Diabetic nephropathy
-
Upload
stephen-thomas -
Category
Documents
-
view
214 -
download
0
Transcript of Diabetic nephropathy
![Page 1: Diabetic nephropathy](https://reader035.fdocuments.in/reader035/viewer/2022080110/575074081a28abdd2e926feb/html5/thumbnails/1.jpg)
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.
![Page 2: Diabetic nephropathy](https://reader035.fdocuments.in/reader035/viewer/2022080110/575074081a28abdd2e926feb/html5/thumbnails/2.jpg)
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.
![Page 3: Diabetic nephropathy](https://reader035.fdocuments.in/reader035/viewer/2022080110/575074081a28abdd2e926feb/html5/thumbnails/3.jpg)
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.
![Page 4: Diabetic nephropathy](https://reader035.fdocuments.in/reader035/viewer/2022080110/575074081a28abdd2e926feb/html5/thumbnails/4.jpg)
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.
![Page 5: Diabetic nephropathy](https://reader035.fdocuments.in/reader035/viewer/2022080110/575074081a28abdd2e926feb/html5/thumbnails/5.jpg)
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
Cooper ME. Pathogenesis, prevention, and treatment of diabetic
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.