Diabetes is the most common cause of end-stage renal disease (ESRD) in the United States today.1 Approximately 40% of patients with type 1 diabetes and 5 - 15% of patients with type 2 diabetes eventually develop ESRD, although the incidence is substantially higher in certain ethnic groups.2
This is thought to be a potentially preventable calamity. Sensitive tests are available to identify patients with renal involvement early in the clinical course, when preventive measures may have greatest impact. For these reasons, it is imperative that clinicians who care for patients with diabetes be knowledgeable about diabetic nephropathy and attentive to its prevention, onset, progression, and treatment in their patients.
The pathophysiologic mechanisms of diabetic nephropathy are incompletely understood but include glycosylation of circulating and intrarenal proteins, hypertension, and abnormal intrarenal hemodynamics. The earliest demonstrable abnormalities include intrarenal hypertension, hyperfiltration (increased glomerular filtration rate [GFR]), and microalbuminuria. Clinically, the most important screening tool for identifying early nephropathy is detection of microalbuminuria.
Risk factors for development of diabetic nephropathy include hyperglycemia, hypertension, positive family history of nephropathy and hypertension, and smoking. Key elements in the primary care of diabetes include glycemic control, blood pressure control, and screening for microalbuminuria. In general, the goal for glycemic control is a blood glucose level as close to normal (HbA1c <7%) as possible without causing dangerous hypoglycemia. Blood pressure control is at least as important as glucose control, especially after the onset of renal damage, and blood pressure should be consistently <130/85. Screening for diabetic nephropathy involves monitoring at least yearly for urinary albumin excretion >30 mg per day.
DEFINITION OF TERMS
For purposes of this discussion, diabetic nephropathy will be a generic term referring to any deleterious effect on kidney structure and/or function caused by diabetes mellitus. More specifically, diabetic nephropathy is thought of in stages, the first being that characterized by microalbuminuria (30300 mg urinary albumin per 24 hours). This may progress to macroalbuminuria, or overt nephropathy (>300 mg urinary albumin per 24 hours). Later still, progressive renal functional decline characterized by decreased GFR results in clinical renal insufficiency and ESRD.
Glucose combines with many proteins in circulation and in tissues via a nonenzymatic, irreversible process to form advanced glycosylation end products (AGEs). The best known of these is glycosylated hemoglobin, a family of glucose-hemoglobin adducts. Hemoglobin A1c (HbA1c) is a specific member of this group and is useful as an indicator of average glycemia during the 23 months before measurement. The assay of HbA1c was standardized for the Diabetes Control and Complications Trial (DCCT) and is now widely accepted as the standard measurement of glycosylated hemoglobin. Other AGEs are presumed to contribute to the complications of diabetes, such as glycosylated proteins of the basement membrane of the renal glomerulus.
Diabetes and its costs are a problem of enormous importance in the United States today. Costs of caring for the complications of diabetes account for 90% of the direct and indirect costs of diabetes care.3 Diabetic nephropathy accounts for 35% of ESRD in the United States today and costs approximately $50,000 per patient per year,4 exceeding $2 billion per year for all patients.1
Patients with type 1 diabetes are at highest individual risk of nephropathy, but those with type 2 diabetes are also at significant risk.5 There is evidence that the incidence of renal failure in type 1 diabetes may be decreasing, perhaps because of better preventive treatment.6 The incidence of renal complications in type 2 diabetes, however, may be increasing.5,7,8 In the San Antonio Heart Study,9 the incidence of new- onset type 2 diabetes during 78 years of follow-up among Mexican Americans enrolling in the study increased significantly from 5.7% among those enrolling in 1979 to 15.7% among those enrolling in 1988. Among non-Hispanic whites, the several-fold increased incidence was borderline significant (P = 0.07). Since type 2 diabetes accounts for at least 90% of all patients with diabetes, the number of type 2 patients with nephropathy and ESRD exceeds those with type 1 diabetes overall. The prevalence of microalbuminuria in patients with diabetes is 1030%.10
The combination of hypertension and diabetes is an especially dangerous clinical situation, both for risk of microvascular and macrovascular complications of diabetes and for diabetes-related and overall mortality. Hypertension is unfortunately also very common in patients with diabetes. Hypertension occurs in 50% of patients with diabetes and results in a sevenfold increase in mortality.11 Concomitant nephropathy in patients with diabetes and hypertension results in a 37-fold increase in mortality.
