OTHER COMPLICATIONS OF DIABETES

Diabetic nephropathyStephen Thomas

AbstractDiabetic nephropathy is a major cause of morbidity and mortality in both

type 1 and type 2 diabetes. This is principally from coronary artery and

other forms of cardiovascular disease, and particularly from heart failure,

the incidence of which is about 15-fold greater in patients with diabetic

kidney disease. Suboptimal glycaemic control and a higher blood pres-

sure are particularly important risk factors for the development of diabetic

nephropathy. The disease can be detected in most cases many years

before the development of advanced renal failure through the detection

of raised urinary albumin excretion e microalbuminuria. This allows

time for the intensive treatment of glycaemic control, blood pressure

and other cardiovascular risk factors, such as lipids, to reduce the

morbidity and mortailty. Despite this, diabetes remains the single most

common cause of end-stage renal failure.

Keywords diabetic nephropathy; end-stage renal failure; glycaemic

control; microalbuminuria

Definition and detection

By convention, diabetic nephropathy is defined as the appear-

ance of persistent ‘clinical’ albuminuria (albumin excretion rate

(AER) >300 mg/24 h) in an individual with diabetes for more

than 5 years and concomitant retinopathy, in the absence of

urinary tract infection (UTI), other renal diseases or heart failure.

This process is often associated with increasing blood pressure.

After initial stabilization of metabolic control, all patients

should be screened for albuminuria at least once per year.

Screening for diabetic nephropathy is usually performed by

measuring the albumin:creatinine ratio (ACR) in a single early-

morning urine sample. Values of 2.5 mg/mmol or more in men,

or 3.5 mg/mmol or more in women are abnormal. An elevated

ACR should be confirmed before the diagnosis of nephropathy is

established.

Epidemiology

In type 1 diabetes, the most common cause of kidney damage is

classical diabetic nephropathy. Kidney disease is relatively rare

in the first 5e10 years, but the incidence increases rapidly over

the next 10 years, to a peak of about 3% per year after 15 years. It

then declines to about 1% per year in patients with type 1 dia-

betes of 40 years duration or more. Those with diabetes for more

than 35 years who have not yet developed kidney disease are at

low risk of doing so. This pattern suggests that only some

patients are susceptible to renal disease in diabetes, and provides

strong evidence that a genetic susceptibility combined with the

Stephen Thomas MRCP is Consultant Physician at Guy’s and St Thomas’

Foundation Trust, London, UK. Competing interests: none declared.

MEDICINE 38:12 639

cumulative effect of hyperglycaemia is necessary. A family

history of diabetic kidney disease, or indeed a parental history of

cardiovascular disease or hypertension, increases the risk of

diabetic kidney disease in the individual with type 1 diabetes.

In type 2 diabetes, classical diabetic kidney disease also

occurs, but in an older population other kidney diseases,

particularly hypertensive ischaemic damage, are more common

and kidney disease in those with type 2 diabetes may have

atypical features.

Classical diabetic kidney disease in type 2 diabetes often

occurs in younger individuals, and may be accompanied by

retinopathy and progression from microalbuminuria to overt

proteinuria.

In older individuals with type 2 diabetes, retinopathy and

proteinuria may be absent or minimal. Although other renal

diseases should be considered and excluded, the kidney lesion is

often related to hypertension or glomerular ischaemia and its

treatment is largely the same.

The cumulative risk of nephropathy in type 2 diabetes varies

with ethnic origin, ranging from 25% in those of European origin

to about 50% in other ethnic groups (e.g. Afro-Caribbeans,

Asian-Indians, Japanese). Those of African, Caribbean or Asian-

Indian origin may develop type 2 diabetes more commonly and

at a younger age.

Type 2 diabetes is more common than type 1, and in some

areas the number of patients with type 2 diabetes requiring renal

replacement therapy (dialysis or transplantation) exceeds that in

type 1. Worsening glycaemic control, higher blood pressure,

smoking and adverse lipid profile are risk factors for diabetic

nephropathy in both type 1 and type 2 diseases.

Clinical course

Diabetic nephropathy is a multi-stage condition that takes several

years to become clinically overt (Figure 1). At the onset of dia-

betes, there are usually changes in renal function, such as

glomerular hyperfiltration, increased renal blood flow and

hypertrophy of the kidney. Most of these changes can be reversed

at an early stage by good glycaemic control, but in many patients

they persist and may be important in the later development of

clinical nephropathy.

