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| As the epidemic of diabetes spreads so does the number of patients at risk for developing diabetic nephropathy, which occurs in 20% to 40% of all diabetic patients. Indeed, diabetes is the most common cause of end-stage renal disease (ESRD) in the United States, accounting for > 40% of patients starting renal replacement therapy each year. Unfortunately, the outcome for diabetic patients with ESRD is worse than that for nondiabetic patients because of comorbid conditions in the diabetic population. However, with early and intensive blood glucose and blood pressure control -- including the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers -- the development and progression of diabetic kidney disease can be slowed. Incidence and Prevalence Diabetic kidney disease is the most frequent cause of end-stage renal disease (ESRD) in the United States, Europe, and Japan. According to the US Renal Data System, in 1999 diabetes was the cause of renal failure in 43% of all ESRD patients commencing dialysis therapy, an incidence rate of 136 per million population[1]. Because of the multiple comorbid conditions in this group of ESRD patients, especially cardiac and cerebrovascular disease, their morbidity and mortality rates are higher than those in nondiabetic patients. For example, the 3-year mortality rate of patients receiving hemodialysis treatment because of diabetic kidney disease exceeds the rate for ESRD due to hypertension by 26% and for ESRD due to glomerulonephritis by 72%[1]. Not surprisingly, the annu- al cost of caring for diabetic patients with ESRD exceeds that for nondiabetic patients. Overall, the treatment of ESRD in the United States is costly, and the annual expenditure exceeds $18 billion. Unfortunately, the incidence of diabetic nephropathy as a cause of ESRD is increasing each year. This increase can be attributed to an increase in the occurrence of diabetes, especially type 2 diabetes; the extended life span of diabetic patients due to improved management of comorbid conditions; and the acceptance of patients for replacement therapy who in the past were excluded[2,3]. Nephropathy develops in about 20% to 40% of all diabetic patients, although a somewhat lower percentage of those with type 2 diabetes progresses to ESRD, perhaps in part because these patients are older and die from cardiovascular complications. Nevertheless, patients with type 2 diabetes account for more than half the diabetic patients reaching ESRD because of the greater prevalence of type 2 diabetes[1]. Although the prevalence of diabetic nephropathy has been increasing, the last decade has seen significant advances in our understanding of the pathogenesis and management of the disease. With earlier and more intensive glycemic and blood pressure control, the introduction of potent drugs that interrupt the generation or action of angiotensin II (AII), and the use of other agents that affect vascular biology, the development and progression of diabetic nephropathy can now be slowed. Natural History of Diabetic Nephropathy There are several clinical similarities between diabetic nephropathy in patients with type 1 diabetes and in patients with type 2 diabetes; however, the clinical course differs in some respects between these 2 groups. In patients with type 1 diabetes, the onset of diabetes is abrupt and usually occurs at a young age, and in those in whom nephropathy develops the clinical course is relatively well defined[4]. Nephropathy usually becomes clinically evident after 15 to 25 years of diabetes and almost inevitably leads to ESRD. In contrast, because of the insidious onset of type 2 diabetes and the advanced age of the patients, and thus the common presence of coexisting vascular disease and hypertension, early renal involvement is frequently missed. In patients with type 2 diabetes, it is not always clear whether renal failure is due solely to or even caused by diabetes[5]. Also, because of the shortened life span of individuals with type 2 diabetes, full-blown manifestations of diabetic nephropathy often are not expressed. Thus, the clinical course of diabetic nephropathy is best defined in type 1 diabetes and proceeds through several stages (Table I), which can be modified by therapy[4,6]. Soon after the onset of type 1 diabetes, the kidneys hypertrophy and renal blood flow (RBF) and the glomerular filtration rate (GFR) increase. Over the ensuing 5 to 15 years, the GFR remains elevated or falls within normal range, and there is no elevation in systemic blood pressure. About a decade after diabetes onset, small amounts of albumin, detectable only by sensitive antibody-based assays, appear in the urine (microalbuminuria) of a substantial fraction of patients. After 1 to 5 years of microalbuminuria, larger amounts of protein appear in the urine, which occurs in 30% to 45% of these patients by 10 years[27]. This macroalbuminuria is detectable by the urine dipstick method. At this time blood pressure is usually elevated