Important clinical concomitants of diabetic nephropathy are retinopathy and cardiovascular disease. Nearly all patients with diabetic nephropathy will also have developed retinopathy. This has important implications for screening and attention to preventive measures in the care of patients with diabetes. The reverse is not as frequently true. That is, a much lower percentage of patients with retinopathy will have evidence of renal involvement.
Diabetic renal disease is also closely associated with coronary artery disease. The presence of microalbuminuria is a powerful predictor of death from cardiovascular disease. Thus, the presence of diabetes, especially if accompanied by microalbuminuria, is a signal for very aggressive attention to all cardiovascular disease risk factors and for improvement to the fullest extent possible by lifestyle modification and pharmacotherapy when appropriate. In addition to direct microvascular effects of diabetes on the heart, associated mechanisms may include hyperlipidemia, hypertension, and coagulation abnormalities.
A variety of factors contribute to the renal damage seen in diabetes. By definition, hyperglycemia is a common etiologic factor in diabetic patients with nephropathy, but a genetic predisposition and smoking contribute as well. Most significant, however, is the presence of hypertension, not only before and after the onset of microalbuminuria but probably also as another familial marker of risk, since patients with diabetes and a positive family history of hypertension are at higher risk of nephropathy.
Genetics and Ethnicity
Although a sizable percentage, only a minority of patients with diabetes are destined to develop ESRD. In addition to the risks of poor glycemic control and hypertension, a subset of patients may be at greater risk for nephropathy based on inherited factors.12 Familial clustering of patients with nephropathy may result from similarly poor glycemic or blood pressure control or may have additional independent genetic bases.12,13
Diabetic siblings of patients with diabetes and renal disease are five times more likely to develop nephropathy than diabetic siblings of diabetic patients without renal disease.14 There is a strong concordance of both nephropathy and renal histopathology in twins with type 1 diabetes.15 In a study of Brazilian families with two or more diabetic members, the presence of diabetic nephropathy in the probands was significantly associated with a 3.75-fold increased risk of diabetic nephropathy in the diabetic siblings.16
Postulates have been advanced linking diabetic nephropathy as well as cardiovascular disease and hypertension with inherited abnormalities of sodium-lithium countertransport.17,18 In a study of 89 patients with type 1 diabetes, an increased maximal velocity of sodium-lithium countertransport and a parent with hypertension each significantly increased the risk of nephropathy in the study patients.17 Moreover, the parents of patients with type 1 diabetes complicated by nephropathy have decreased survival, notably a fourfold increased risk of strokes.19
Familial clustering and the beneficial effects of angiotensin-converting enzyme (ACE) inhibition on diabetic nephropathy have also led to investigation of the genetics of the renin-angiotensin system. Increased levels of ACE have been found in patients with type 1 diabetes and nephropathy, particularly carriers of certain abnormal alleles of the ACE gene.20 In a study of type 1 patients with ESRD compared with type 1 patients with diabetes for at least 15 years and no microalbuminuria, the presence of the DD genotype at the ACE locus increased the risk of end-stage nephropathy twofold.21
ESRD is known to be more prevalent in certain ethnic groupsNative Americans, Mexican Americans, and African Americansthan in Caucasian Americans. Certainly, there is reason for special vigilance for early signs of nephropathy in these high-risk populations, whose members presumably have a genetic predisposition to nephropathy.
It is well established that poor metabolic control is critical in the etiology of diabetic nephropathy. Nephropathy is uncommon in patients with HbA1c consistently <7.58.0%.10,22 The degree to which glucose toxicity itself is directly causative in the renal lesion is still debated. At the very least, glucose is a meaningful and clinically relevant marker for the metabolic abnormality that leads to nephropathy, as shown in the DCCT23 and other treatment trials that demonstrate decreased nephropathy with lowered serum glucose.
