

trol

led)

,60

to75

year

s,hy

pert

ensi

ven

=14

7

AC

Eivs

CC

BU

AE,

crea

tini

necl

eara

nce

24A

t24

mon

ths

UA

Esi

gnifi

cant

lyde

crea

sed

inbo

thtr

eatm

ents

.Cre

atin

ine

clea

ranc

eun

affe

cted

byA

CEi

,but

incr

ease

dby

CC

B

Gal

leet

al.

(200

8)86

RC

TM

ulti

cent

ric

Type

2di

abet

esw

ith

hype

rten

sion

,pr

otei

nuri

aan

dse

rum

crea

tini

ne2

3.0

mg/

dL)

n=

885

Telm

isar

tan

vsva

lsar

tan.

(add

itio

naln

on-A

CEi

/AR

Ban

tihy

pert

ensi

ves

perm

itte

das

nece

ssar

y)

24h

prot

einu

ria,

eGFR

12M

ean

redu

ctio

nin

prot

einu

ria

33%

(sam

efo

rbo

thtr

eatm

ents

).G

reat

erre

nopr

otec

tion

seen

amon

gpa

tien

tsw

ith

bett

erbl

ood

pres

sure

cont

rol.

Hol

lenb

erg

etal

.(2

007)

87R

CT

Mul

tice

ntri

cTy

pe2

diab

etes

wit

hhy

pert

ensi

onan

dal

bum

inur

ia(A

ER20

–700

mg/m

in)

n=

391

vals

arta

n16

0m

g/da

yvs

320

mg/

day

vs64

0m

g/da

y(a

ddon

med

icat

ions

for

BP

cont

rola

sre

quir

ed)

AER

,ser

umcr

eati

nine

7.5

Hig

hdo

seva

lsar

tan

abov

e16

0m

g/da

y–

grea

ter

redu

ctio

nfr

omba

selin

eA

ERw

ith

grea

ter

num

ber

(12%

)re

gres

sing

tono

rmoa

lbum

inur

ia.

Jeru

ms

etal

.(2

004)

80R

CT

pros

pect

ive

open

,blin

ded

endp

oint

Type

2di

abet

esn

=77

AC

EiC

CB

vsPl

aceb

oG

FR,a

lbum

inur

ia66

(med

ian)

Long

-ter

mco

ntro

lofb

lood

pres

sure

wit

hA

CEi

orC

CB

stab

ilize

sA

ERan

dat

tenu

ates

GFR

decl

ine

inpr

opor

tion

toM

AP

inno

n-hy

pert

ensi

vepe

ople

wit

hty

pe2

diab

etes

and

mic

roal

bum

inur

ia.

Laco

urci

ere

etal

.(1

993)

75R

CT

doub

lebl

ind

Cau

casi

an(4

5to

75ye

ars)

Type

2di

abet

esM

ildto

mod

erat

ehy

pert

ensi

onn

=10

9

AC

Eivs

conv

enti

onal

ther

apy

UA

E36

Trea

tmen

tw

ith

capt

opri

ldec

reas

edal

bum

inur

iaan

dre

duce

dth

ede

velo

pmen

tof

mac

roal

bum

inur

iain

thos

ew

ith

pers

iste

ntm

icro

albu

min

uria

.


Tab

leA

3C

ontin

ued

Stud

yID

Stud

yde

scri

ptio

nIn

terv

enti

onO

utco

me

rele

vant

toC

KD

Follo

wup

(mon

ths)

Com

men

ts

Laco

urci

ere

etal

.(2

000)

84R

CT

pros

pect

ive

Mul

tice

ntre

Can

ada

Type

2di

abet

esH

yper

tens

ive

Earl

yne

phro

path

yn

=92

AC

Eivs

AR

BR

enal

bioi

ndic

ator

s12

Trea

tmen

tw

ith

eith

erA

CEi

orA

RB

sign

ifica

ntly

redu

ced

UA

E.R

educ

tion

inU

AE

wit

hea

chtr

eatm

ent

was

sim

ilarl

yre

late

dto

decr

emen

tsin

AB

P.R

ate

ofde

clin

ein

GFR

was

sim

ilar

inbo

thtr

eatm

ent

grou

ps.

Lebo

vitz

etal

.(1

994)

71R

CT,

doub

lebl

ind

Type

2di

abet

esH

yper

tens

ive

n=

121

AC

Eivs

Plac

ebo

UA

E,pr

otei

n,ur

ea,

nitr

ogen

,cre

atin

ine,

GFR

36A

CEi

pres

erve

dG

FRbe

tter

inpa

tien

tsw

ith

sub-

clin

ical

prot

einu

ria

atba

selin

ebe

tter

than

othe

ran

tihy

pert

ensi

ves

wit

hout

AC

Ei.S

mal

ler

perc

enta

gepr

ocee

ded

tocl

inic

alal

bum

inur

ia.

Mar

reet

al.

(200

4)81

RC

Tdo

uble

blin

d,pa

ralle

lgro

upM

ulti

cent

re,p

rim

ary

care

,16

Euro

pean

and

Nor

thA

fric

anTy

pe2

diab

etes

>50

year

sPe

rsis

tent

mic

roal

bum

inur

iaor

prot

einu

ria

n=

4912

AC

Ei(o

nto

pof

usua

ltr

eatm

ent)

vsPl

aceb

oES

KD

Seco

ndar

y–

UA

E,ur

inar

ypr

otei

n

72(m

edia

n)Lo

wdo

sera

mip

rilo

nce

daily

has

noef

fect

onC

VD

and

kidn

eyou

tcom

es(t

ype

2di

abet

esan

dal

bum

inur

ia)

desp

ite

slig

htde

crea

sein

bloo

dpr

essu

rean

dU

AE.

Mui

rhea

det

al.

(199

9)10

0R

CT,

doub

lebl

ind,

plac

ebo

Mul

tice

ntre

,Cau

casi

anTy

pe2

diab

etes

,nor

mot

ensi

ve,

mic

roal

bum

inur

ian

=12

2

AC

EiA

RB

vsPl

aceb

oU

AE

12T

heA

RB

slow

edpr

ogre

ssiv

eri

seof

UA

Eco

mpa

red

wit

hth

eA

CEi

.

Nak

amur

aet

al.

(200

2)13

4R

CT,

Type

2di

abet

es,

norm

oten

sive

,mic

roal

bum

inur

ian

=60

AC

EiA

RB

AC

Ei+

AR

Bvs

Plac

ebo

UA

E18

Dat

asu

gges

tth

eco

mbi

nati

onof

AR

B/A

CEi

has

anad

diti

veef

fect

.On

the

redu

ctio

nof

mic

roal

bum

inur

ia.