and renal function begins to decline. The rate of decline in function varies considerably among patients but averages 1 mL/min per month in patients not receiving renoprotective therapy. Typically ESRD is reached 15 to 25 years after the onset of diabetes. In type 2 diabetes, the appearance of proteinuria and the decline in GFR occur at a frequency similar to that seen in type 1 diabetes[3,7]. In the child with prepubertal onset of diabetes, microvascular complications, including renal disease, tend to accelerate during puberty[8]. In addition to causing nephropathy, diabetes affects other components of the urinary system. Diabetes may predispose patients to urinary tract infection and papillary necrosis. Autonomic dysfunction can lead to bladder dysfunction with obstructive uropathy, which predisposes patients to urinary tract infection and, if obstruction is severe, often leads to loss of kidney function. Indeed, it is not uncommon for patients with type 2 diabetes to have renal failure due to causes other than diabetic nephropathy. Renal artery stenosis due to accelerated atherosclerosis occurs more frequently in these patients than in the general population[9]. Morphologic Changes The central pathologic change in the diabetic kidney is overproduction and impaired degradation of extracellular matrix components that lead to their accumulation in the basement membranes and mesangial regions of the glomerulus (Table II). The expanded mesangium results in a diffuse glomerulosclerosis and is sometimes accompanied by the formation of structures termed Kimmelstiel-Wilson nodules[10,11]. This process eventually leads to a reduction in the density of capillaries and in the glomerular filtration surface area. Permeability of the filtration barrier falls and, consequently, GFR declines. Extracellular matrix accumulates also in the tubular basement membranes and interstitial compartment. Progressive tubulointerstitial fibrosis also leads to nephron destruction and renal failure. The decline in GFR correlates better with the interstitial changes than with the glomerular changes[10,11]. Pathogenesis of Diabetic Renal Hypertrophy and Disease As stated, soon after the onset of diabetes, the kidneys hypertrophy and RBF and the GFR increase. This hyperfiltration is a consequence of renal vasodilatation, with greater dilatation of the afferent than the efferent glomerular arterioles (Table III). The result is an increase in the intraglomerular pressure, which drives more ultrafiltrate through the glomerular capillary wall[12]. These hemodynamic changes contribute to the development of diabetic nephropathy by the effect of shear stress on the endothelial and mesangial cells, which respond by increasing growth factor, cytokine, and extracellular matrix production[13]. The mechanisms for the altered intrarenal hemodynamics are not completely understood but appear to involve vasodilatators such as nitrous oxide, prostanoids, and insulin-like growth factor-I. Systemic hypertension worsens the hemodynamic effects of diabetes on the kidneys and is an important, treatable mediator of progressive renal damage[14]. Indeed, hypertension and diabetes are comorbid conditions that independently increase the risk of developing and accelerating both cardiovascular and renal disease[15]. Hypertension develops in 20% to 60% of diabetic patients, depending on age, ethnicity, and fat mass[14,15]. In type 1 diabetes hypertension usually appears only after many years and develops in 12% to 25% of those with microalbuminuria; its prevalence increases to 75% to 85% of patients with overt nephropathy[4]. In type 2 diabetes hypertension is present in ~30% to 40% of newly diagnosed patients and its prevalence increases with time[5]. Whereas in type 1 diabetes hypertension appears to be of renal origin, in type 2 diabetes hypertension is often present as part of the metabolic syndrome of insulin resistance where hyperinsulinemia may play an important role[15,16]. Key to the development of diabetic nephropathy is the hyperglycemic state, which has been postulated to mediate its effects in several different ways. First, glucose in sustained high concentrations may be directly toxic to cells, altering cell growth and gene and protein expression and increasing extracellular matrix and growth factor production[13]. Second, glucose may induce its effects indirectly through the formation of metabolic derivatives such as oxidants and glycation products[17,18]. Formation of advanced glycation endproducts (AGEs) may damage cells because of modifications to extracellular matrix proteins and to cellular proteins[19]. The AGEs may also bind to cell-associated proteins that trigger abnormal cellular function. Sustained production of certain glucose metabolites may result in the continuous activation of signaling pathways involving phospholipids and kinases[17,18]. The polyol pathway is one such pathway. Excessive entry of glucose into this pathway results in tissue accumulation of sorbitol, which leads to cataract