Diabetic nephropathy
Prevention and early referral
G. Pylypchuk, MD, FRCPC E. Beaubien, MD
OBJECTIVE To review the clinical and pathophysiologic features of diabetic nephropathy and to examine evidence supporting primary, secondary, and tertiary treatment strategies.
QUALITY OF EVIDENCE The medical literature provides both level 1 and level 2 evidence on treatment of diabetic nephropathy, including randomized controlled trials, well-designed clinical trials without randomization, consensus papers, and cohort and case-control analytic studies.
MAIN MESSAGE Diabetes is the most common cause of end-stage renal failure in Canada and the United States, and both diabetes and its renal complications are increasing. Diabetic nephropathy, in both type 1 and type 2 diabetes, usually progresses through five stages. Treatment and prevention strategies depend on stage of disease. Primar y prevention includes addressing hyperglycemia, hypertension, and smoking. Secondar y prevention adds angiotensin-converting enzyme inhibitors, cholesterol lowering, and perhaps restrictions on dietary protein. Tertiary care, including dialysis or transplantation, is generally managed by nephrologists, but family physicians continue to play an important role in the care of these patients.
CONCLUSIONS Diabetic nephropathy is a serious cause of morbidity and mortality for patients with type 1 and type 2 diabetes. To reduce end-stage diabetic nephropathy and its complications, both spe- cialists and family physicians need to focus efforts on primary and secondary prevention strategies.
OBJECTIF Passer en revue les caractéristiques cliniques et pathophysiologiques de la néphropathie diabétique et examiner les données probantes à l’appui des stratégies thérapeutiques primaires, secon- daires et tertiaires.
QUALITÉ DES DONNÉES Les ouvrages médicaux offrent à la fois des données probantes de niveaux 1 et 2 sur le traitement de la néphropathie diabétique, notamment des essais aléatoires contrôlés, des essais cliniques biens conçus sans randomisation, des documents consensuels et des études analyti- ques par cohortes et cas témoins.
PRINCIPAL MESSAGE Le diabète est, au Canada et aux États-Unis, la cause la plus fréquente d’insuffi- sance rénale chronique au stade ultime. Le diabète et ses complications rénales sont à la hausse. La néphropathie diabétique, dans le diabète tant de type 1 que de type 2, progresse habituellement en cinq stades. Les stratégies de traitement et de prévention dépendent du stade de la maladie. La prévention primaire comporte la prise en charge de l’hyperglycémie, de l’hypertension et du tabagisme. La pré- vention secondaire y ajoute les inhibiteurs de l’enzyme de conversion de l’angiotensine, la réduction du cholestérol et peut-être des restrictions sur les protéines alimentaires. Les soins tertiaires, notamment la dialyse ou la transplantation, sont généralement pris en charge par des néphrologues, mais les méde- cins de famille continuent d’exercer un rôle important dans les soins à ces patients.
CONCLUSIONS La néphropathie diabétique est une cause sérieuse de morbidité et de mortalité chez les patients souffrant de diabète de type 1 et de type 2. Pour réduire la néphropathie diabétique et ses complications, tant les spécialistes que les médecins de famille doivent concentrer leurs efforts sur les stratégies de prévention primaire et secondaire.
This article has been peer reviewed.
Cet article a fait l’objet d’une évaluation externe.
Can Fam Physician2000;46:636-642.
résumé abstract
he annual cost of end-stage renal failure (ESRF) in the United States is estimated at $13 billion US.1 A recent ar ticle by Schaubel et al2showed a marked increase in ESRF in Canada from 1981 to 1996 and predicted that by the year 2005, approximately 33 000 patients would require therapy for ESRF. Diabetes is the most common cause of ESRF in Canada and the United States, and the incidence of both diabetes and its renal complications are increasing.3,4 Costs will no doubt continue to increase as long as dia- betes remains unchecked and we continue to focus on dialysis and transplantation in treating diabetic nephropathy.
In Canada, and especially the wester n pro- vinces, populations such as First Nations* peoples are developing diabetes and diabetic complications in epidemic propor tions.5 Projection studies esti- mate that the number of patients with diabetes worldwide is expected to reach 221 million by the year 2010; 97% of them will have type 2 diabetes.6It is, therefore, necessar y that we take a more pre- ventive approach in treating this disorder. If not, we will see the continued need to increase dialysis and transplant programs with their attendant finan- cial implications. Family physicians must play a leading role in this area, especially in prevention.
This paper discusses the pathophysiology and clini- cal features of diabetic nephropathy, which we hope will aid in understanding the methods of treating this disorder.
Quality of evidence
References for this ar ticle were obtained from MEDLINE (1966 to 1999) using the search terms diabetes, diabetic nephropathy, renal failure, dialy- sis, microalbuminuria, diabetic renal disease, and review articles. Articles were selected preferentially if they were randomized controlled trials, consensus papers, or practice guidelines. Articles also included case-control analytic studies, well designed cohort studies, and comprehensive reviews.