ON

TAR

GET

(200

8)97

and

Man

net

al.

(200

8)98

RC

TH

eart

dise

ase,

incl

uded

38%

wit

hdi

abet

es(t

ype

1an

dty

pe2)

and

13%

wit

hm

icro

albu

min

uria

n=

2500

0

AC

Ei(R

amip

ril)

vsA

RB

(Tel

mis

arta

n)vs

Com

bina

tion

eGFR

,UA

ESe

cond

ary-

Ren

alim

pair

men

t(b

ased

oncl

inic

alin

vest

igat

ors

repo

rt)

Ren

alfa

ilure

requ

irin

gdi

alys

is.

56(m

edia

n)N

osu

bgro

upan

alys

isha

sbe

enpr

esen

ted

incl

udin

gdi

abet

esan

dm

icro

albu

min

uria

.The

refo

reno

tge

nera

lisea

ble

toty

pe2

diab

etes

.Ove

rall,

nosi

gnifi

cant

diffe

renc

esno

ted

betw

een

trea

tmen

tsex

cept

for

rena

lim

pair

men

t.C

ombi

nati

ontr

eatm

ent

resu

lted

inlo

wer

AC

Ran

dlo

wer

onse

tof

new

mic

roal

bum

inur

iaat

the

end

ofth

efo

llow

uppe

riod

,how

ever

gree

ter

rate

ofde

clin

ein

eGFR

.

Parv

ing

etal

.(2

001)

72

and

Bre

nner

etal

.(2

001)

19

RC

T,do

uble

blin

dM

ulti

cent

re,m

ulti

nati

onal

Type

2di

abet

esn

=15

13

AR

B15

0m

g/da

yA

RB

300

mg/

day

vsPl

aceb

o(a

ndco

nven

tion

alhy

pert

ensi

vetr

eatm

ent)

Seru

mcr

eati

nine

doub

ling,

ESK

D,d

eath

,pro

tein

uria

,pr

ogre

ssio

nof

kidn

eydi

seas

e

40(m

ean)

Losa

rtan

conf

erre

dsi

gnifi

cant

rena

lben

efits

inty

pe2

diab

etes

wit

hne

urop

athy

and

was

gene

rally

wel

lto

lera

ted.

Parv

ing

etal

.(2

008)

99R

CT,

doub

lebl

ind,

plac

ebo

cont

rolle

dM

ulti

cent

ric,

mul

tina

tion

alTy

pe2

diab

etes

,nep

hrop

athy

.Ex

clud

ed–

know

nno

n-di

abet

icne

phro

path

y,A

CR

>350

0m

g/g,

eGFR

<30

mL/

min

,chr

onic

UT

I,se

vere

hype

rten

sion

,car

diov

ascu

lar

dise

ase

wit

hin

the

prev

ious

6m

onth

s.n

=59

9

Alis

kire

n(d

irec

tre

nin

inhi

bito

r)15

0m

gfo

r3

mon

ths

300

mg

for

3m

onth

s.vs

plac

ebo

Bot

h–

max

imal

losa

rtan

(100

mg)

plus

addi

tion

alhy

pert

ensi

veto

achi

eve

opti

mal

BP

(i.e

.tar

get

of13

0/80

mm

Hg)

.

Uri

nary

AC

R,e

GFR

.6

Aft

erad

just

men

tfo

rch

ange

sfr

omba

selin

ein

syst

olic

BP,

the

alis

kire

ntr

eatm

ent

redu

ced

the

mea

nur

inar

yA

CR

by18

%co

mpa

red

wit

hth

epl

aceb

o.T

hetr

eatm

ent

grou

pha

da

grea

ter

num

ber

ofpa

tien

tsw

here

albu

min

uria

redu

ctio

nw

asgr

eate

rth

an50

%(2

4.7%

vs12

.5%

).T

hebe

nefit

ofal

iski

ren

appe

ared

tobe

inde

pend

ent

ofdi

ffere

nces

(sm

all)

inbl

ood

pres

sure

.


Rav

idet

al.

(199

3)14

RC

T–

doub

lebl

ind

fist

phas

ean

dop

ense

cond

phas

e.Is

rael

,Mul

tice

ntre

Type

2di

abet

esN

orm

oten

sive

Mic

roal

bum

inur

ian

=94

AC

Eivs

Plac

ebo

AER

60–

ontr

eatm

ent

24–

choi

cefo

rtr

eatm

ent

AC

Eiof

fers

long

term

prot

ecti

onag

ains

tth

ede

velo

pmen

tof

neph

ropa

thy

inno

rmot

ensi

vew

ith

mic

roal

bum

inur

ia,a

ndit

stab

ilize

sre

nalf

unct

ion

inpr

evio

usly

untr

eate

dpa

tien

tsw

ith

impa

ired

rena

lfu

ncti

on.D

isco

ntin

uati

onof

trea

tmen

tre

sult

sin

rene

wed

prog

ress

ion

ofne

phro

path

y.

Rav

idet

al.

(199

8)66

RC

Tdo

uble

blin

dM

ulti

cent

reTy

pe2

diab

etes

Nor

mot

ensi

veN

orm

oalb

umin

uria

n=

156

AC

Eivs

Plac

ebo

UA

E,cr

eati

nine

clea

ranc

e70

AC

Eiat

tenu

ated

the

decl

ine

inre

nalf

unct

ion

and

redu

ced

the

exte

ntof

albu

min

uria

inno

rmot

ensi

ve,

norm

oalb

umin

uric

peop

lew

ith

type

2di

abet

es.

Ros

eiet

al.

(200

5)94

RC

TM

ulti

cent

reTy

pe2

diab

etes

Mild

hype

rten

sion

,eit

her

prev

ious

lyun

trea

ted

for

hype

rten

sion

orun

succ

essf

ully

trea

ted.

n=

129

AC

Ei–

enal

apri

l(20

mg/

day)

vsA

RB

–ca

ndes

arta

n(1

6m

g/da

y)(H

CT

used

for

addi

tion

altr

eatm

ent

asre

quir

ed.)

