Diabetic nephropathy

Abstract

Introduction

Up to a third of people with type 1 or 2 diabetes will develop microalbuminuria or macroalbuminuria after 20 years.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in people with type 1 diabetes and early nephropathy? What are the effects of treatments in people with type 1 diabetes and late nephropathy? What are the effects of treatments in people with type 2 diabetes and early nephropathy? What are the effects of treatments in people with type 2 diabetes and late nephropathy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 15 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, captopril, glycaemic control, protein restriction, and tight control of blood pressure.

Key Points

Up to a third of people with type 1 or 2 diabetes will develop microalbuminuria or macroalbuminuria after 20 years. Smoking, poor glycaemic control, male sex, older age, and ethnicity are also risk factors.

• Microalbuminuria can also be caused by hypertension, which often complicates type 2 diabetes and makes the diagnosis more difficult.

• Diabetic nephropathy increases the risk of end-stage renal disease and mortality, and is associated with increased cardiovascular risk.

In people with type 1 diabetes, ACE inhibitors reduce progression of early nephropathy while, in people with late nephropathy, they reduce the risk of end-stage renal failure and death.

• Intensive glycaemic control reduces progression of nephropathy compared with conventional control in people with early renal disease, but we don't know whether glycaemic control is effective in people with late nephropathy.

• We don't know whether angiotensin II receptor antagonists, dietary protein restriction, or tight control of blood pressure reduce the risks of renal or cardiovascular disease, or improve survival, in people with early or late nephropathy.

In people with type 2 diabetes, ACE inhibitors reduce progression from early to late nephropathy and may reduce cardiovascular events, but we don't know whether they are beneficial in late nephropathy.

• Angiotensin II receptor antagonists may reduce progression of nephropathy in people with early or late nephropathy.

• Lowering of diastolic blood pressure, even if not raised initially, reduces the risk of progression of early nephropathy, but we don't know whether it is effective in late nephropathy.

• We don't know whether protein restriction or tight glycaemic control are beneficial in early or late nephropathy.

About this condition

Definition

Diabetic nephropathy is a clinical syndrome in people with diabetes, characterised by albuminuria on at least two occasions separated by 3-6 months. Diabetic nephropathy is usually accompanied by hypertension, progressive rise in proteinuria, and decline in renal function. In type 1 diabetes, five stages have been proposed (see table 1 ). Of these, stages 1 and 2 are equivalent to pre-clinical nephropathy, and are detected only by imaging or biopsy. Stage 3 is synonymous with early nephropathy — the clinical term used in this review. Stage 4 nephropathy is also known clinically as late nephropathy, and this term will be used for the remainder of this review. Stage 5 represents the progression to end-stage renal disease. Population: For the purpose of this review, we have included people with diabetes and both early and late nephropathy. Early nephropathy presents as microalbuminuria, usually defined by albuminuria level of 30-300 mg a day (or albumin/creatinine ratio of 30-300 mg/g [3.4-34.0 mg/mmol]). Late nephropathy presents as macroalbuminuria, characterised by albuminuria greater than 300 mg a day (or albumin/creatinine ratio greater than 300 mg/g [34 mg/mmol]). The treatment of people with diabetes and end-stage renal disease is not covered in this review.

Table 1.

Stages of progression of nephropathy in type 1 diabetes.