Other hyperglycemia-dependent metabolic abnormalities that may also play a role in the development of nephropathy include AGEs and polyols. AGEs are the result of nonenzymatic covalent attachment of glucose to proteins, which not only changes the tertiary structure of proteins but also results in intra- and intermolecular crosslinking. Proteins of many types are affected by this process, and levels of circulating and tissue AGEs have been shown to correlate with microalbuminuria in diabetic patients. In a study of low- and high-molecular-weight AGEs in subjects with and without diabetes, AGE content in arterial wall collagen was fourfold higher in diabetes.24 Diabetic patients with ESRD had twice as much tissue AGE as patients without renal disease. Circulating AGEs were elevated in patients with diabetes compared to those without diabetes, and the levels correlated directly with creatinine.
Flux through the polyol pathway beginning with the conversion of glucose to sorbitol by aldose reductase is enhanced in hyperglycemia. The resultant increase in tissue sorbitol has been postulated to contribute to the microvascular complications of diabetes. Clinical trials of aldose reductase inhibitors have not shown beneficial effects in reducing microalbuminuria in humans; however, research continues in this arena.
Hypertension is probably both a cause and an effect of diabetic nephropathy. In the glomerulus, an early effect of systemic hypertension is dilatation of the afferent arteriole, contributing to intraglomerular hypertension, hyperfiltration, and hemodynamically mediated damage. Renal responsiveness to the renin-angiotensin system may be abnormal in the diabetic kidney.25 For these reasons, agents that help to correct the abnormal intraglomerular pressures are preferentially selected for treatment of hypertension in diabetes. ACE inhibitors specifically decrease the efferent arteriolar pressure, thereby decreasing intraglomerular pressure and helping to protect the glomerulus from further damage, as seen in their beneficial effect on microalbuminuria.
Particularly after microalbuminuria is present, metabolic control is only one factor in preventing the progression of renal disease. Hypertension at this stage predicts a more rapid downhill progression of the renal damage. Blood pressure control is increasingly important once the renal lesion is present and as renal damage progresses.
Several lines of evidence have shown that smoking increases the risk and progression of diabetic nephropathy.26,27 In the Appropriate Blood Pressure in Diabetes Trial, 61% of enrollees were smokers. Analysis of a number of risk factors showed a 1.6-fold increased risk of nephropathy among smokers.28
The key pathophysiologic event in diabetic nephropathy is basement membrane damage.29 With renal damage, there is progressive thickening of the basement membrane, pathologic change in mesangial and vascular cells, formation of AGEs, accumulation of polyols via the aldose reductase pathway, and activation of protein kinase C.22,30,31 Passage of macromolecules through the basement membrane may also activate inflammatory pathways that contribute to the damage secondarily.32
The renal hemodynamic abnormality is similar in type 1 and type 2 diabetes.8 An early physiologic abnormality is glomerular hyperfiltration33 associated with intraglomerular hypertension.31 This is accompanied by the onset of microalbuminuria, the first practical evidence of renal involvement in diabetes. This is a critical time in the evolution of diabetic renal disease, since the greatest impact of treatment is to intercept this point in the otherwise inexorable downward path of renal function.
A clinically asymptomatic period of decline follows, with progression of microalbuminuria (30300 mg albumin per day) to macroalbuminuria (>300 mg albumin per day). Once overt nephropathy (macroalbuminuria) has developed, renal function falls at a significant but variable rate (decline in GFR of 220 ml/min/year). The rate of decline depends on type of diabetes, genetic predisposition, glycemic control, and, very importantly, blood pressure. Hypertension is the single most important cause of progression and point of successful intervention in diabetic nephropathy. Later stages may also be accompanied by clinically significant albuminuria, edema, and nephrotic syndrome. Eventually, the characteristic clinical picture of renal failure develops.
It has become clear over time that once overt nephropathy has developed, treatment is a delaying rather than a preventive tactic. Though not all patients with early renal involvement (microalbuminuria) will progress to ESRD, the likelihood is much greater among these patients, and our ability to stabilize or reverse the downward progression once started is diminished. Ideally, it would be useful to be able to predict which patients were at risk for ESRD before onset, but there is currently no way to definitively identify those patients at increased risk. Consequently, a high priority in the care of patients with diabetes is screening for early signs of microvascular disease so that measures can be taken to prevent progression to overt complications. For this reason, regular screening for microalbuminuria should be part of routine diabetic preventive care.