UA

E6

Can

dest

arta

nan

den

alap

rils

how

edsi

mila

ref

fect

son

BP

and

circ

ulat

ing

adhe

sion

mol

ecul

es.U

AE

was

redu

ced

sign

ifica

ntly

mor

eby

cand

esta

rtan

.How

ever

,the

maj

orit

yof

pati

ents

had

norm

alpr

otei

nex

cret

ion

and

ther

efor

edi

fficu

ltto

extr

apol

ate

the

resu

lts

obta

ined

.

Rug

gene

ntie

tal

.(1

998)

91al

soR

emuz

ziet

al.

(200

6)92

BEN

EDIC

T

RC

TM

ulti

cent

reTy

pe2

diab

etes

Hyp

erte

nsio

nN

orm

oalb

umin

uria

n=

1204

–V

erap

amil

–24

0m

g/da

y–

Trad

olap

ril–

2m

g/da

y–

Ver

apam

ilpl

ustr

ando

lapr

ilvs

Plac

ebo

UA

E43

.2A

ddit

iona

lage

nts

perm

itte

dto

achi

eve

BP

cont

rol.

Tran

dola

pril

plus

vera

pam

ilan

dtr

ando

lapr

ilal

one

decr

ease

din

cide

nce

ofm

icro

albu

min

uria

tosi

mila

rex

tent

.Ver

apam

ilal

one

nodi

ffere

ntto

plac

ebo.

Sano

etal

.(1

996)

69R

CT

pros

pect

ive

Japa

nTy

pe2

diab

etes

Nor

mot

ensi

veM

icro

albu

min

uria

n=

62

AC

Eivs

No

trea

tmen

tU

AE,

crea

tini

necl

eara

nce

48U

AE

intr

eate

dgr

oup

decr

ease

dan

din

crea

sed

slow

lyin

untr

eate

dgr

oup.

Schr

amet

al.

(200

5)93

RC

T,do

uble

blin

d,do

uble

dum

my

Mul

ti-c

entr

e,T

heN

ethe

rlan

ds,

Cau

casi

an.

Type

2di

abet

es,H

yper

tens

ive,

mea

nag

ein

trea

tmen

ts60

to63

,UA

E<1

00m

g/d

(nor

mo

and

mic

roal

bum

inur

ic)

n=

70

HC

T–

12.5

mg/

dA

CEi

–10

mg/

dA

RB

–8

mg/

dvs

Dum

my

plac

ebos

used

tom

aint

ain

doub

lebl

ind.

UA

E(s

econ

dary

outc

ome)

1ru

nin

4to

6ti

trat

ion

peri

od12

stud

y

The

rew

asno

sign

ifica

ntdi

ffere

nce

inth

eU

AE

betw

een

the

trea

tmen

tgr

oups

,whi

chm

aybe

aco

nseq

uenc

eof

the

smal

lsam

ple

size

.A

ggre

ssiv

ean

tihy

pert

ensi

veth

erap

yca

nim

prov

eU

AE

inhy

pert

ensi

vepe

ople

wit

hty

pe2

diab

etes

rega

rdle

ssof

the

type

ofth

erap

yus

ed.

SMA

RT

Gro

up(2

007)

88R

CT

Type

2di

abet

esw

ith

mic

roal

bum

inur

ian

=34

1

Val

sart

anvs

mlo

dipi

neA

CR

3V

alsa

rtan

–A

CR

68%

ofba

selin

eA

mlo

dipi

ne–

AC

R11

8%of

base

line

Rem

issi

on–

23vs

11%

Reg

ress

ion

–34

vs16

%

Tan

etal

.(2

002)

89R

CT

doub

lebl

ind

Type

2di

abet

esM

icro

albu

min

uria

n=

80

AR

Bvs

Plac

ebo

UA

E6

Peop

lew

ith

type

2di

abet

esan

dm

icro

albu

min

uria

have

impa

ired

endo

thel

ium

-dep

ende

ntan

d–i

ndep

ende

ntva

sodi

lata

tion

.Tre

atm

ent

wit

hlo

wdo

selo

sart

anis

suffi

cien

tto

redu

cem

icro

albu

min

uria

wit

hout

alte

rati

onin

endo

thel

ialf

unct

ion

and

syst

emic

bloo

dpr

essu

re.


Tab

leA

3C

ontin

ued

Stud

yID

Stud

yde

scri

ptio

nIn

terv

enti

onO

utco

me

rele

vant

toC

KD

Follo

wup

(mon

ths)

Com

men

ts

The

HO

PESt

udy

Gro

up(2

000)

18R

CT

Mul

tice

ntre

CV

Dor

diab

etes

plus

high

CV

Dri

sk.

(98%

type

2di

abet

es)

n=

3577

Ram

ipri

lvs

Plac

ebo

Alb

umin

uria

(sec

onda

ryou

tcom

e)54

Sign

ifica

ntre

duct

ion

inri

skof

over

tne

phro

path

yin

ram

ipri

ltre

atm

ent

grou

p.N

odi

ffere

nce

inri

skof

new

mic

roal

bum

inur

ia.

Trev

isan

&Ti

engo

(199

5)10

3R

CT

doub

lebl

ind

Ital

y–

mul

tice

ntre

Type

2di

abet

esM

icro

albu

min

uria

Nor

mal

orm

ildhy

pert

ensi

onn

=12

2

AC

Eivs

Plac

ebo

AER

6Lo

wdo

seA

CEi

can

arre

stth

epr

ogre

ssiv

eri

sein

albu

min

uria

inty

pe2

diab

etes

wit

hpe

rsis

tent

mic

roal

bum

inur

ia.

UK

PDS

(199

8)65

RC

TM

ulti

cent

reU

K20

hosp

ital

clin

ics

Type

2di

abet

esH

yper

tens

ive

n=

1148

AC

Eivs

Bet

abl

ocke

rU

AE

100

(med

ian)

BP

low

erin

gw

ith

capt

opri

lwas

sim

ilarl

yef

fect

ive

inre

duci

ngth

ein

cide

nce

ofdi

abet

icco

mpl

icat

ions

.

UK

PDS

(199

8)8

RC

TM

ulti

cent

reU

K20

hosp

ital

clin

ics

Type

2di

abet

esH

yper

tens

ive

n=

1148

AC

Eivs

Bet

abl

ocke

rD

iabe

tes

rela

ted

deat

hsan

dal

lcau

sem

orta

lity.