Pathophysiology
Approximately 40% of type 1 and 10% of type 2 diabet- ic patients develop renal failure; however, type 2 dia- betes accounts for more than 90% of ESRF patients because of its markedly increased prevalence in the North American population.7,8Both types progress to ESRF in a similar fashion, with only a few minor dif- ferences. Type 2 patients with nephropathy are older, and hypertension usually precedes development of renal insuf ficiency. Renal morphology of diabetes (ie, diffuse or nodular sclerosis) is seen in both type 1 and type 2 diabetes, but is more variable in type 2.8 About 16% of type 2 patients have associated glomerulonephritis.9
Renal hemodynamics play an impor tant role in development of renal failure. In the early stages of diabetic renal disease, hyperfiltration and glomerular hypertension initiate a vicious circle of glomerular hypertrophy, sclerosis, and finally nephron loss.10 Poor glucose control and elevated blood pressure accelerate this process.
Clinical stages
Some diabetic patients do not develop diabetic nephropathy, and the exact explanation for this is unclear, although genetics, sex, and coexisting hyper- tension are important.8In type 1 patients who devel- op diabetic nephropathy, the disease progresses through five distinct stages (Figure 111).11-14Type 2 diabetes follows a similar pattern, but the timing of the stages is more variable because of patients’ age and presence of pre-existing hypertension.8
Stage I.Stage I, or the hyperfiltration stage, is seen at first diagnosis in approximately 40% of diabetics.
Hyperglycemia leads to increased glomerular filtra- tion rate (> 135 mL/min for ever y 1.73 m2) and glomerular hypertrophy.
Stage II. Stage II, or the microalbuminuric stage, occurs approximately 5 years after diagnosis in type 1 patients, but can occur much earlier in type 2 patients.
Those who are going to develop nephropathy begin now to show signs of glomerular hypertension and stress by spilling small amounts of albumin, termed microalbuminuria.15This is defined as urinary excre- tion of between 30 mg and 300 mg of albumin per day (current routine dipstick methods detect albumin only when it exceeds 300 mg).14Microalbuminuria is seen not only in diabetic patients but also in elderly and hypertensive patients where it is a strong predic- tor of cardiovascular mortality.
T
Dr Pylypchuk is a Nephrologist and Clinical Professor of Medicine at the University of Saskatchewan in Saskatoon and former Head of Medicine at the Saskatoon District Health Board. Dr Beaubien is a senior resident in the Department of Internal Medicine at the University of Saskatchewan.
…
*First Nations is used to refer to the earliest inhabitants of Canada and their descendants.
The importance of microalbuminuria as an “early marker” of renal disease cannot be understated, as it represents a time when renal biopsy shows no changes or minimal changes due to glomer ular hyper trophy and mesangial expansion.7 Although long-term studies are not yet available, common sense suggests that the earlier diabetic nephropathy is treated, especially if there is no morphologic dam- age, the more likely we are to either attenuate or
“cure” the condition. At present, we know that good blood sugar and blood pressure control, along with angiotensin-conver ting enzyme (ACE) inhibitors, reduce microalbuminuria and retard early progres- sion of renal disease.16,17
Stage III. Intermittent spikes of microalbuminuria continue throughout stage II, and if unchecked, lead to overt proteinuria, or stage III disease, approxi- mately 10 years after diagnosis of type 1 diabetes.13,14 Type 2 diabetes might follow a more variable time course, but results are similar. During stage III, 24-hour protein excretion exceeds 300 mg and might proceed into the nephrotic range. Renal biopsy at this time shows severe damage, diabetic nephrosclerosis,
heralding a progressive decline in renal function and subsequent renal insufficiency.
Stages IV and V. Renal insuf ficiency (elevated serum creatinine levels) indicates stage IV disease.
In type 1 diabetes, hypertension develops in stage III or IV disease and increases the rate of progression to ESRF. Patients with type 2 diabetes usually have pre- existing hypertension. The fall in creatinine clearance is progressive and predictable, ranging from 0.1 to 2.4 mL/min per month. Patients soon develop ESRF (stage V diabetic nephropathy) and require dialysis or transplantation.