Among the earliest changes demonstrable in diabetic nephropathy is glomerular hyperperfusion. This is accompanied by microalbuminuria, which serves as a sensitive early indicator of adverse effects of diabetes on the kidney and is a powerful predictor of the subsequent course. Eighty percent of type 1 diabetes patients with microalbuminuria will progress to overt nephropathy within 1015 years. Of those, 50% will develop ESRD within 10 years and 75% within 20 years in the absence of specific intervention.1 Among patients with type 2 diabetes, 2040% of patients with microalbuminuria will progress to overt nephropathy, though only 20% of those patients will go on to ESRD within the next 20 years.1 Microalbuminuria is also a powerful predictor of cardiovascular disease in both type 1 and type 2 diabetes.
Microalbuminuria is defined as the urinary excretion of 30300 mg of albumin per day. Standard urinalysis dipsticks are not sensitive enough to detect this level of albuminuria, so more sensitive tests must be done for effective screening. If protein is detectable on a standard urinalysis dipstick, macroalbuminuria (>300 mg of urinary albumin per day) is probably already present. In type 1 diabetes, annual screening should begin after puberty and 5 years after initial diagnosis. In type 2 diabetes, because of the likelihood that diabetes has been present for several years by the time it is diagnosed, annual microalbuminuria screening should begin at the time of diagnosis.
Despite the importance of microalbuminuria screening, however, it has not yet become a routine practice, probably because of lack of understanding of the difference between microalbuminuria and macroalbuminuria. In a study of more than 1,000 primary care physicians, 86% screened more than half of their type 1 patients and 82% screened more than half of their type 2 patients for overt macroalbuminuria, mostly by dipstick techniques. However, only 17% screened type 1 patients and 12% screened type 2 patients for microalbuminuria.34
Several methods are available for screening and give comparable results. The gold standard is the 24-hour urine collection (normal albumin excretion <30 mg per 24 hours), which, if accompanied by serum and urine creatinine, also allows calculation of creatinine clearance rate and serves as a reference for future comparison. Somewhat more convenient for the patient is the albumin/creatinine ratio on a spot urine sample (normal <30 mg albumin per g creatinine) or albumin excretion rate in a timed specimen (4 hours or overnight, normal <20 mg albumin per min). Measuring albumin without relating it to a duration of collection or creatinine concentration is less sensitive and specific because of dilution variability.
Clinicians should remember that there is a diurnal variation in urinary protein excretion, with less glomerular protein leak during nighttime and recumbency. Thus, measurement on collections of less than 24 hours may show the effect of time of day. There is also considerable variation from day to day, so three collections should be carried out over a 6-month period with the designation of microalbuminuria reserved for those with elevations on two out of three measurements. Furthermore, screening should avoid other factors that may temporarily induce albuminuria, such as poor glycemic control, exercise, fever, urinary or systemic infections, and marked hypertension.
PREVENTION AND TREATMENT STRATEGIES
Significant progress has been made in recent years in understanding the pathophysiology, prevention, and treatment of diabetic nephropathy. Median survival after the onset of nephropathy has increased from 6 to 15 years.35 Benefits accrue not only in younger patients with many years of potential life expectancy but also in the elderly.36
Both glycemic control and rigorous control of blood pressure have significant impact on prevention and progression of diabetic nephropathy.37 Identification of patients with microalbuminuria selects a population of patients with increased mortality. Studies in both type 1 and type 2 patients show that the use of ACE inhibitors leads to decreased albumin excretion and may postpone or even prevent overt nephropathy.3
The importance of prevention cannot be overemphasized, however. Once overt nephropathy is present, progression cannot be halted, only slowed. It is much more effective to screen for early nephropathy with sensitive tests for microalbuminuria and to prevent or halt the earliest stages of damage by vigorous control of hyperglycemia and hypertension.
Additional targets of potential intervention include smoking, hyperlipidemia, AGEs, the polyol pathway, and systemic and intrarenal vasoactive substances and pathways.30 Earlier trials of inhibitors of the aldose reductase pathway production of polyols did not show the hoped-for benefit, but research continues in this area.