UA

E

100

(med

ian)

Tigh

tbl

ood

pres

sure

cont

roli

npa

tien

tsw

ith

hype

rten

sion

and

type

2di

abet

esac

hiev

esa

clin

ical

lyim

port

ant

redu

ctio

nin

the

risk

ofde

aths

rela

ted

todi

abet

es,c

ompl

icat

ions

rela

ted

todi

abet

es,p

rogr

essi

onof

diab

etic

reti

nopa

thy,

and

dete

rior

atio

nin

visu

alac

uity

Vib

erti

(200

2)90

RC

TTy

pe2

diab

etes

wit

hm

icro

albu

min

uria

n=

332

Val

sart

anvs

amlo

dipi

ne(a

ddit

iona

lage

nts

used

tom

eet

BP

targ

etof

135/

80m

m/H

g)

AER

6M

ore

pati

ents

reve

rted

tono

rmoa

lbum

inur

iaw

ith

losa

rtan

29.9

%vs

14.5

%).

BP

redu

ctio

nsw

ere

sim

ilar.

Yasu

daet

al.

(200

5)79

Ope

n-la

belp

aral

lelp

rosp

ecti

veR

CT

Japa

nTy

pe2

diab

etes

,Ove

rtne

phro

path

y(U

AE

betw

een

300

and

3000

mg/

day)

,31

and

80ye

ars

(ave

rage

44),

hype

rten

sive

n=

87

AR

B–

losa

rtan

25up

to10

0m

g/d

CC

B–

amlo

dipi

ne2.

5up

to10

mg/

d

UA

E,A

CR

6A

RB

–U

AE

redu

ced

from

810

mg/

day

to57

0m

g/da

y(P

<0.

001)

.CC

Bno

drop

.Sim

ilar

for

AC

Rsi

gnifi

cant

drop

for

AR

Bns

for

CC

B.N

oco

rrel

atio

nbe

twee

nB

Pan

dU

AE

orA

CR

.Bot

hA

RB

and

CC

Bde

crea

sed

BP

toth

esa

me

degr

ee.

Res

ults

sugg

est

that

regu

lati

ng24

hbl

ood

pres

sure

alon

eis

inad

equa

teto

redu

cem

acro

albu

min

uria

and

addi

tion

alef

fect

sof

AR

B(l

osar

tan)

are

cruc

ialf

oran

tipr

otei

nuri

cac

tion

.


Tab

leA

4Su

mm

ary

ofst

udie

sre

leva

ntto

the

role

ofbl

ood

lipid

profi

les

inC

KD

inin

divi

dual

sw

ith

type

2di

abet

es

Stud

yID

Stud

yde

scri

ptio

nIn

terv

enti

onO

utco

me

(rel

evan

tto

CK

D)

Follo

wup

(mon

ths)

Com

men

ts/c

oncl

usio

ns

Ans

quer

etal

.(2

005)

113

RC

T11

Cen

tres

loca

ted

inC

anad

a,Fi

nlan

d,Fr

ance

and

Swed

enTy

pe2

diab

etes

(40

to65

year

s),n

orm

oor

mic

roal

bum

inur

ia,a

dequ

ate

gluc

ose

cont

rol,

mild

tom

oder

ate

lipid

abno

rmal

itie

s.n

=31

4

Feno

fibra

tevs

Plac

ebo

UA

E(s

econ

dary

tom

ain

stud

y)38

(ave

rage

)Im

prov

emen

tin

lipid

profi

les

was

asso

ciat

edw

ith

redu

ced

prog

ress

ion

from

norm

alto

mic

roal

bum

inur

ia,h

ighe

rre

gres

sion

and

larg

ernu

mbe

rof

pati

ents

wit

hun

chan

ged

albu

min

uria

.The

pers

iste

nce

ofef

fect

afte

rtr

eatm

ent

was

not

asse

ssed

.

Endo

etal

.(2

006)

117

RC

T,op

enst

udy,

Sing

lece

ntre

,Jap

anTy

pe2

diab

etes

,clin

ical

albu

min

uria

(UA

E>3

00m

g/g

Cr)

.102

defin

edas

adva

nced

pati

ents

onth

eba

sis

ofse

rum

Cr

>2.0

mg/

dL.

n=

102

Prob

ucol

(500

mg/

day)

.Pro

tein

rest

rict

ion

diet

.Blo

odgl

ucos

eco

ntro

lto

HbA

1c(<

6.5%

).B

lood

pres

sure

cont

rolw

ith

CC

Bor

a-bl

ocke

r.vs

No

trea

tmen

tPr

otei

nre

stri

ctio

ndi

et.B

lood

gluc

ose

cont

rolt

oH

bA1c

(<6.

5%).

Blo

odpr

essu

reco

ntro

lwit

hC

CB

ora-

bloc

ker.

UA

E36

(max

)28

.5(m

ean

all)

18.6

(mea

nfo

rad

vanc

edca

ses)

Mea

nin

terv

alto

init

iati

onof

haem

odia

lysi

sw

assi

gnifi

cant

lylo

nger

inpr

obuc

olpa

tien

ts.I

nad

vanc

edca

ses

incr

ease

sin

seru

mcr

eati

nine

and

urin

ary

prot

ein

wer

esi

gnifi

cant

ly.

supp

ress

ed.I

nad

vanc

edca

ses

the

haem

odia

lysi

s-fr

eera

tew

assi

gnifi

cant

lyhi

gher

inpr

obuc

olgr

oup.

Sugg

est

prop

ucol

may

supp

ress

the

prog

ress

ion

ofdi

abet

icne

phro

path

y.

Gae

deet

al.

(200

3)63

RC

TTy

pe2

diab

etes

,mic

roal

bum

inur

ian

=16

0

Mul

tifa

ctor

iali

nten

sive

trea

tmen

tvs

Stan

dard

trea

tmen

tU

AE

94(m

ean)

Targ

etdr

iven

long

-ter

min

tens

ified

trea

tmen

tai

med

atm

ulti

ple

risk

fact

ors

redu

ced

neph

ropa

thy

byab

out

50%

.

Kee

chet

al.

(200

5)11

4

Rad

erm

ecke

r&

Sche

en(2

005)

115

RC

TM

ulti

cent

re,m

ulti

coun

try

Type

2di

abet

es,n

otta

king

stat

inth

erap

y.n

=9

795

Feno

fibra

tevs

Plac

ebo

UA

E60

(ave

rage

)R

ate

ofpr

ogre

ssio

nto

albu

min

uria

was

sign

ifica

ntly

redu

ced

byfe

nofib

rate

and

rate

ofre

gres

sion

was

sign

ifica

ntly

incr

ease

d.H

owev

er,

the

diffe

renc

esin

term

sof

num

bers

ofpa

tien

tsw

assm

all(

inth

eor

der

of2%

).