Progression through the above stages is consis- tent in type 1 diabetes, with minor differences in tim- ing depending on blood pressure, glucose control, and other concomitant diseases, such as infections and drug use. Type 2 diabetes appears to follow a similar patter n. Occasionally, patients progress through all stages in a few years. Rarely, nephropathy is seen even before clinical diabetes in type 2 patients. This variability in clinical course is most likely explained by type 2 patients being older, by an increased prevalence of concomitant renal diseases
PRIMARY PREVENTION SECONDARY PREVENTION LIFE SUPPORT
Figure 1.Typical course of diabetic nephropathy
Adapted from Mogenson.11
STAGE I STAGE II STAGE III STAGE IV STAGE V
160
120
80
40
0
8
6
4
2
0 Microalbuminuria
Proteinuria
GLOMULAR FILTRATION RATE (ML/MIN) PROTEIN EXCRETION (G/D)
DURATION OF DIABETES
in this age group, and by pre-existing hypertension and atherosclerosis.8,18
Treatment
Our approach to treatment focuses on the following three distinct areas: ter tiar y care (stage V), sec- ondary prevention (stages III and IV), and primary prevention (stages I and II).
Tertiary care.Tertiary care, or life support includ- ing dialysis or transplantation, is usually not managed by family practitioners; however, we believe family physicians have a role in the care of these patients.
Stage V patients can be very complicated, ill patients.
They usually have concomitant diabetic complica- tions, such as retinopathy, amputations, neuropathy, and especially cardiovascular disease, the most com- mon cause of death among these patients.19-21 In many situations, nephrologists become the primary care providers for their chronic dialysis patients, because patients come for dialysis two to three times a week and are usually seen by a nephrologist at that time. A recent study showed that more than 90% of nephrologists spend a substantial por tion of their time as primary care providers.22Family physicians, who are trained in primary care, must be encouraged to be partners in the care of these patients, especially for controlling blood sugar and hypertension. The psychosocial problems that accompany chronic dis- ease also need attention, and family practitioners can be invaluable in this area.
Major advances in treatment have resulted in longer sur vival of dialysis and transplant patients.
This means that ESRF patients should participate in cancer screening and detection programs, such as yearly Pap smears for cer vical cancer for women, breast examinations for women, and prostate screen- ing examinations for men. Family physicians are best equipped to address screening issues.
Secondary prevention.Secondary prevention con- sists of slowing the progression of over t diabetic nephropathy before development of ESRF. At this time renal morphology is already abnormal. Table 1 outlines factors that have been shown to slow renal deterioration.
The ef fectiveness of dietar y protein restriction remains controversial. Some studies show that pro- tein restriction is beneficial in reducing albumin excretion,19but a recent editorial on rate of progres- sion of renal disease in patients on low-protein diets reviewed a meta-analysis on protein restriction and
concluded that the effect of protein restriction on glomerular filtration rate was minimal.23,24In view of current data, we believe strict restriction of protein is not required in diabetic nephropathy; however, it con- tinues to be debated.
Hyperglycemia is an impor tant determinant of diabetes prognosis, especially for renal decline. The United Kingdom Prospective Diabetes Study showed that, in type 2 diabetes, good blood sugar control reduced this microvascular complication significant- ly.25The Diabetes Control and Complications Trial26 has shown that blood sugar control with Hb AIcless than 8.0% greatly slows progression of nephropathy;
however, it is generally believed that any improve- ment in glucose control is beneficial. Therefore, all patients with proteinuria or elevated creatinine levels must optimize glucose control.27
Hyper tension can markedly accelerate renal decline, as well as lead to coronary artery disease, stroke, hypertensive retinopathy, and peripheral vas- cular disease. Although a blood pressure goal of 140/83 mm Hg has been suggested for the general population,28even lower blood pressure appears to be beneficial in diabetic nephropathy.27,29,30In a large study of renal patients with proteinuria, a mean arter- ial pressure of 92 (equivalent to 125/75 mm Hg) was recommended for slowing progression of renal dis- ease.29Even when there is little or no proteinuria, tight blood pressure control appears equally impor- tant for diabetics.
In the Hypertension Optimal Treatment study,28 diabetic patients randomized to a diastolic blood pres- sure goal of below 80 mm Hg had half the cardiovas- cular complications of those randomized to less than 90 mm Hg. The sixth repor t of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure has suggested a blood pressure goal of 130/85 mm Hg for diabetics,31 Table 1. Secondar y prevention: Some factors slow renal deterioration.
Treat hypercholesterolemia Control hyperglycemia Treat hypertension Consider ACE inhibitors Advise smoking cessation
? Restrict dietary protein
however, recent WHO guidelines and the Canadian hyper tension guidelines indicate that diabetics should maintain even lower blood pressure levels.32,33 The Canadian guidelines suggest a target blood pres- sure below 130/80 mm Hg. We must be aware, how- ever, in treating hypertension in diabetic patients, of the possibility of concomitant autonomic neuropathy and resultant or thostatic hypotension. Sitting and standing pressures must be taken.