Tight glycemic control has been shown in several studies to decrease the risk of microvascular disease in both type 1 and type 2 diabetes.22,23,38,39 In the DCCT, intensive glucose control in patients with type 1 diabetes decreased the incidence of microalbuminuria by 39% in the primary prevention group and decreased the progression from microalbuminuria to macroalbuminuria by 54% in the secondary prevention group.23 In the United Kingdom Prospective Diabetes Study (UKPDS), there was a 34% decrease in the risk of microalbuminuria in patients with type 2 diabetes treated more intensively for glycemic control.38
The DCCT benefit in type 1 diabetes was accomplished with an average 20% reduction in HbA1c (9.07.1%). In the UKPDS, the benefit was seen with an 11% reduction in HbA1c (7.97.0%). This suggests that there is benefit to be gained by decreasing hyperglycemia at any level of starting glucose control. Furthermore, it suggests that this benefit can be attained in patients with either type 1 or type 2 diabetes.
Glycemic control remains critical in stabilizing and slowing nephropathy even with established renal damage. As noted above, not only was primary prevention of microalbuminuria slowed by tight glycemic control in the DCCT, but also secondary progression from microalbuminuria to macroalbuminuria was slowed.23 A similar result was found in the Steno studies.40 Very persuasive was a study of eight patients with type 1 diabetes who received pancreas transplants and were studied with renal biopsies before transplantation and at 5 and 10 years after transplantation.41 All patients had lesions of diabetic nephropathy, from mild to advanced, at the time of transplantation and normal glycosylated hemoglobin after transplantation. At 5 years after transplant, microalbuminuria had improved, but basement membrane thickness had not changed, and creatinine clearance and mesangial volume had worsened compared with pretransplant values. At 10 years, however, albumin excretion had returned to normal, creatinine clearance had stabilized, and basement membrane thickness and mesangial volume had improved.
In general, the goal for glycemic control is blood glucose as close to normal as possible without causing significant hypoglycemia or other dangerous complications/side effects. Specific goals outlined by the American Diabetes Association (ADA) for optimum glycemic control include preprandial blood glucose levels of 80120 mg/dl, bedtime blood glucose levels of 100140 mg/dl, and HbA1c <7%.42
Blood Pressure Control
Hypertension is more common in people with diabetes than in the nondiabetic population43 and is well established as a contributing cause of the microvascular complications of diabetes.44 Hypertension control decreases albuminuria, delays nephropathy, and improves survival in both type 1 and type 2 diabetes.3
The renin-angiotensin system has become the target of the most effective strategy for both hypertension control and, independently, for reduction of the pathophysiologic abnormalities that lead to renal protein leakage.45 This is best established in type 1 diabetes, but evidence is accumulating that the same pathophysiologic principles and treatment also apply in type 2 diabetes.44 In addition, hypertension is probably a common primary risk for the renal and other nonrenal cardiovascular complications of diabetes.7,46
ACE inhibitors should be used when microalbuminuria is present regardless of the presence or absence of hypertension in type 1 diabetes1,47 and are widely used in normotensive patients with type 2 diabetes, as well.48,49 The effect of ACE inhibitors is probably not only via lowered systemic blood pressure but also via direct effects on intraglomerular hemodynamics.50 In a prospective study of type 2 diabetic patients with microalbuminuria but normal blood pressure, patients were randomized to enalapril (Vasotec) 5 mg/day or no treatment.51 After 4 years, urinary albumin excretion had increased in the untreated patients from 93.9 to 150.0 mg per 24 hours. In the enalapril-treated group during this 4-year period, however, albumin excretion decreased significantly from 115.4 to 75.3 mg per 24 hours. There was no change in creatinine clearance, blood pressure, or HbA1c in either group, suggesting that the beneficial effect of the ACE inhibitor was independent of its systemic antihypertensive action.