Nag

aiet

al.

(200

0)11

6R

CT

Type

2di

abet

esn

=71

Ben

zafib

rate

vsPr

avas

tati

nU

AE

48U

AE

–no

sign

ifica

ntch

ange

over

the

48m

onth

sw

ith

eith

erdr

ug.C

oncl

ude

usef

ulin

prev

enta

tive

trea

tmen

tof

albu

min

uria

and

lipid

low

erin

g.

Nak

amur

aet

al.

(200

1)11

2R

CT,

doub

lebl

ind

Type

2di

abet

es,m

icro

albu

min

uria

,dy

slip

idae

mia

n=

60

Cer

ivas

tati

nvs

Plac

ebo

UA

E6

BP,

HbA

c1no

tsi

gnifi

cant

lyaf

fect

ed.T

otal

chl

and

LDL

chlr

educ

edan

dco

ncom

itan

tde

crea

sein

UA

E.

Nis

him

ura

etal

.(2

001)

135

RC

TM

ulti

cent

re,J

apan

Type

2di

abet

es,n

orm

oan

dm

icro

albu

min

uric

n=

168

AC

EiPr

obuc

olvs

Plac

ebo

UA

E24

AC

Eiha

sa

bene

ficia

leffe

ctan

dpr

obuc

olm

ayha

vea

bene

ficia

leffe

ctin

prev

enti

ngth

epr

ogre

ssio

nof

earl

ydi

abet

icne

phro

path

y.

Soro

fet

al.

(200

6)11

1R

CT,

doub

lebl

ind,

para

llelg

roup

Mul

tice

ntre

,Sw

eden

Type

2di

abet

es,d

yslip

idae

mia

(fas

ting

LDL-

C>3

.3m

mol

/L)

>18

year

s(a

ctua

l65

year

sav

erag

e),e

xclu

sion

sin

clud

ed–

neph

roti

csy

ndro

me,

seve

rere

nal

dysf

unct

ion,

unco

ntro

lled

hype

rten

sion

.n

=34

4

Ros

uvas

tati

n–

10m

gw

ith

titr

atio

nup

to40

mg

vsA

torv

asta

tin

–10

mg

wit

hpo

ssib

leti

trat

ion

to80

mg

UA

E,G

FR6

wee

ksru

nin

4m

onth

trea

tmen

t.N

och

ange

from

base

line

UA

Efo

rei

ther

trea

tmen

tgr

oup,

nosi

gnifi

cant

chan

gein

GFR

for

eith

ertr

eatm

ent

grou

p.

The

Hea

rtPr

otec

tion

Stud

y(2

003)

108

RC

TM

ulti

cent

re,U

KTy

pe1

diab

etes

(10%

)an

dty

pe2

diab

etes

(90%

)59

63–

Dia

bete

s11

307

–N

odi

abet

es

Sim

vast

atin

(40

mg/

day)

vsPl

aceb

oPl

asm

acr

eati

nine

,eG

FR(r

etro

spec

tive

ly)

60A

lloca

tion

tosi

mva

stat

inw

asas

soci

ated

wit

ha

sign

ifica

ntly

smal

ler

fall

ineG

FRov

erth

etr

ial

peri

od(5

.9m

L/m

invs

6.7

mL/

min

)an

dw

assl

ight

lyla

rger

amon

gth

ose

wit

hdi

abet

es.


Tab

leA

5Su

mm

ary

ofst

udie

sre

leva

ntto

the

asse

ssm

ent

ofth

ero

leof

diet

ary

fat

Stud

yID

Stud

yde

scri

ptio

nIn

terv

enti

onO

utco

me

(rel

evan

tto

CK

D)

Follo

wup

(mon

ths)

Com

men

ts/c

oncl

usio

ns

Bar

nard

etal

.(2

006)

136

RC

TTy

pe2

diab

etes

n=

99

Low

Fat

Veg

anvs

AD

Adi

etU

AE

5U

AE

grea

ter

redu

ctio

nin

vega

ndi

et.A

lso

impr

oved

glyc

aem

ican

dlip

idco

ntro

l.

Car

dena

set

al.

(200

4)11

8Pr

ospe

ctiv

eco

hort

Popu

lati

onba

sed,

mul

tice

ntre

Type

1di

abet

es,t

ype

2di

abet

esn

=19

2

AC

R84

Nor

moa

lbum

inur

iaan

dne

phro

path

yre

gres

sion

inw

ell-

cont

rolle

ddi

abet

esin

peop

lew

ith

long

term

diab

etes

dura

tion

are

asso

ciat

edw

ith

grea

ter

PUFA

cons

umpt

ion

and

less

erSF

Aco

nsum

ptio

n,sp

ecifi

cally

high

erPU

FA/S

FAan

dM

UFA

/SFA

rati

os–

the

oppo

site

patt

ern

isas

soci

ated

wit

hpr

ogre

ssio

nof

neur

opat

hy.

Nic

hols

onet

al.

(199

9)13

7R

CT

Type

2di

abet

esn

=11

Low

fat

vega

nvs

Con

vent

iona

llow

fat

UA

E3

No

sign

ifica

ntef

fect

onU

AE.

Nie

lsen

etal

.(1

995)

138

Bef

ore

and

afte

rcr

oss

over

.Pse

udo

rand

omiz

edtr

ial.

Type

2di

abet

es,p

ersi

sten

tm

icro

albu

min

uria

n=

10

Die

tri

chin

MU

Fvs

Rec

omm

ende

dhi

ghca

rboh

ydra

tedi

et

UA

E3

wee

ksN

oef

fect

onU

AE.

How

ever

apo

tent

ialb

enefi

cial

effe

cton

LDL/

HD

Lra

tio

was

dete

cted

.

Shim

izu

etal

.(1

995)

139

Bef

ore

and

afte

rno

n-ra

ndom

ized

tria

l.C

ompa

rati

vest

udy

usin

gpa

tien

tsgr

oupe

dac

cord

ing

toal

bum

inur

icst

atus

.Ty

pe2

diab

etes

n=

115

Eico

sape

ntae

noic

acid

ethy

l(EP

A-E

)(p

rese

ntin

cod

liver

oil)

AC

R12

Impr

oved

incr

ease

dal

bum

inex

cret

ion

inty

pe2

diab

etes

wit

hne

phro

path

yan

dth

eef

fect

sw

ere

sust

aine

dat

leas

t12

mon

ths

afte

rth

est

art

oftr

eatm

ent.