Microalbuminuria

In the past, the definition of diabetic nephropathy was dictated by

the lower limit of detection of available urinary albumin assays.

Development of sensitive assays enabled detection of previously

undetectable sub-clinical increases in urinary albumin excretion,

which were termed ‘microalbuminuria’. This is the first indication

of diabetic nephropathy, and is defined as a persistent increase (at

least two of three consecutive, urine specimens) in urinary AER to

20e200 mg/min (30e300 mg/day). It may be detected 1 year after

the onset of diabetes in post-pubertal patients with type 1 disease,

and at diagnosis in type 2. There is significant structural glomer-

ular disease even at this early phase, and the glomerular filtration

rate (GFR) starts to decline during the phase of microalbuminuria,

though it may remain within the normal range until the AER

approaches 200 mg/min (300 mg/day).

Microalbuminuria is also strongly predictive of death from

cardiovascular disease, particularly in older patients with type 2

� 2010 Published by Elsevier Ltd.

Natural history of diabetic nephropathy

Duration of diabetes (years)

0 5 10 15 20

Glomerular filtration rate

Serum creatinine

End-stage renal failure

Proteinuria ≥ 200 μ?g/minute

Microalbuminuria ≥ 20–< 200 ?μg/minute

Figure 1

HbA and mean arterial pressure are raised in microalbuminuria in type 1 diabetes

Alb

um

in e

xcre

tio

n r

ate

( μg

/min

ute

)

Me

an

art

eri

al

pre

ssu

re

(mm

Hg

)

Hb

A (

%)

0

60

30

20

0

8

50

40

120

110

100

90

80

13

12

11

10

9

10

12 24 36 48 60 72 84 96

OTHER COMPLICATIONS OF DIABETES

diabetes (Figure 2). Furthermore, in those with type 1 diabetes

who develop microalbuminuria after a very long duration of

disease, it is more a predictor of cardiovascular than progressive

renal disease.

Microalbuminuria is also associated with retinopathy,

peripheral vascular disease and neuropathy.

In type 1 diabetes, blood pressure increases in this phase

(Figure 3), and lipid abnormalities, including increased low-

density lipoprotein cholesterol, total triglycerides and apolipo-

protein B, and reduced high-density lipoprotein (subclass 2)

cholesterol, develop. These progressive abnormalities are seen in

both type 1 and type 2 diabetes, though in the latter they often

Diabetic nephropathy is associated with cardiovascular mortality in type 2 diabetes

Source: Adler et al. Kidney Int 2000; 63: 225–32.

Normal albumin excretion

Microalbuminuria

Overt proteinuria

Elevated plasma creatinine

or renal replacement therapy

Death

2.0%

2.8%

1.4%

3.0%

4.6%

19.2%

2.3%

Figure 2

Source: Microalbuminuria Collaborative Study Group. Diabet Med 1999; 16: 918.

Months

Progressors Non-progressors

Figure 3

MEDICINE 38:12 640

occur on a background of pre-existing hypertension and dysli-

pidaemia. Microalbuminuria is also associated with generalized

endothelial dysfunction in both type 1 and type 2 diabetes.

Persistent albuminuria

An increase in AER to persistently more than 200 mg/min (>300

mg/day) marks the onset of clinically defined ‘overt diabetic

nephropathy’ and is a harbinger of renal failure and cardiovas-

cular complications in both types of diabetes. Blood Pressure

rises progressively in this phase in both type 1 and type 2

diabetes.

Over time, the protein loss may increase to >3e4 g/day and

occasionally lead to nephrotic syndrome with hypo-

albuminaemia, hypercholesterolaemia and peripheral oedema,

although this is less common. As proteinuria rises the urine

protein:creatinine ratio (PCR) is measured more than the ACR as

the proteinuria becomes less selective. The heavier the protein-

uria, particularly if this exceeds 2e3 g/day, carries a very high

� 2010 Published by Elsevier Ltd.

OTHER COMPLICATIONS OF DIABETES

risk of more rapid loss of GFR. Lipid disturbances and athero-

sclerotic complications are prominent in this phase.

Uraemia

Persistent albuminuria is accompanied by a gradual decline in

GFR; untreated, this eventually leads to uraemia and death after

an average of 7e10 years.

