JRSM >
Volume 94, Number 5 >
Pp. 210-217
Dialysis Centre, Box 118 Addenbrooke's Hospital, Cambridge CB2 2QQ, UK
Correspondence to: Dr Lukas Foggensteiner E-mail: lukasfoggensteiner{at}ntlworld.com
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TOPINTRODUCTIONTHE STAGES OF DIABETIC...RISK FACTORS FOR DEVELOPMENT...SCREENING FOR DIABETIC...MANAGEMENTCONCLUSIONREFERENCES |
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The association of proteinuria with diabetes was first recognized in the eighteenth century but it was Kimmelstiel and Wilson1 in 1936 who defined the condition by describing the lesions of nodular glomerulosclerosis and the association with proteinuria and hypertension in type 2 diabetes. These features represent a late stage in the progression of the condition. Subsequent work, mainly on type 1 diabetes, led to the definition of several distinct phases in the evolution2 of the disease.
Hyperfiltration
Hyperfiltration, characterized by renal enlargement, intrarenal
hypertension and high glomerular filtration rate (GFR), may be seen early in
the course of
diabetes3. These
haemodynamic phenomena, although partly reversible by glycaemic and blood
pressure control, have been linked with the development of
microalbuminuria4,5.
Early microalbuminuria is usually associated with a raised GFR, and a normal
GFR in this context may indicate that renal function has already been
lost.
Silent phase
Very few patients develop microalbuminuria during the first ten years of
their diabetes (type 2 diabetes may of course remain undiagnosed for many
years and present with advanced disease). During this so-called silent phase
early histological abnormalities in the kidney may be seen, including
glomerular hypertrophy and subtle thickening of the glomerular basement
membrane, best seen by electronmicroscopy.
Microalbuminuria
The normal urinary protein excretion rate is up to 300 mg/24 h, of which
about 10% is albumin, equivalent to an albumin excretion rate of 20 µg/min.
Albumin excretion rates of 20-200 µg/min, equivalent to a urine albumin
creatinine ratio (ACR) of 10-25 mg/mmol, are defined as microalbuminuria (also
called incipient nephropathy) as these levels are not detectable by
conventional urine dipstick analysis (Table
1). The onset of microalbuminuria is highly significant since its
presence predicts the development of overt renal disease in both type 1 and
type 2
diabetes6,7.
Furthermore, microalbuminuria is associated with an increased risk of
cardiovascular and microvascular complications as well as an increase in
all-cause mortality, especially in type 2
diabetes8 (Box 1).
Renal histology at this stage reveals typical glomerulosclerosis. Once
microalbuminuria is established the trend is one of increasing proteinuria
until overt nephropathy develops.
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Overt nephropathy
Albumin excretion rates above 200 µg/min or 300 mg/day (equivalent to an
ACR of >25 mg/mmol) are dipstick positive and defined as overt nephropathy.
This is usually associated with a relentless loss of GFR (by 1-24 mL/min per
year) until end-stage renal failure necessitates dialysis or renal
transplantation. The rate of progression of microalbuminuria and overt
nephropathy is heavily influenced by blood pressure control, diabetic control
and the use of angiotensin converting enzyme (ACE) inhibitors—strategies
that form the cornerstone of management.
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Blood pressure
Hypertension is much more common amongst diabetic patients than in the
general population and has been identified as a major risk factor for both
macrovascular and microvascular complications including diabetic nephropathy.
Total cardiovascular mortality in diabetes is strongly associated with raised
blood pressure, particularly in type 2 disease.
Hypertension is strongly associated with insulin resistance, even in the absence of diabetes, and some 40-70% of type 2 patients will become hypertensive during their disease12. Only 25% of patients with type 1 diabetes are hypertensive and many of these will already have microalbuminuria or overt nephropathy13. Nevertheless, in both type 1 and type 2 diabetes with overt nephropathy the rate of decline of renal function correlates strongly with hypertension14,15, and in microalbuminuric patients hypertension correlates with the degree of albuminuria16. In both these situations antihypertensive therapy is beneficial. Furthermore in normoalbuminuric type 1 diabetes small increases in blood pressure have been correlated with the subsequent development of microalbuminuria17. There can therefore now be little doubt that a raised blood pressure is a risk factor for the development and progression of diabetic nephropathy as well as a potent risk factor for cardiovascular morbidity and mortality.
