Abstract
Introduction
Up to one 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 November 2009 (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 19 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 blockers, glycaemic control, protein restriction, and tight control of blood pressure.
Key Points
Up to one 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, angiotensin-converting enzyme (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 blockers (ARBs), 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.
ARBs 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 to 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 to 300 mg a day (or albumin/creatinine ratio of 30 to 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 | Characterised by renal hypertrophy and hyperfiltration, and is present at the time of diagnosis of type 1 diabetes. |
| Stage 2 | 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 one 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 blockers. 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 | Late-stage nephropathy occurs 15 to 20 years after the onset of diabetes. Urine albumin increases beyond microalbuminuria to macroalbuminuria (greater 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 greater than 500 mg/day. The glomerular filtration rate declines on average between 0.5 and 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 | The development of end-stage renal disease, which occurs a median of 7 years from the development of persistent proteinuria. |
Incidence/ Prevalence
After 20 years of type 1 or 2 diabetes, the cumulative risk of proteinuria is 27% to 28% and the overall prevalence of microalbuminuria and macroalbuminuria is 30% to 35%. In addition, the incidence of diabetic nephropathy is increasing, partly due to 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 at greater risk (see prognosis). Microalbuminuria is less pathognomonic of nephropathy among people with type 2 diabetes because hypertension, which is a common complication of type 2 diabetes, 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% to 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 (ESRD). In the UK, it is the most common cause of ESRD, 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 ESRD in the setting of diabetes compared with white people. In the USA, African-American people with diabetes progress to ESRD at a much more rapid rate than white people with diabetes. In England, the rates for initiating treatment for ESRD are 4.2 times higher for African-Caribbean people and 3.7 times higher for Indo-Asian people 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 ESRD 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; rate of end-stage renal disease (ESRD); or rate of cardiovascular events (stroke, heart failure, and MI). Late nephropathy: All-cause mortality; rate of ESRD; or rate 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 November 2009. The following databases were used to identify studies for this systematic review: Medline 1966 to November 2009, Embase 1980 to November 2009, and The Cochrane Database of Systematic Reviews 2009, Issue 4 (1966 to date of issue). An additional search within the Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded (where possible), and containing 20 or more individuals, 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. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. Many of the identified systematic reviews do not stratify results based on type of diabetes or stage of nephropathy. Here, we have reported systematic reviews in the question to which they are most relevant based on the participants of included trials. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. 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 relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table 1.
GRADE evaluation of interventions for diabetic nephropathy (preventing progression)
| 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 to prevent progression of nephropathy in people with type 1 diabetes and early nephropathy? | |||||||||
| 12 (698) | Progression to 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 to late nephropathy | Intensive glycaemic control v conventional control | 4 | 0 | 0 | 0 | +1 | High | Effect-size point added for OR less than 0.5 |
| 3 (99) | Adverse effects: diabetic ketoacidosis | Intensive glycaemic control v conventional control | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 6 (number of people unclear) | Severe hypoglycaemia | Intensive glycaemic control v conventional control | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results (number of people in analysis not clear) |
| What are the effects of treatments to prevent progression of nephropathy in people with type 1 diabetes and late nephropathy? | |||||||||
| 1 (409) | Mortality | ACE inhibitors v placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for use of a composite outcome |
| 1 (82) | Mortality | Protein-restricted diet v usual-protein diet | 4 | –2 | 0 | –1 | +1 | Low | Quality points deducted for sparse data and lack of blinding. Directness point deducted for use of a composite outcome. Effect-size point added for RR less than 0.5 |
| What are the effects of treatments to prevent progression of nephropathy in people with type 2 diabetes and early nephropathy? | |||||||||
| 2 (6052) | Mortality | ACE inhibitors v placebo | 4 | 0 | –1 | –2 | 0 | Very low | Consistency point deducted for conflicting results. Directness points deducted for inclusion of people with type 2 diabetes without nephropathy and for dose assessed in one RCT being less than that used clinically |
| 2 (197) | Progression to late nephropathy | ACE inhibitors v placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (4912) | End-stage renal disease | ACE inhibitors v placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for dose assessed being less than that used clinically |
| 2 (6052) | Cardiovascular events | ACE inhibitors v placebo | 4 | –2 | –1 | –2 | 0 | Very low | Quality points deducted for subgroup analysis in one RCT and incomplete reporting of results. Consistency point deducted for conflicting results. Directness points deducted for use of a composite outcome in one RCT and for dose assessed being less than that used clinically in another RCT |
| 1 (590) | Progression to late nephropathy | ARBs v placebo | 4 | 0 | +1 | –1 | 0 | High | Consistency point added for dose response. Directness point deducted for restricted population |
| 1 (250) | Mortality | ARBs v ACE inhibitors | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for dose inconsistency between interventions. Directness point deducted for low number of comparators |
| 1 (250) | Progression to late nephropathy | ARBs v ACE inhibitors | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for dose inconsistency between interventions. Directness point deducted for low number of comparators |
| 1 (250) | Cardiovascular events | ARBs v ACE inhibitors | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for dose inconsistency between interventions. Directness point deducted for low number of comparators |
| 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 to prevent progression of nephropathy in people with type 2 diabetes and late nephropathy? | |||||||||
| 5 (3409) | Mortality | ARBs v placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of range of disease severity |
| 3 (3251) | End-stage renal disease | ARBs v placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of range of disease severity |
| 3 (307) | Mortality | ARBs v ACE inhibitors | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for uncertainty about significance of result. Directness point deducted for inclusion of people with early-stage nephropathy |
Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies. Directness: generalisability of population or outcomes. ACE inhibitor, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker
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.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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