Stage 1	is characterised by renal hypertrophy and hyperfiltration, and is present at the time of diagnosis of type 1 diabetes.
Stage 2	is typically asymptomatic, lasting for an average of 10 years. The earliest notable changes are renal hypertrophy seen on renal ultrasound, and an increase in the glomerular filtration rate due to hyperfiltration. At this stage, the kidneys show typical histological abnormalities, including diffuse thickening of the glomerular and tubular basement membranes. Glomerular and tubuloepithelial cell hypertrophy are also evident. About a third of people who develop these changes will develop microalbuminuria.
Stage 3	develops an average of 10 years after the onset of diabetes. People develop microalbuminuria (defined as a urine albumin excretion greater than 30 mg/day but less than 300 mg/day). The development of microalbuminuria is the earliest clinically detectable evidence of diabetic nephropathy. At this stage, serum creatinine level is typically normal. About 80% of people who develop microalbuminuria will progress to overt proteinuria. This proportion may be decreasing in the current era as a result of aggressive early treatment with ACE inhibitors and angiotensin II receptor antagonists. Microalbuminuria is well correlated with renal biopsy findings, particularly nodular glomerulosclerosis. The diagnosis of microalbuminuria is traditionally made with a 24-hour urine collection to measure urine albumin using radioimmunoassay or enzyme-linked immunosorbent assays. An alternative and easier method of detecting microalbuminuria is measurement of the albumin/creatinine ratio in a spot urine specimen. A ratio between 0.03 and 0.30 (mg albumin/mg creatinine) or 30/300 mg/g (mg albumin/g creatinine [3.4/34.0 mg/mmol]) is well correlated with 24-hour collections, and is now the preferred screening test for diabetic nephropathy.
Stage 4	or late nephropathy occurs 15–20 years after the onset of diabetes. Urine albumin increases beyond microalbuminuria to macroalbuminuria (less than 300 mg/day or greater than 200 micrograms/minute). It is at this stage that glomerular filtration rate declines and urine protein excretion increases to more than 500 mg/day. The glomerular filtration rate declines on average 0.5–1.0 mL/minute/month. Blood pressure also rises, probably reflecting renal parenchymal disease in sodium retention. Histologically, renal fibrosis becomes more evident. Mesangial expansion develops, resulting in diffuse and nodular glomerulosclerosis. The degree of mesangial expansion correlates well with increases in urine albumin excretion, and loss of renal function.
Stage 5	or the development of end-stage renal disease, occurs a median of 7 years from the development of persistent proteinuria.

Incidence/ Prevalence

The worldwide prevalence of diabetes in 1997 was 124 million, and this is expected to increase to 221 million by 2010. In the UK, 2.5 million people had been diagnosed with diabetes in 1998, and estimates suggest that half a million more have diabetes which has not yet been diagnosed.After 20 years of type 1 or 2 diabetes, the cumulative risk of proteinuria is 27-28% and the overall prevalence of microalbuminuria and macroalbuminuria is 30-35%. In addition, the incidence of diabetic nephropathy is increasing, partly because of the growing epidemic of type 2 diabetes, and because of increased life expectancies: for example, in the USA, the incidence has increased by 150% in the past decade.

Aetiology/ Risk factors

Duration of diabetes, older age, male sex, smoking, and poor glycaemic control have all been found to be risk factors in the development of nephropathy. In addition, certain ethnic groups seem to be at greater risk (see prognosis). Microalbuminuria is less pathognomonic of nephropathy among people with type 2 diabetes because hypertension, which is a common complication, can also cause microalbuminuria. Hypertension can also cause renal insufficiency; so, the time to development of renal insufficiency can be shorter in type 2 diabetes than in type 1. For people who have an atypical course, renal biopsy may be advisable. In addition, there are some differences in the progression of type 1 and type 2 diabetic nephropathy. In people with type 2 diabetes, albuminuria is more often present at diagnosis. Hypertension is also more common in type 2 diabetic nephropathy. Finally, microalbuminuria is less predictive of late nephropathy in people with type 2 diabetes compared with type 1.

Prognosis

People with microalbuminuria are at increased risk for progression to macroalbuminuria and end-stage renal disease. The natural history of diabetic nephropathy is better defined in type 1 than type 2 diabetes. In type 2 diabetes, the course can be more difficult to predict, primarily because the date of onset of diabetes is less commonly known, and comorbid conditions can contribute to renal disease. Without specific interventions, about 80% of people with type 1 diabetes, and 20-40% of people with type 2 diabetes with microalbuminuria will progress to macroalbuminuria. Diabetic nephropathy is associated with poor outcomes. In the USA, diabetes accounts for 48% of all new cases of end-stage renal disease. In the UK, it is the most common cause of end-stage renal disease, accounting for 20% of cases. People with type 1 diabetes and proteinuria have been found to have a 40-fold greater risk of mortality than people without proteinuria. The prognostic significance of proteinuria is less extreme in type 2 diabetes, although people with proteinuria have a fourfold risk of death compared with people without proteinuria. In addition, increased cardiovascular risk has been associated with albuminuria in people with diabetes. African-American, Native American, and Mexican-American people have a much higher risk of developing end-stage renal disease in the setting of diabetes compared with white people. In the USA, African-American people with diabetes progress to end-stage renal disease at a much more rapid rate than white people with diabetes. In England, the rates for initiating treatment for end-stage renal disease are 4.2 and 3.7 times higher for African-Caribbean and Indo-Asian people respectively than for white people. Native American people of the Pima tribe, in southwestern USA, have much higher rates of diabetic nephropathy than white people, and also progress to end-stage renal disease at a faster rate.