Glycaemic control
Type 1 and type 2 diabetes have in common the state of chronic
hyperglycaemia, and glucose-dependent processes are likely to be involved in
the pathogenesis of diabetic complications, including nephropathy.
Glucose-induced tissue injury may be mediated by the generation of advanced
glycated proteins or via other mechanisms such as the polyol pathway, both of
which have been implicated in
nephropathy18.
Consistent with this hypothesis are observational studies correlating
haemoglobin A1c (HbA1c) concentration with the development and progression of
microalbuminuria and overt
nephropathy17.
Proteinuria
Proteinuria is generally regarded as a marker for the degree of glomerular
damage: the level of proteinuria correlates well with the prognosis for renal
function, and interventions that retard the progression of diabetic renal
disease also reduce proteinuria. However, we do not yet know whether the flux
of protein across the glomerular basement membrane is causally implicated in
the evolution of diabetic renal disease or simply reflects glomerular
damage19.
Genetic factors
Genetic factors are likely to be important in diabetic nephropathy. Recent
interest has focused on genes of the renin angiotensin system, which are known
to be highly polymorphic and have been extensively studied in relation to
cardiovascular disease. An insertion(1)/deletion(D) polymorphism in the ACE
gene has been identified that is strongly associated with raised circulating
ACE levels and with increased risk of coronary heart disease in non-diabetic
individuals. Some studies have found the DD genotype to be associated with an
increased risk of diabetic nephropathy and a rapid decline of GFR in both type
1 and type 2
diabetes20. The
clinical implications have yet to be explored. Other genetic loci that may be
involved include the sodium—lithium exchanger and the
sodium—hydrogen antiporter genes.
Hyperlipidaemia
Hyperlipidaemia is common in both type 1 and type 2 diabetes. Raised plasma
triglycerides and low levels of highdensity liproproteins (HDL) have been
correlated with the development of diabetic nephropathy as well as with
cardiovascular diabetic
complications9,21,22.
Triglyceride and cholesterol reduction, although important in reducing
cardiovascular risk, has not been found to alter the progression of renal
disease and the importance of hyperlipidaemia remains to be established in
this respect.
Others
Other risk factors for diabetic nephropathy include
smoking23, dietary
protein intake, levels of circulating von Willebrand factor and other plasma
proteins, the presence of other diabetic complications (notably retinopathy),
and non-attendance at follow-up
clinics24.
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Microalbuminuria
Several methods can be used for detection of microalbuminuria. The urinary
albumin/creatinine ratio (ACR) can be determined from a random, or preferably
earlymorning, urine sample. This is often the easiest test in the setting of
primary care and provides a practical screening method less prone to patient
error than timed
collection25,26.
The albumin excretion rate (AER) is more precise and can be measured formally
from any timed collection, most commonly overnight (8 hours)—which is
technically easier for the patient than a 24-hour collection. Recently
developed urine dipstick assays provide a useful initial screening test that
can be performed in the surgery if assays for microalbuminuria are not readily
available. However, they are subject to error from alterations in urine
concentration and all positive tests should be confirmed by more specific
methods.
Microalbuminuria should be diagnosed on the basis of three positive tests—ACR, AER or a combination of the two—over a 3-6 month period. Albumin excretion can vary by as much as 40% and physicians should be aware of potential confounding factors (Box 2) and non-diabetic causes of renal impairment and proteinuria.
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Because microalbuminuria rarely occurs within the first 5-10 years in type 1 diabetes or before puberty, screening should begin with onset of puberty or after 5 years' disease duration. In type 2 diabetes, where the precise onset of the disease cannot be dated, screening should begin at diagnosis27. Annual screening is generally recommended though some groups advocate more frequent testing28. Once microalbuminuria has been identified the patient should have measurements every 3-6 months.
Further investigations
When microalbuminuria has been confirmed, serum creatinine, urea and
electrolytes should be measured at baseline and then yearly or half-yearly.
Haematuria should also be tested for. It is helpful to monitor GFR annually.
Isotopic GFR measurements may not be readily available and are rarely used in
routine practice. Creatinine clearance approximates to GFR and can be measured
by 24-hour urine collection or calculated from serum
creatinine29.