formation and possibly osmotic vascular damage. Activation of this pathway may also alter various enzyme activities and thus contribute to the pathologic changes. Sustained hyperglycemia may also result in increased diacylglycerol levels with activation of protein kinase C. This kinase has been implicated as a cause of altered RBF, vascular permeability, and increased growth factor and extracellular matrix production in the diabetic kidney. Several hormones, growth factors, and cytokines have been implicated in the pathogenesis of diabetic kidney disease[20,21]. AII is a key mediator, and blockade of its generation or receptor binding has provided a major advance in the management of diabetic nephropathy[3,22,23]. Apart from its hemodynamic actions, AII has several nonhemodynamic effects[22]. These effects include the generation of reactive oxygen species, increased extracellular matrix accumulation, stimulation of transforming growth factor-b (TGF-b), connective tissue growth factor, and platelet-derived growth factor production and macrophage activation[12,22]. There is increasing evidence that TGF-b is a major prosclerotic mediator. Its production is stimulated by AII and by glucose directly. Preclinical studies have shown that TGF-b blockade prevents and also ameliorates diabetic nephropathy. Recently it has been suggested that severe proteinuria, apart from being a marker of significant glomerular damage, may well serve to speed the progression of diabetic and other proteinuric kidney diseases[24]. Studies in animals indicate that exposure of the tubular cells to high concentrations of filtered proteins and growth factors produces a tubulointerstitial inflammatory response that leads to progressive interstitial fibrosis. Correlative studies in humans lend further support to this idea. Thus, reducing proteinuria, such as that occurring with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), may be of therapeutic value[3]. Since nephropathy develops in only 20% to 40% of diabetic patients, it is apparent that factors other than hyperglycemia are operative in the pathogenesis of kidney disease. Among these factors, genetics is important, as highlighted by the tendency of diabetic nephropathy to cluster in families and in ethnic groups such as the Pima Indian[25]. Although the susceptibility genes have not been clearly delineated, genes encoding the angiotensin I converting enzyme, aldose reductase, and heparan sulfate may be involved. Diagnosis and Management of Diabetic Nephropathy The onset of diabetic nephropathy is often silent, and because early intervention can slow its development and progression, it is important that diabetic patients be routinely screened for early evidence of renal involvement[2]. A small increase in the amount of albumin excreted in the urine (microalbuminuria) is the earliest manifestation of nephropathy (Table IV)[4,26]. Trace amounts of albumin are undetectable by dipstick; they must be measured by sensitive immunologic-based assays. The amount of albumin excreted is expressed relative to time or urinary creatinine level, which serves to correct for variations in urine concentration. Screening assays can be done on spot urine collections or timed collections over 24 hours or less. Because of the normal variability of albumin excretion, assays should be repeated on 2 or 3 occasions over several months before the results can be considered indicative of renal involvement (Table IV)[2]. In patients with microalbuminuria, ~30% to 45% progress to macroalbuminuria over ~10 years, whereas a much smaller number regress to normoalbuminuria[27]. Accordingly, when microalbuminuria is first detected, it is advisable to include a nephrologist in patient management. In addition to being predictive of the development of overt diabetic nephropathy, microalbuminuria represents a risk factor for the development of cardiovascular disease[16]. Hypertension Fortunately for the hypertensive diabetic patient, it is now well established that in addition to modifying the risk of cardiovascular disease and retinopathy, aggressive hypertension control can modify the natural history of diabetic kidney disease. Accordingly, careful measurement of blood pressure is important whenever the diabetic patient has an office visit. Several excellent studies (3,14,15,23) have established that antihypertensive therapy with a variety of agents can slow the progression of diabetic nephropathy. Among the antihypertensive agents shown to be effective in lowering blood pressure in diabetic patients are diuretics, b-blockers, a-blockers, calcium channel blockers, ACE inhibitors, and ARBs. Although there are only a few head-to-head comparisons of antihypertensive drugs, it is well documented that ACE inhibitors or ARBs can modify the progression of diabetic kidney disease, even in normotensive subjects. It appears these agents have a salutary effect beyond that obtained from lowering blood pressure. In the landmark captopril study of type 1 diabetics[28], this ACE