Diabetic retinopathy

Diabetic retinopathy usually accompanies persistent proteinuria,

and its absence should alert health professionals to the possibility

of a non-diabetic cause of the proteinuria. It should be remem-

bered that proteinuria may have a non-diabetic cause. The

absence of other microvascular complications, the presence of

nephrotic syndrome and unusually fast progression are features

that should raise suspicion of non-diabetic kidney disease.

Diagnosis

Normal values are:

� urinary albumin concentration <20 mg/l

� ACR <2.5 mg/mmol in men, <3.5 mg/mmol in women

� AER <20 mg/min

� eGFR often >90 ml/min and always greater than 60 ml/min.

Screening tests (Figure 4)

All patients over the age of 12 years should have their ACR, blood

pressure and eGFR measured at least once per year. Measure-

ment of the ACR in a mid-stream, first-morning urine sample is

a reliable screening method. Alternatively, semi-quantitative

dipstick tests (developed to determine albumin concentration in

the microalbuminuria range) may be used as first-line screening.

It should be remembered that heavy exercise, UTI, acute

illness and cardiac failure can transiently increase the AER.

Confirmation

If the ACR is raised, the test should be repeated. If confirmed in

two of three urine samples tested within 6e12 weeks, this

Screening for renal complications

Annual dipstick urinalysis

Annual albumin:creatinine ratio

Plasma creatinine > 150 mol/litre

Estimated glomerular filtration rate < 50 ml/minute

Refer to diabetes/renal clinic

Positive dipstick protein Negative dipstick protein

Positive dipstick protein

confirmed x 2 (proteinuria)

Urine for albumin:creatinine rati

< 2.5 in men, < 3.5 in women

Annual albumin:creatinine ratio

Figure 4

MEDICINE 38:12 641

establishes the presence of microalbuminuria. The implied

kidney disease can be staged using eGFR (>90 ml/min is stage 1;

60e90 ml/min is stage 2). If the eGFR already confirms stage 3

kidney disease (eGFR <60 ml/min) then the presence of micro-

albuminuria or proteinuria has prognostic significance, indi-

cating a higher risk of renal progression and cardiovascular

disease.

Progression of the albuminuria should be checked usually by

repeated measurements of ACR or, as the proteinuria rises, by

the measurement of PCR in an early morning urine sample,

occasionally timed collections are performed at higher levels

of proteinuria, as the greater the degree of albuminuria the higher

the renal and cardiovascular risk.

In these patients, regular and more frequent check-ups should

be undertaken to assess blood pressure, glycaemic control,

serum lipids, and serum creatinine or eGFR. Timed urine

collections are only occasionally performed nowadays. As

proteinuria rises and becomes less selective, measurement of

protein:creatinine ratio is the preferred measurement.

Management

Glycaemic control

Good glycaemic control can prevent diabetic nephropathy in

both type 1 and type 2 diabetes and there is evidence that, once

microalbuminuria has developed, good glycaemic control slows

the progression of the kidney lesion.

In type 1 diabetes, improved blood glucose control and

intensified insulin treatment reduce histological worsening of

glomerulopathy in those with microalbuminuria, and worse

glycaemic control is associated with a faster decline in GFR.

There are no conclusive data on the effects of good glycaemic

control on the progression of established kidney disease in type 2

diabetes, but this should also be achieved and maintained.

Once renal function is impaired, renally excreted sulphony-

lureas, such as glibenclamide, glipizide and glimepiride, must

not be used.

o

> 2.5 in men, > 3.5 in women

Confirm within 3–6 months x 2 (microalbuminuria)

Start renin–angiotensin inhibitor

or

Refer to diabetes clinic as appropriate

� 2010 Published by Elsevier Ltd.

OTHER COMPLICATIONS OF DIABETES

Guidelines for metformin vary. In advanced renal failure met-

formin carries the risk of potentially life-threatening lactic

acidosis. Nowadays this mostly happens in the context of acute

kidney injury on the background of chronic kidney disease.

Caution should be exercised in all those with an eGFR<45ml/min

and the risk/benefit ratio of using the drug considered particularly

in those with a previous history of acute kidney injury.1 Having

assessed the risk, metformin may be continued provided eGFR

does not fall below 30 ml/min. It is important to consider

temporary discontinuation of the drug during illnesses that can

lead to dehydration, such as nausea and diarrhoea or vomiting, as

these acute illnesses carry a higher risk of acute kidney injury.