Risk factors associated with the progression of renal disease and/or the development of coronary heart disease (CHD) should be identified early and regular assessment of blood pressure is mandatory. Lipid levels should be checked at baseline and yearly or half-yearly—see Management.
Non-diabetic renal disease
Some groups have proposed a high rate of non-diabetic renal disease in type
2 diabetes but there is no conclusive evidence that complicating renal disease
is more frequent in this group of patients than in the background
population30. Most
patients with diabetes and renal impairment will not require a renal biopsy.
Certain factors raise the suspicion of a non-diabetic renal diagnosis and
referral to a renal physician may then be required (Box 3).
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Hypertension
The beneficial effect of lowering blood pressure, on both progression of
renal disease and overall cardiovascular mortality, is now so well established
that monitoring and control of blood pressure has become a major component of
diabetic care. Current debates centre mainly on the choice of antihypertensive
agents and on blood pressure targets.
The benefit of antihypertensive therapy on declining renal function was first demonstrated in small studies of type 1 diabetes. Mogensen31 reduced the mean blood pressure of a group of type 1 diabetic patients with overt nephropathy from 163/103 to 144/95 mmHg and reported a drop in the monthly decline in GFR from 1.23 to 0.49 mL/min. A larger prospective study in similar patients32,33 demonstrated a decline in the rate of loss of GFR from 0.94 to 0.29 mL/min per month during the first three years of effective antihypertensive treatment and 0.10 mL/min per month over the subsequent 10 years. This was associated with a 50% reduction in albuminuria and an anticipated increase in renal survival from 7 to more than 20 years. Total mortality and progression to end-stage renal disease are also substantially lower in treated than in untreated hypertensive type 1 diabetic patients with renal impairment34.
In both type 1 and type 2 diabetic patients with microalbuminuria, blood pressure reduction also reduces or stabilizes AER35,36 and retards the rate of progression to overt nephropathy.
The overall cardiovascular benefit of intensive control of blood pressure
was illustrated by several recent studies. The United Kingdom Prospective
Diabetes Study
(UKPDS)37 compared
intensive with less intensive blood pressure control in type 2 diabetes,
achieving a mean blood pressure of 144/82 and 154/87 Hg in the two groups,
respectively. Intensive control resulted in a 32% lower mortality,
predominantly from cardiovascular disease, and a reduction in microvascular
complications including the development of microalbuminuria. The Hypertension
Optimal Treatment (HOT)
trial38, which
included a subset of mainly type 2 diabetic patients, compared three
intensities of blood pressure control. Target blood pressures were diastolic
90, 85 and 80 mmHg while achieved blood pressures were 144/85,
141/83 and 140/81 mmHg respectively. Despite the small differences in achieved
diastolic pressure, major cardiovascular events in the 80 mmHg diabetic
subset were only half those in the 90 mmHg group.
Blood pressure targets
Although the level of blood pressure below which further benefit would not
be seen has yet to be firmly defined, the British Hypertension
Society39 has
recommended initiating therapy in diabetic patients with blood pressure >
140/90 mmHg and a target blood pressure of < 140/80, or < 125/75 mmHg in
type 1 diabetic patients with > 1 g/day of proteinuria. The Joint British
Recommendations on the Prevention of Coronary Heart Disease in Clinical
Practice40 suggest
maintaining blood pressure < 130/80 or < 125/75 in type 1 diabetes with
> 1 g/day of proteinuria. The US Joint National Committee on the detection,
evaluation and treatment of high blood
pressure41 has
recommended keeping blood pressure in diabetic patients below 130/85 mmHg.
However, both the UKPDS and the HOT trial have illustrated the difficulty in
achieving such ambitious targets, which require multiple antihypertensive
therapy and good adherence to treatment. In the UKPDS, for example, 27% of
patients in the tight blood pressure control group were prescribed three or
more antihypertensive agents but 44% still had blood pressures of > 150/85
mmHg at the end of the study period. Isolated systolic hypertension,
reflecting reduced vascular compliance, is commonly seen in elderly type 2
diabetic patients. Although difficult to achieve, the benefits of even small
reductions in systolic hypertension are
established42 and
this condition should be actively treated.