Angiotensin-converting enzyme inhibitors are use- ful in diabetic nephropathy independently of their blood pressure lowering effect.34,35A large study of type 1 diabetes has shown a 50% reduction in risk of the following end points with use of ACE inhibitors:
death, dialysis, and transplantation.36 The ACE inhibitors are effective because of their positive influ- ence on intrarenal hemodynamics and decreasing intraglomerular hyper tension; however, potential problems with these agents include hyperkalemia, development of acute renal failure in bilateral renal artery stenosis, and cough.
Smoking also aggravates diabetic renal disease.37 It is believed that smoking increases plasma endothe- lin I (a potent vasoconstrictor produced by endothe- lial cells) concentration and decreases renal plasma flow.38All patients must be advised to quit smoking.
Hypercholesterolemia is important to address for two reasons. First, it has been shown experimentally to decrease renal function, and second, it is a modifi- able risk factor for cardiac disease.25Elevated choles- terol might be a risk factor in development of diabetic nephropathy,39 and recent evidence suggests that decreasing cholesterol might substantially reduce rate of progression of renal disease.40We therefore recommend that patients be screened and treated aggressively for hypercholesterolemia.39
Secondary prevention must be a shared responsi- bility between nephrologists and family practitioners;
it is important that patients receive a consistent uni- fied treatment plan. Diabetic education centres and pre-dialysis clinics can be used to educate patients on lifestyle modifications and glucose control in order to reduce development and progression of diabetic nephropathy.
Primary prevention.Secondary prevention, how- ever, addresses treatment of disease only when the glomerulus has irreversible changes and damage. A strong focus must, therefore, be placed on primary prevention if we hope to see a decline in the number of patients presenting for dialysis or transplantation.
Primar y prevention factors are listed in Table 2.
As in secondar y prevention, hyperglycemia, hyper tension, and smoking must be addressed.
Experimental animal studies have revealed that hypertension control and ACE inhibition afford renal protection.19Hyperglycemic control has been shown to be beneficial in delaying development of albumin- uria.26Although we do not have the benefit of long- term studies yet, we hope that inter vention with respect to these factors will have an effect on devel- opment of ESRF and, therefore, the requirement for renal replacement therapies in the future.
We are fortunate to have an early warning test to detect development of diabetic kidney disease: the urine microalbumin test.15Detecting microalbumin- uria is important because there are usually no or min- imal renal morphologic changes early in disease.12-14,19 Microalbuminuria testing can be done by various dip- stick and instrument methods as a screening proce- dure. When screening indicates disease, it should be confirmed by 24-hour urine determination, and treat- ment should be based on these results. Established guidelines with respect to microalbuminuria detec- tion and treatment have been published in the United States41and Canada.42
Studies have shown that microalbuminuria can resolve or at least be stabilized by blood sugar and blood pressure control as well as ACE inhibi- tion.12,13,23,28,30
Knowing that microalbuminuria (stage II diabetic nephropathy) progresses to overt protein- uria (stage III), we believe its treatment will be a cor- nerstone of primary prevention of ESRF.
Conclusion
Diabetes prevalence is increasing in North America, and there is a parallel increase in ESRF from dia- betes. Diabetic nepropathy has an immense human and financial cost when end stage or “life support stage” treatment is necessary. It is, therefore, impor- tant to focus our efforts on primary and secondary prevention programs if we wish to reduce end stage diabetic nephropathy. Family physicians should play a leading role in this effort.
Table 2. Primar y prevention of end-stage renal failure
Screen for microalbuminuria Control hyperglycemia Treat hypertension Advise smoking cessation
Correspondence to: Dr George Pylypchuk, 182 Wall St, Saskatoon, SK S7K 1N4
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Key points
• Diabetes is the most common cause of end-stage renal failure (ESRF) in Canada.
• Family physicians can slow progression to ESRF through excellent blood sugar control, lowering blood pressure levels, encouraging smoking ces- sation, and lowering abnormal lipid levels.
• Angiotensin-conver ting enzyme inhibitors markedly reduce progression to ESRF indepen- dently from their blood pressure lowering effects.
• Family physicians should tr y to maintain good primar y care of their patients using dialysis despite the propensity for that care to be taken over by the dialysis unit.
Points de repère
• Le diabète est la cause la plus fréquente de l’insuffisance rénale chronique en stade terminal au Canada.
• Les médecins de famille peuvent freiner la pro- gression vers ce stade de la maladie en exerçant un excellent contrôle de la glycémie, en abaissant la tension artérielle, en encourageant l’abandon du tabagisme et en réduisant les taux anormaux de lipides.
• Les inhibiteurs de l’enzyme de conversion de l’angiotensine réduisent de façon remarquable la progression vers l’insuffisance rénale chronique en stade terminal, indépendamment de leurs effets de réduire l’hypertension.
• Les médecins de famille devraient essayer de dis- penser de manière constante de bons soins de première ligne à leurs patients en dialyse malgré la tendance que de tels soins soient pris en charge par l’unité de dialyse.
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