Tab

leA

6Su

mm

ary

ofst

udie

sre

leva

ntto

the

asse

ssm

ent

ofth

ero

leof

prot

ein

rest

rict

ion

Stud

yID

Stud

yde

sign

Inte

rven

tion

Out

com

e(r

elev

ant

toC

KD

)Fo

llow

up(m

onth

s)C

omm

ents

/con

clus

ions

Bar

sott

iet

al.

(199

8)14

0R

CT

Type

1di

abet

es,t

ype

2di

abet

esw

ith

chro

nic

rena

lfai

lure

n=

32

Low

prot

ein

diet

vsFr

eeR

esid

ualr

enal

func

tion

62.4

(med

ian)

Stud

yco

nfirm

sth

epr

otec

tive

effe

ctof

low

prot

ein

diet

son

neph

ropa

thy

inth

eab

senc

eof

any

sign

ofpr

otei

nm

alnu

trit

ion.

deM

ello

etal

.(2

006)

141

Bef

ore

and

afte

r–

rand

omor

der

ofdi

etC

ross

over

Type

2di

abet

es,m

acro

albu

min

uric

n=

17

Chi

cken

(CD

)La

ctov

eget

aria

nLo

wPr

otei

n(L

PD)

vsU

sual

(UD

)

GFR

,UA

E4

wk

for

each

diet

Wit

hdra

win

gre

dm

eat

from

diet

redu

ces

UA

Era

te.

Dus

sole

tal

.(2

005)

121

RC

T(u

nblin

ded)

Sing

lece

ntre

Type

1di

abet

esan

dty

pe2

diab

etes

Inci

pien

tor

over

tne

phro

path

yan

dm

ildre

nalf

ailu

re,S

tric

tB

Pco

ntro

lus

ing

AC

Eior

AR

Bn

=63

Low

prot

ein

vsU

sual

prot

ein

(pro

vide

dno

tgr

eate

rth

an1.

2g/

kgpe

rda

y)

GFR

,UA

E24

The

low

prot

ein

diet

did

not

alte

rth

eco

urse

ofG

FRor

UA

E.T

heim

pact

ofa

low

prot

ein

diet

inpr

even

ting

the

prog

ress

ion

ofdi

abet

icne

phro

path

y,if

any,

issm

all.

Gro

sset

al.

(200

2)14

2R

CT,

cros

sov

erTy

pe2

diab

etes

,nor

mo

orm

icro

albu

min

uric

n=

28

Low

prot

ein

Chi

cken

(no

red

mea

t)vs

Usu

aldi

et

GFR

,UA

E1/

1w

ith

1w

asho

utbe

twee

nN

orm

oalb

umin

uric

–bo

thLP

and

chic

ken

redu

ced

UA

Eco

mpa

red

wit

hno

rmal

diet

.M

icro

albu

min

uric

–on

lych

icke

nre

duce

dU

AE

com

pare

dw

ith

norm

aldi

et.

Mel

onie

tal

.(2

004)

143

RC

T,pr

ospe

ctiv

eN

ephr

olog

you

tpa

tien

ts,8

0w

ith

DK

D(2

4ty

pe1

diab

etes

,56

type

2di

abet

es)

n=

169

Low

prot

ein

diet

vsFr

eepr

otei

ndi

etR

enal

func

tion

12Si

gnifi

cant

slow

ing

ofth

epr

ogre

ssio

nof

kidn

eyda

mag

ew

ason

lyob

serv

edin

non-

diab

etic

s.

Pijls

etal

.(1

999)

144

RC

TTy

pe2

diab

etes

,mic

roal

bum

inur

ian

=12

1

Cou

nsel

ling

onpr

otei

nre

stri

ctio

nvs

Usu

alad

vice

UA

E6

and

12A

t6

mon

ths

expe

rim

enta

lgro

upha

dsi

gnifi

cant

ly.L

ower

prot

ein

inta

kean

dsi

gnifi

cant

ly.L

ower

UA

E.A

t12

mon

ths

diffe

renc

esbe

twee

ngr

oups

had

decr

ease

d.

Pijls

etal

.(2

002)

145

RC

TTy

pe2

diab

etes

,mic

roal

bum

inur

ian

=13

1

Die

tary

coun

selli

ng–

prot

ein

rest

rict

ion

vsU

sual

diet

ary

advi

ce

GFR

,UA

E281

7Pr

otei

nin

take

betw

een

grou

psat

follo

wat

6m

onth

sdi

ffere

dby

only

0.08

g/kg

per

day.

No

diffe

renc

esby

end

oftr

ial.

Wit

hin

the

inte

rven

tion

grou

pin

divi

dual

sw

ith

redu

ctio

nof

atle

ast

0.2

mg/

kgpe

rda

ypr

otei

nco

mpa

red

wit

hco

ntro

lsw

ith

noch

ange

–sh

owed

non-

sign

ifica

ntly

diffe

renc

ein

GFR

.Con

clud

eth

atpr

otei

nre

stri

ctio

nis

neit

her

feas

ible

oref

ficac

ious

.

Pom

erle

auet

al.

(199

3)14

6R

CT,

cros

sov

erTy

pe2

diab

etes

,nor

mot

ensi

ven

=12

3w

eek

mod

erat

epr

otei

nvs

3w

eek

high

prot

ein

UA

E,G

FR,c

reat

inin

ecl

eara

nce

3w

eeks

/3w

eeks

Mod

erat

edi

etre

duce

dth

eU

AE,

GFR

,pr

otei

nuri

aan

dcr

eati

nine

clea

ranc

ew

itho

utad

vers

ely

affe

ctin

ggl

ycae

mic

cont

rol.

Hig

hpr

otei

ndi

etin

duce

dsm

allc

hang

esin

rena

lfu

ncti

on.

Teix

eira

etal

.(2

004)

147

Bef

ore

and

afte

rcr

oss

over

.R

ando

mor

der

ofin

terv

enti

ons

Type

2di

abet

esn

=14

Isol

ated

soy

prot

ein

vsC

asei

nU

AE

2/2

wit

h1

lead

inan

dw

ash

out

UA

Esi

gnifi

cant

lyre

duce

din

ISP

com

pare

dw

ith

case

in.

Whe

eler

etal

.(2

002)

148

RC

T,cr

oss

over

Type

2di

abet

es,m

icro

albu

min

uric

n=

17

Plan

tba

sed

prot

ein

vsA

nim

alba

sed

prot

ein

GFR

,UA

E1.