In all diabetic patients blood pressure should be monitored at least 6-monthly, and when microalbuminuria develops at least 3-monthly. Instructing patients in self-measurement of blood pressure can be helpful in some circumstances. Borderline or inconsistent readings can be investigated with 24-hour ambulatory blood pressure measurement, but interpretation can be difficult and the utility of this method in clinical practice has yet to be defined.
ACE inhibitors
Although blood pressure reduction with any of the standard antihypertensive
agents (ß-blockers, diuretics, dihydropyridine calcium antagonists,
-blockers) is beneficial, ACE inhibitors exert a renoprotective effect
beyond their antihypertensive properties in some circumstances. A combined
analysis of two large studies of captopril versus placebo in microalbuminuric
type 1 diabetes with controlled hypertension suggested a 63% reduction in
progression to overt proteinuria over 2 years along with a decline in albumin
excretion rate43.
In type 1 diabetic patients with overt nephropathy captopril was associated
with a substantial reduction in the rate of decline in renal function as well
as a 50% reduction in death and end-stage renal disease over a four-year
follow-up44.
However, the preferential use of ACE inhibitors is not supported in type 1
diabetes without
microalbuminuria45.
In type 2 diabetes the evidence for the superiority of ACE inhibitors is less clear. In type 2 patients with microalbuminuria, ACE inhibition has stabilized AER and renal function in some studies46 whereas others (including UKPDS) support the notion that blood pressure reduction per se is more important than the agent used. In the diabetic arm of the Heart Outcomes Prevention Evaluation (HOPE) study47, which compared an ACE inhibitor with placebo in a mixed diabetic population (98% type 2) with controlled blood pressure and with at least one other cardiovascular risk factor, the incidence of myocardial infarction, stroke or cardiovascular death was 25% lower and the progression of microalbuminuria was slowed in the ACE inhibitor group.
In the light of this evidence and their favourable side-effect profile, ACE inhibitors should now be the first-line antihypertensive agent in both type 1 and type 2 diabetes. ACE inhibition is also indicated in non-hypertensive type 1 and type 2 diabetic patients with microalbuminuria or overt nephropathy48, the dose being increased until AER falls into the normal range or hypotension develops. The main side-effect of ACE inhibitors is cough, which may limit use. Although up to 60% of type 2 diabetic patients have radiological evidence of atheromatous renovascular disease, acute reduction of GFR is seldom observed with ACE inhibitors; this effect, and hyperkalaemia, should be screened for by measuring serum creatinine and electrolytes shortly after the start of treatment and 6-monthly thereafter. In the presence of peripheral vascular disease, ischaemic heart disease or congestive cardiac failure it is prudent to start ACE inhibitors at a low dose given at night, and temporarily to suspend the use of loop diuretics. Concomitant use of ACE inhibitors and potassium-sparing diuretics should always be avoided.
Angiotensin II receptor blockers offer a theoretical alternative to ACE inhibitors. They are effective anti-hypertensives but have not been validated in large outcome studies and should be reserved for patients who do not tolerate ACE inhibition. Other antihypertensive drugs may be added according to standard protocols39. In general, once-daily preparations with long intrinsic half-lives are preferable in terms of adherence to treatment and the consequences of missing a dose.
A low-salt diet is a non-pharmacological measure commonly advocated, but the evidence is not clear-cut and patients are not receptive to salt restriction at the level likely to be effective.
Glycaemic control
Good glycaemic control reduces the risk of microalbuminuria and overt renal
disease49,50,51
though there is no clear evidence that it affects the progression of
nephropathy in diabetes complicated by
microalbuminuria50,52.
The benefits on the progression of both retinopathy and neuropathy are well
documented50,51.
In view of this and the potential benefits in both renal and cardiovascular
disease the British and US recommendations are to establish and maintain tight
blood glucose control, with a target HbA1c of
7%27,40.
Lipids
Dyslipidaemia is a risk factor for both
development53 and
progression54,55
of renal dysfunction in primary renal disease. There are no primary prevention
studies to show whether intervention with lipid-lowering therapy significantly
affects the rate of decline of renal function in either diabetic or
non-diabetic renal disease; nevertheless there are compelling reasons for
aggressive management of dyslipidaemia in patients with microalbuminuria or
overt nephropathy, and a full lipid profile should be checked at baseline and
then yearly or half-yearly in these patients. As previously discussed, this
group of patients are at greatly increased risk of cardiovascular disease.