Aims of intervention

To prevent death and complications of chronic renal failure and to prevent the need for chronic dialysis or transplantation (end-stage renal disease), with minimal adverse events.

Outcomes

Early nephropathy: Progression to late nephropathy (proteinuria determined by albumin excretion rate greater than 300 mg/day [34 mg/mmol]); all-cause mortality; incidence of end-stage renal disease; or incidence of cardiovascular events (stroke, heart failure, and MI). Late nephropathy: All-cause mortality; incidence of end-stage renal disease; or incidence of cardiovascular events (stroke, heart failure, and MI). Excluded outcomes: Change or doubling of serum creatinine as a surrogate marker.

Methods

Clinical Evidence search and appraisal June 2008. The following databases were used to identify studies for this review: Medline 1966 to June 2008, Embase 1980 to June 2008, and The Cochrane Library (all databases) Issue 2, 2008. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) (all databases), Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded (where possible), and containing 20 individuals or more, of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs.

Table.

GRADE evaluation of interventions for diabetic nephropathy

Important outcomes	Mortality, progression to late nephropathy, end-stage renal disease, cardiovascular events, adverse effects
Number of studies (participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of treatments in people with type 1 diabetes and early nephropathy?
12 (698)	Late nephropathy	ACE inhibitors v placebo	4	0	0	0	+1	High	Effect-size point added for OR less than 0.5
7 (266)	Progression of nephropathy	Intensive glycaemic control v conventional control	4	0	0	0	+1	High	Effect-size point added for OR less than 0.5
6 (fewer than 266)	Severe hypoglycaemia	Intensive glycaemic control v conventional control	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
3 (99)	Diabetic ketoacidosis	Intensive glycaemic control v conventional control	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
What are the effects of treatments in people with type 1 diabetes and late nephropathy?
1 (409)	Mortality, renal transplant or end-stage renal failure	ACE inhibitors v placebo	4	0	0	0	0	High
1 (82)	Mortality or end-stage renal failure	Low-protein diet v usual-protein diet	4	–2	0	0	+1	Moderate	Quality points deducted for sparse data and lack of blinding. Effect-size point added for RR less than 0.5
What are the effects of treatments in people with type 2 diabetes and early nephropathy?
11 (5648)	Progression to late nephropathy	ACE inhibitors v placebo	4	0	0	–1	0	Moderate	Directness point deducted for differences in outcomes and disease status
3 (8489)	Mortality	ACE inhibitors v placebo	4	0	–1	–2	0	Very low	Consistency point deducted for conflicting results. Directness points deducted for inclusion of different disease states and outcomes
1 (250)	Mortality	ACE inhibitors v angiotensin II receptor antagonists	4	–1	0	–1	0	Low	Quality point deducted for dose inconsistency between interventions. Directness point deducted for composite outcome
1 (590)	Progression to late nephropathy	Angiotensin II receptor antagonists v placebo	4	0	+1	–1	+1	High	Consistency point added for dose response. Directness point deducted for restricted population. Effect-size point added for HR less than 0.5
1 (250)	Cardiovascular events	ACE inhibitors v angiotensin II receptor antagonists	4	–1	0	–1	0	Low	Quality point deducted for dose inconsistency between interventions. Directness point deducted for composite outcome
1 (250)	Progression to late nephropathy	ACE inhibitors v angiotensin II receptor antagonists	4	–1	0	–1	0	Low	Quality point deducted for dose inconsistency between interventions. Directness point deducted for composite outcome
1 (480)	Progression to late nephropathy	Tight blood pressure control v moderate diastolic blood pressure target	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
What are the effects of treatments in people with type 2 diabetes and late nephropathy?
5 (3409)	Mortality	Angiotensin II receptor antagonists v placebo	4	0	0	–2	0	Low	Directness points deducted for range of disease severity included and composite primary outcome
3 (3251)	End-stage renal failure	Angiotensin II receptor antagonists v placebo	4	0	–1	–2	0	Very low	Consistency point deducted for inconsistent results. Directness points deducted for range of disease severity included and composite primary outcome
3 (307)	Mortality	Angiotensin II receptor antagonists v ACE inhibitors	4	–1	0	0	0	Moderate	Quality point deducted for uncertainty about significance of result

Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies. Directness: generalisability of population or outcomes.

Glossary

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

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