Glitazones, gliptins and injectable incretin therapy are not

currently licensed at eGFR <30e40 ml/min. There have been

sporadic reports of an acute kidney injury with exenatide, one of

the injectable incretins.

Insulin clearance through the kidney starts to fall when eGFR

<30 ml/min (stage 4 kidney disease), and the risk of hypo-

glycaemia increases progressively. This may be compounded by

reduced appetite and worsening nutritional status.

Blood pressure

Raised blood pressure has particularly damaging consequences

for the kidney, heart and retina. Current recommendations

suggest that blood pressure should be lowered to 130/80 mm Hg

or less (although in younger patients especially in type 1 diabetes

a blood pressure less than 125/80 mmHg is desirable to reduce

proteinuria further) in those with microalbuminuria or overt

clinical nephropathy.2 Non-pharmacological interventions such

as dietary and lifestyle changes (e.g. restriction of salt and

alcohol intake, weight reduction, increased exercise) are impor-

tant, though most patients require anti-hypertensive agents

(often more than one) to achieve target blood pressures. Tighter

blood pressure control in the elderly or those with evidence of

heart disease may be associated with increased risk, and

lowering systolic blood pressure below 120 mm Hg in these

individuals affords no extra benefit.

First-line treatment is usually with an inhibitor of the

renineangiotensin system. These agents are effective blood

pressure-lowering agents in those with diabetic nephropathy and

are more anti-proteinuric than other classes of agents. Overall,

these agents reduce renal and cardiovascular risks, as well as

disease progression. The evidence-base is different in type 1 and

type 2 diabetes but the benefits appear similar in both.

First-line treatment in those with microalbuminuria or dia-

betic nephropathy in both type 1 and type 2 diabetes is usually an

angiotensin converting-enzyme (ACE) inhibitor, though some

authorities favour angiotensin II (AII) receptor antagonists in

those with type 2 diabetes in view of the greater evidence-base.

The renin inhibitor, aliskiren, which also lowers blood pressure

and is anti-proteinuric, may prove useful as a second-line agent.

There is evidence that a combined ACE inhibitor and AII

receptor antagonist therapy may reduce blood pressure and

proteinuria to a greater extent than either agent alone, especially

in those with concomitant heart failure or heavy proteinuria,

though large studies are lacking and long-term safety data are

conflicting.3 After starting ACE inhibitor or AII antagonist

therapy, serum creatinine and potassium should be closely

monitored, especially in patients with peripheral vascular

MEDICINE 38:12 642

disease, because of the possible co-existence of renal artery

stenosis. Hyperkalaemia may be a particular concern in those

with ‘hyporeninaemic pseudohypoaldosteronism e type IV renal

tubular acidosis’ particularly in those with type 1 diabetes.

More than one anti-hypertensive agent is likely to be required.

In type 2 diabetes with microalbuminuria, there is evidence that

the combination of a low-dose thiazide diuretic with

a renineangiotensin system inhibitor may be beneficial.

Serum lipids

From the phase of microalbuminuria, cholesterol and triglycer-

ides may be elevated in both type 1 and type 2 diabetes. Statin

therapy should be considered for all patients with diabetic

nephropathy.

Dietary restriction, weight reduction and improved metabolic

control should be considered in all cases. In type 2 diabetes,

statin therapy should be used to reduce the total cholesterol to

less than 4 and the LDL to less than 2 in the patient with diabetic

nephropathy, and it seems reasonable to extrapolate this to type

1 diabetes with microalbuminuria/overt nephropathy, given the

association with premature cardiovascular disease.

Smoking is associated with the development and progression

of diabetic nephropathy and with cardiovascular disease, and

should be discouraged in all patients.

Protein restriction is controversial, but has been shown to

have a beneficial effect in type 1 diabetes patients with overt

nephropathy. Reduction in animal protein intake to 0.6e0.7

g/kg/day should be considered. Replacement of animal by

vegetable protein sources may also be considered, because

vegetable protein seems to be less damaging to the kidney. An

expert nutritionist should supervise all such treatment, and care

should be taken to minimize any potentially detrimental effects.

No prospective data are available for type 2 diabetes.