Several observational studies have pointed to both total cholesterol and
triglyceride concentrations as significant predictors of coronary heart
disease in type 2
diabetes56,57,58.
In the UKPDS50,
high levels of LDL cholesterol or total cholesterol, and low HDL cholesterol,
were major independent risk factors for coronary artery disease. High
triglycerides were not an independent risk factor.
The benefits of lipid lowering in diabetic patients with proven coronary heart disease are certain. In two large secondary prevention studies, the Scandinavian Simvastatin Survival Study59 and the Cholesterol and Recurrent Events Trial60,61, diabetic subgroups have been looked at and the benefit of statins in reducing coronary events were equal to if not greater than those in the total group.
Studies are underway to test the role of both fibrates and statins in the primary prevention of cardiovascular disease in the diabetic population. One primary prevention study with gemfibrozil, the Helsinki Heart Study62, has shown a non-significant reduction in coronary events in a small diabetic subgroup. Primary prevention studies in non-diabetic individuals have focused mainly on hyper-cholesterolaemia in middle-aged men63, in whom statins seem to reduce not only coronary events but also overall mortality.
Diabetic patients with CHD have poor outcomes64. This fact coupled with the high cardiovascular risk in diabetic patients with nephropathy identifies a group of patients very likely to benefit from early and aggressive treatment of dyslipidaemia before the onset of clinical CHD.
Improvement of glycaemic control reduces hyper-triglyceridaemia but may have only modest effects on HDL and LDL levels; thus pharmacological intervention is usually required. Current recommendations in the UK are to maintain total cholesterol < 5.0 mmol/L (LDL cholesterol < 3.0 mmol/L)40. Statins are the drugs of choice in patients with established CHD. Information needed from future trials includes target levels, first-choice agents in primary prevention and the value of lipid lowering in young diabetic patients with nephropathy.
Low-protein diet
Two meta-analyses have shown a beneficial effect of dietary protein
restriction on the progression of diabetic nephropathy in type 1
diabetes65,66.
It remains unclear what level of protein restriction should be used, how
acceptable this will prove to patients and how this will relate to treatment
adherence in the setting of routine primary care. Long-term prospective
studies are required to look at these issues in both type 1 and type 2
diabetes.
Aspirin
A meta-analysis of 145 prospective trials of antiplatelet therapy has
confirmed the benefit of secondary prevention with aspirin treatment in
patients with established atherosclerotic disease, with similar benefits seen
in diabetic and non-diabetic
patients6,7.
Two primary prevention studies, the General Practice Research Framework
Thrombosis Prevention
Trial68 and the US
Physicians Health
Study69, have shown
a reduction in non-fatal events in men at increased risk of coronary heart
disease treated with aspirin. In the US Physicians study fatal events were
also reduced, and a subgroup analysis in the diabetic group showed a reduction
in myocardial infarction from 10.1% in the placebo group to 4.0% in the
aspirin group. People aged 50 or more seemed to benefit most. Current
recommendations on prevention of coronary heart
disease40 suggest
aspirin treatment (75 mg daily) in individuals aged over 50 years whose
hypertension, if present, is controlled and who are at high risk (absolute CHD
risk 
15% per 10 years). The high cardiovascular risk in patients with
microalbuminuria or overt nephropathy argues strongly for the use of aspirin
as a primary prevention strategy in some of these patients, but there are no
data on the use of aspirin in younger diabetic patients (< 30 years
old).
Lifestyle targets
Stopping smoking, increasing aerobic exercise and cutting excessive alcohol
consumption are important lifestyle targets. Aerobic exercise in particular
has been shown to improve insulin sensitivity and reduce cardiovascular risk
in type 2 diabetes. A body mass index of < 25 kg/m2 with no
central obesity is desirable but often very hard to achieve.
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TOPINTRODUCTIONTHE STAGES OF DIABETIC...RISK FACTORS FOR DEVELOPMENT...SCREENING FOR DIABETIC...MANAGEMENTCONCLUSIONREFERENCES |
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