5/1.

5N

osi

gnifi

cant

diffe

renc

ebe

twee

nG

FRan

dU

AE.


Tab

leA

7Su

mm

ary

ofst

udie

sre

leva

ntto

the

asse

ssm

ent

ofth

ero

leof

rest

rict

edsa

ltin

take

Stud

yID

Stud

yde

sign

Inte

rven

tion

Out

com

e(r

elev

ant

toC

KD

)Fo

llow

up(m

onth

s)C

omm

ents

/con

clus

ions

Hou

lihan

etal

.(2

000)

149

RC

T–

w.r.

tlo

sart

anan

dpl

aceb

oTy

pe2

diab

etes

,hyp

erte

nsiv

e,m

icro

albu

min

uric

n=

17

Low

sodi

umvs

Nor

mal

sodi

umU

AE

1/1

Low

salt

ampl

ified

both

anti

-hyp

erte

nsiv

ean

dan

ti-p

rote

inur

icef

fect

sof

losa

rtan

and

nosi

gnifi

cant

effe

ctin

the

plac

ebo.

Hou

lihan

etal

.(2

002)

150

RC

TTy

pe2

diab

etes

,UA

E10

–200

mg/d

ay,h

yper

tens

ion

n=

21

Losa

rtan

+lo

wan

dhi

ghsa

ltvs

Plac

ebo

+lo

wan

dhi

ghsa

lt

TG

F-be

ta(u

rine

),U

AE

1/1

The

AR

Bno

tso

dium

rest

rict

ion

redu

ced

urin

ary

TG

F-be

ta.

Hou

lihan

etal

.(2

002)

151

RC

TTy

pe2

diab

etes

,UA

E10

–200

mg/d

ayn

=20

Losa

rtan

+lo

wan

dhi

ghsa

ltvs

Plac

ebo

+lo

wan

dhi

ghsa

lt

AC

R1/

1A

CR

inlo

sart

angr

oup

decr

ease

dsi

gnifi

cant

lyw

ith

low

salt

.No

sign

ifica

ntly

chan

ges

inpl

aceb

ogr

oup.

Dem

onst

rate

da

low

-sod

ium

diet

pote

ntia

tes

the

anti

hype

rten

sive

and

anti

prot

einu

ric

effe

cts

oflo

sart

an.

Iman

ishi

etal

.(2

001)

152

Bef

ore

and

afte

rcr

oss

over

Type

2di

abet

es–

norm

oto

mac

roal

bum

inur

ia,n

orm

alle

vels

ofse

rum

crea

tini

nen

=32

Sodi

umre

stri

cted

diet

vsN

orm

also

dium

diet

.U

AE

1w

eek/

1w

eek

Sodi

umse

nsit

ivit

yof

bloo

dpr

essu

reap

pear

sbe

fore

hype

rten

sion

and

isre

late

dto

albu

min

uria

.

Ved

ovat

oet

al.

(200

4)15

3B

efor

ean

daf

ter

Type

2di

abet

esC

ase

–m

icro

albu

min

uria

Con

trol

–no

rmoa

lbum

inur

ian

=42

Red

uced

salt

vsH

igh

salt

UA

E1

wee

kH

igh

salt

incr

ease

dB

Pan

dU

AE.

Yosh

ioka

etal

.(1

998)

154

Cro

ssov

erra

ndom

izat

ion

islim

ited

toth

eor

der

ofdi

etTy

pe2

diab

etes

,nor

mo

tom

acro

albu

min

uria

.n

=19

Sodi

umre

stri

cted

diet

vsN

orm

also

dium

diet

.C

alcu

late

dIg

Gan

dal

bum

infr

acti

onal

clea

ranc

es.

1w

eek/

1w

eek

Cha

rge

sele

ctiv

ity

islo

stbe

fore

size

sele

ctiv

ity

asdi

abet

icne

phro

path

ypr

ogre

sses

.


Tab

leA

8Su

mm

ary

tabl

esof

stud

ies

ofsm

okin

gas

risk

fact

orfo

rth

ede

velo

pmen

tan

dpr

ogre

ssio

nof

CK

Din

peop

lew

ith

type

2di

abet

es

Stud

yID

Stud

yde

sign

Out

com

e(r

elev

ant

toC

KD

)Fo

llow

up(m

onth

s)C

omm

ents

/con

clus

ions

Ana

net

al.

(200

7)15

5C

ross

sect

iona

l.Ty

pe2

diab

etes

prem

enop

ausa

lw

omen

,n

=20

/35

(Sm

oker

s/no

n-sm

oker

s)

UA

EU

AE

was

inde

pend

entl

yas

soci

ated

wit

hcu

rren

tsm

okin

gsu

gges

ting

smok

ing

asa

risk

fact

orfo

rde

velo

pmen

tof

incr

ease

dU

AE.

Bag

gio

etal

.(2

002)

156

Cro

ssse

ctio

nal

Type

2di

abet

esw

ith

abno

rmal

AER

n=

96

UA

E,G

FR,G

BM

wid

thSm

okin

gaf

fect

sgl

omer

ular

stru

ctur

ean

dfu

ncti

onin

type

2di

abet

esan

dm

aybe

anim

port

ant

fact

orfo

rth

eon

set

and

prog

ress

ion

ofdi

abet

icne

phro

path

y.

Bia

rnes

etal

.(2

005)

132

Pros

pect

ive

coho

rtTy

pe2

diab

etes

,hig

hch

oles

tero

ln

=93

0

Alb

umin

uria

24O

Rfo

rsm

oker

and

deve

lopm

ent

ofm

icro

albu

min

uria

3.19

(1.0

2–9.

96).

Bru

noet

al.

(199

6)26

Cro

ssse

ctio

nal

Type

2di

abet

esn

=15

74

UA

ESm

okin

gha

bits

are

inde

pend

entl

yre

late

dto

both

mic

roan

dm

acro

albu

min

uria

.

Ced

erho

lmet

al.

(200

5)13

1Pr

ospe

ctiv

eco

hort

Type

2di

abet

esan

dty

pe1

diab

etes

4097

(typ

e1

diab

etes

)65

13(t

ype

2di

abet

es)

Alb

umin

uria

60Sm

okin

gid

enti

fied

asan

inde

pend

ent

risk

fact

orfo

res

tabl

ishe

dm

icro

albu

min

uria

and

for

the

deve

lopm

ent

ofm

icro

albu

min

uria

.

Chu

ahir

unet

al.