Associated complications

Microvascular and macrovascular complications may progress

rapidly in patients with clinical albuminuria. Retinopathy,

neuropathy and atherosclerotic complications should be moni-

tored more often and any abnormalities treated promptly.

Anaemia is common in diabetic nephropathy and may occur at

an earlier stage than in other kidney diseases; this is particularly

the case in type 1 diabetes, and in women.

Nephrological referral

Current guidelines suggest joint treatment by diabetes and renal

specialists in patients whose eGFR is <30 ml/min, where the rate

of progression is unduly fast and where atypical kidney disease is

suspected.

Referral to a joint clinic may be necessary earlier for

management of anaemia.

Late referral

Late referral (within 6 months of the need for renal replacement

therapy) is associated with higher mortality.

Stage 5 kidney disease e end-stage renal failure

The mode of therapy (dialysis or transplantation) depends on

clinical judgement and local facilities and resources. Good

� 2010 Published by Elsevier Ltd.

OTHER COMPLICATIONS OF DIABETES

glycaemic control is important for patients’ well-being before and

during renal replacement therapy and is associated with lower

mortality.

In specialized centres, combined kidney and pancreas trans-

plantation may be considered, mostly for type 1 diabetes.

In stage 5 kidney disease, interpretation of HbA1c, and

particularly fructosamine, may be less reliable, undermining

their use as indices for monitoring diabetes control. HbA1c is

probably preferable, but should be interpreted with caution as

reduced red cell life span may lead to lower values, especially in

those undergoing haemodialysis.

The outcome of renal replacement therapy remains poorer in

patients with diabetic chronic renal failure than in those with

non-diabetic disease. Furthermore, the associated vascular,

neuropathic and infective complications increase the socioeco-

nomic costs of renal replacement therapy in diabetes.

Practice points

C Diabetic nephropathy is associated with much higher cardio-

vascular risk.

C Diabetic nephropathy is characterized by abnormal urinary

protein with rising blood pressure and other microvascular

complications usually retinopathy.

C Worsening glycaemic control, rising blood pressure, higher

LDL cholesterol and triglycerides and family history of kidney/

cardiovascular disease all increase the risk of diabetic

nephropathy.

C Different ethnic groups have different risks.

C Caution with oral hypoglycaemics, especially metformin, in

stage 3 kidney disease or worse.

Pregnancy and proteinuria

Development of microalbuminuria or macroalbuminuria during

pregnancy in a woman with diabetes should alert the physician

to the risk of pre-eclampsia. Pregnancy is no longer contra-

indicated in women with diabetic proteinuria. However,

proteinuria may increase and the risk of eclampsia is increased.

Pre-pregnancy counselling and planning is vital in those with

diabetic nephropathy. The risk of further loss of kidney function

appears to be greatest in those whose eGFR is less than 50 ml/

min at conception or in whom proteinuria is particularly heavy.

Specialist renal pre-pregnancy counselling may be advisable.A

REFERENCES

1 National Collaborating Centre for Chronic Conditions. Type 2 diabetes:

national clinical guideline for management in primary and secondary

care (update). London: Royal College of Physicians, 2008.

2 National Institute for Health and Clinical Excellence. Management of

type 2 diabetes. Renal disease e prevention and early management.

London: NICE, 2002.

MEDICINE 38:12 643

3 Rossing K, Jacobsen P, Pietraszek L, Parving H. Renoprotective effects

of adding angiotensin II receptor blocker to maximal recommended

doses of ACE inhibitor in diabetic nephropathy: a randomized double-

blind crossover trial. Diabetes Care 2003; 26: 2268e74.

FURTHER READING

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nephropathy. Lancet 1998; 352: 213e9.

Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multi-

factorial intervention and cardiovascular disease in patients with type

2 diabetes. N Engl J Med 2003; 348: 383e93.

Heart Outcomes Prevention Evaluation (HOPE) Study Investigators.

Effects of ramipril on cardiovascular and microvascular outcomes in

people with diabetes mellitus: results of the HOPE study and

MICROHOPE substudy. Lancet 2000; 355: 253e9.

Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-convert-

ing-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;

329: 1456e62. The Collaborative Study Group.

Microalbuminuria Collaborative Study Group. Predictors of the develop-

ment of microalbuminuria in patients with type 1 diabetes mellitus:

a seven-year prospective study. Diabet Med 1999; 16: 918.

� 2010 Published by Elsevier Ltd.