The debate is expanding to include normotensive, normoalbuminuric patients and the role of ACE inhibitors in preventing diabetic nephropathy before there is any evidence of its presence.32 In a double-blind, placebo-controlled trial, 156 type 2 diabetic, normotensive patients without micro- albuminuria were randomized to treatment with enalapril (10 mg/day) or placebo.52 After 6 years, microalbuminuria developed in 19% of placebo patients and 6.5% of enalapril patients. During this period, creatinine clearance decreased at a rate of 2.4 ml/min/year in the placebo group and 1.5 ml/min/year in the enalapril group. HbA1c decreased slightly in both groups, and blood pressure remained normal. If confirmed and expanded, these studies have important implications for strategies to prevent diabetic nephropathy at or before the earliest stages of damage.
Currently most evidence and published guidelines suggest ACE inhibitors as first-choice antihypertensives in patients with diabetes.1,53 The extent of blood-pressure lowering, however, rather than the class of antihypertensive agent used appears to be the most important factor in renal protection. Blood pressure <130/85 mm Hg is associated with preserved renal function.46,54-57 Calcium-channel blocking agents have been shown to have beneficial effects,35 and combinations of ACE inhibition and calcium-channel blockade have shown positive results,58 but further clarification is needed of the relative effects of dihydropyridine versus nondihydropyridine agents. Evidence is accumulating that angiotensin II receptor blockers have similar renal protective effects in diabetes,59 with further studies now in progress.7
Current ADA recommendations are to lower the blood pressure to 130/85 mm Hg in nonpregnant adults.1 For patients with isolated systolic hypertension >180 mm Hg, the goal is systolic pressure <160 mm Hg, and for those with isolated systolic pressure 160179 mm Hg, the goal is to lower systolic pressure by 20 mm Hg. The use of ACE inhibitors is recommended in patients with type 1 diabetes and microalbuminuria even if they are normotensive. In type 2 patients, the evidence for ACE inhibitor use in normotensive patients with microalbuminuria is not as conclusive at this point, but it is accumulating.48,49,52
Dietary Protein Restriction
High dietary protein has renal hemodynamic effects that include increased GFR, hyperfiltration, and increased intraglomerular pressure. This effect is probably accentuated by poor glycemic control. The typical diet in most industrialized societies contains considerably more protein than required for nutritional balance, and dietary protein has been shown to decrease renal functional deterioration in both type 1 and type 2 diabetes.60,61 In a 5-year prospective study of patients with type 1 diabetes,62 those on a protein- and phosphate-restricted diet showed a decline of GFR of only 0.26 ml/min/month compared with 1.01 ml/min/month in those on unrestricted diets.
Current recommendations are for dietary protein at the level of the Recommended Dietary Allowance of 0.8 g/kg/day, accounting for 10% of total calories. In selected patients with decreasing GFR, it may be useful to decrease the prescribed protein intake to 0.6 g/kg/day as directed by a professional nutritionist.
The single most common cause of ESRD in the United States today is diabetic nephropathy, and the incidence in type 2 diabetes appears to be increasing. Several factors probably contribute to the renal damage, including hyperglycemia and other metabolic by-products of elevated glucose, hypertension (both systemic and intrarenal), and a genetic predisposition in some patients. Patients with diabetic nephropathy usually also have diabetic retinopathy and have a much higher mortality from coronary artery disease.
Critically important is attention to prevention as preferential to treatment of diabetic nephropathy. Once overt nephropathy is present, progression cannot be avoided, only delayed. The earliest clinical indicator of renal damage is microalbuminuria, which should be screened for at regular intervals with sensitive tests.
Several studies demonstrate the preventive effect of lowered blood glucose on the microvascular complications of diabetes, including nephropathy, and serve as the rationale for the emphasis on tight rather than casual glycemic control. Before and especially after the onset of early nephropathy, blood pressure control is critical in preventing or slowing the progression of renal damage. First-choice agents for treating microalbuminuria are the ACE inhibitors, but lowered blood pressure by any means is the single most important factor in saving the diabetic kidney from the downward path to ESRD.
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Timothy C. Evans, MD, PhD, is an assistant professor and Peter Capell, MD, is a clinical professor in the Department of Medicine at the University of Washington School of Medicine in Seattle.
Note of disclosure: Dr. Evans is a stock shareholder in the Merck and Pfizer pharmaceutical companies and has received honoraria from Merck and Bristol-Myers Squibb. These companies manufacture products for the treatment of diabetes and/or hypertension.
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