(200

3)13

0Pr

ospe

ctiv

eco

hort

Type

2di

abet

esun

derg

oing

BP

cont

rol

n=

84

Plas

ma

crea

tini

ne,

UA

E64

Smok

ing

and

incr

ease

dU

AE

are

inte

rrel

ated

pred

icto

rsof

neph

ropa

thy

prog

ress

ion

and

smok

ing

incr

ease

sU

AE

inpa

tien

tsde

spit

eim

prov

edB

Pco

ntro

land

AC

Ein

hibi

tion

.

Chu

ahir

unet

al.

(200

4)12

9Pr

ospe

ctiv

eco

hort

Type

2di

abet

esw

ith

and

wit

hout

mac

roal

bum

inur

ia.S

mok

ing

cess

atio

nin

type

2di

abet

esm

icro

albu

min

uria

n=

237

Uri

neex

cret

ion

ofT

GFb

etaV

,UA

E6

Cig

aret

tesm

okin

gex

acer

bate

sre

nal

inju

ryde

spit

eB

Pco

ntro

land

AC

Ei–

cess

atio

nby

thos

ew

ith

mic

roal

bum

inur

iaam

elio

rate

sth

epr

ogre

ssiv

ere

nali

njur

yca

used

byco

ntin

uals

mok

ing.

Cor

radi

etal

.(1

993)

157

Cro

ssse

ctio

nal

Type

2di

abet

es,h

yper

tens

ive,

mal

esn

=90

UA

ET

hede

term

inan

tsof

ade

crea

sein

UA

Eaf

ter

lisin

opri

ltre

atm

ent

wer

eth

edu

rati

onof

hype

rten

sion

inno

n-sm

oker

san

dda

ilyto

bacc

oco

nsum

ptio

nan

ddu

rati

onof

smok

ing

insm

oker

s.Sm

okin

gm

aybe

anin

depe

nden

tde

term

inan

tof

mic

roal

bum

inur

iain

hype

rten

sive

indi

vidu

als.

Dea

net

al.

(199

4)15

8C

ross

sect

iona

lTy

pe2

diab

etes

,nor

mot

ensi

ven

=87

UA

ER

elat

ions

hip

ifan

ybe

twee

nsm

okin

gan

dU

AE

not

stat

edin

abst

ract

.


Tab

leA

8C

ontin

ued

Stud

yID

Stud

yde

sign

Out

com

e(r

elev

ant

toC

KD

)Fo

llow

up(m

onth

s)C

omm

ents

/con

clus

ions

Fors

blom

etal

.(1

998)

125

Ret

rosp

ecti

veco

hort

Type

2di

abet

esn-

134

UA

E10

8T

here

was

anov

er-r

epre

sent

atio

nof

smok

ers

(55%

vs27

%;P

=0.

01)

inpe

ople

who

prog

ress

edto

mic

ro-

orm

acro

albu

min

uria

vsth

ose

who

did

not

prog

ress

.

Gam

baro

etal

.(2

001)

126

Ret

rosp

ecti

veco

hort

Ital

yTy

pe2

diab

etes

n=

273

AER

,ser

umcr

eati

nine

.36

Logi

stic

regr

essi

on–

smok

ing

was

the

mos

tim

port

ant

risk

fact

orfo

rpr

ogre

ssio

nof

neph

ropa

thy.

Qui

ttin

gsm

okin

gsh

ould

bepa

rtof

the

prev

enti

onth

erap

y.

Gat

ling

etal

.(1

988)

159

Cro

ssse

ctio

nal

Type

2di

abet

esn

=84

2

UA

E,A

CR

Sign

ifica

ntas

soci

atio

nfo

und

betw

een

UA

Ean

dsm

okin

gca

tego

ry.

Iked

aet

al.

(199

7)16

0C

ross

sect

iona

lTy

pe2

diab

etes

–m

enn

=14

8

AC

RO

Rfo

rth

epr

eval

ence

ofm

icro

/mac

roal

bum

inur

iaw

assi

gnifi

cant

lyhi

gher

for

smok

ers

than

exsm

oker

s.

Nils

son

etal

.(2

004)

161

Cro

ssse

ctio

nal

Type

1di

abet

esan

dty

pe2

diab

etes

Hos

pita

ls,p

rim

ary

heal

thca

ren3

1700

0ty

pe2

diab

etes

Alb

umin

uria

Smok

ing

was

asso

ciat

edw

ith

poor

glyc

aem

icco

ntro

land

mic

roal

bum

inur

ia.

Pijls

etal

.(2

001)

162

Cro

ssse

ctio

nal

Type

2di

abet

es–

prim

ary

care

pati

ents

n=

335

AC

RSm

okin

gin

depe

nden

tly

asso

ciat

edw

ith

AC

R.

Sava

geet

al.

(199

5)16

3C

ross

sect

iona

lTy

pe2

diab

etes

wit

hap

prop

riat

eB

Pco

ntro

ln

=93

3

UA

ET

hem

ost

sign

ifica

ntpr

edic

tors

ofm

icro

and

mac

roal

bum

inur

iaw

ere

syst

olic

hype

rten

sion

,BM

I,H

DL,

insu

linus

ean

dsm

okin

gpa

ckye

ars.

Smul

ders

etal

.(1

997)

127

Pros

pect

ive

coho

rtTy

pe2

diab

etes

wit

hm

icro

albu

min

uria

n=

58

AC

R24

Smok

ing

was

not

asi

gnifi

cant

pred

icto

rof

the

prog

ress

ofal

bum

inur

ia.

Tho

mas

etal

.(2

006)

164

Cro

ssse

ctio

nTy

pe2

diab

etes

Chi

nese

mal

esn

=49

6

AC

RA

CR

elev

ated

insm

oker

s.Sm

okin

gw

asas

soci

ated

wit

ha

mor

ead

vers

em

etab

olic

profi

lean

dpe

riph

eral

vasc

ular

dise

ase.

Mal

esm

oker

sco

mpa

red

wit

hne

ver

smok

ers

had

low

erH

DL-

chol

este

roll

evel

s(1

.121

0.31

vs1.

201

0.30

mm

ol/L

,P

=0.

006)

,and

elev

ated

albu

min

-to

-cre

atin

ine

rati

o(3

.57

(2.6

8–4.

75)

vs2.

47(1

.99–

3.05

)m

g/m

mol

,P

=0.

040)

.


Prevention and management of chronic kidney disease in type 2 diabetes

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Transcript of Prevention and management of chronic kidney disease in type 2 diabetes