inhibitor significantly reduced the progression of diabetic nephropathy. Proteinuria decreased and the endpoints of doubling of the serum creatinine level, death, or ESRD were reduced by 50%. The effectiveness of ACE inhibitors in type 1 diabetes was subsequently confirmed in a meta-analysis of 12 clinical trials that showed ACE inhibitors reduced the risk of progression from microalbuminuria to macroalbuminuria by 62% and that regression to normoalbuminuria was 3 times greater among treated patients than in control patients[29]. Three recent studies with the ARBs losartan and irbesartan in type 2 diabetic patients demonstrated the value of this class of agent[30-32]. In microalbuminuric patients, irbesartan reduced the progression from microalbuminuria to macroalbuminuria. In patients with established nephropathy, the relative risk of time to the doubling of the serum creatinine and development of ESRD was reduced by irbesartan 33% and 37%, respectively, and by losartan 25% and 28%, respectively. Both losartan and irbesartan reduced overt proteinuria. Because ACE inhibitors and ARBs have a salutary effect on the course of diabetic nephropathy over and above their blood pressure lowering effect, their usage forms the mainstay of hypertension control and renoprotection in diabetes. To date, there are no large-scale trials comparing the efficacy of ACE inhibitors with that of ARBs or studying the value of combination therapy. However, if hypertension or proteinuria persists with the use of a single agent, it has been suggested that these 2 agents be used in combination[33]. Antihypertensive treatment should be especially aggressive in the diabetic patient because of the high cardiovascular complication rate in these patients and the established benefit of lowering blood pressure (Table V). The recommended treatment goal is 130/80 mm Hg[15,34] or, in patients with proteinuria of >1g/day and impaired renal function, 125/75 mm Hg[34]. The scheme for the use of antihypertensive agents needs to be adjusted on an individual basis, taking into account preexisting cardiovascular disease and the age of the patient. Initiation of therapy should include attention to lifestyle modifications, including weight loss, sodium restriction, moderate exercise, reduction of alcohol consumption, and smoking cessation. The latter is important since cigarette smoking has an adverse effect on the kidneys[35]. Hyperglycemia Two major clinical trials, the Diabetes Control and Complications Trial (DCCT)[36] and the United Kingdom Prospective Diabetes Study (UKPDS)[37], convincingly demonstrated that intensive glycemic control reduces the risk of developing microalbuminuria and nephropathy. Accordingly, the glycemic control recommendations provided by the American Diabetes Association should be rigorously followed. Dietary Protein Restriction Although a clear benefit of dietary protein restriction has not been established, based on small positive clinical studies a protein intake of < 0.8 g/kg is recommended for patients with macroalbuminuria with further restriction when GFR falls. Special Considerations When managing diabetic patients with impaired renal function it should be kept in mind that drug pharmacokinetics may change as renal function declines. Thus, drug dosage may have to be modified. For example, insulin requirements may fall as kidney function declines, necessitating a reduction in dosage[38]. In addition, metformin accumulates in renal failure and, as the risk of lactic acidosis increases, the drug should be discontinued. It is also important to recognize that patients with diabetic nephropathy are at increased risk for developing radiocontrast-induced renal failure[39]; thus, radiocontrast-requiring procedures should only be carried out if essential. Azotemic patients should be well hydrated and low doses of contrast medium used. It is also important to consider that renal failure in diabetic patients may arise for the same reasons it occurs in nondiabetic patients. For example, in the patient with autonomic neuropathy or in the older man who may have benign prostatic hypertrophy, an ultrasound to rule out obstructive uropathy is prudent. Also, since retinopathy eventually develops in virtually all patients with long-standing advanced diabetic nephropathy[14], the absence of retinopathy in a diabetic patient with overt renal disease raises the question whether a cause other than diabetes is responsible for the nephropathy. Unfortunately, even with vigorous management and slowing of the course of the disease, established diabetic nephropathy is progressive, and when the advanced stage of renal failure is reached the criteria for transplantation or dialysis therapy for diabetic patients are the same as for nondiabetic subjects. Early placement of a vascular access is especially important in diabetic patients because of problems caused by advanced atherosclerosis. It is generally believed that early initiation of dialysis may improve the clinical course. Summary Because of the frequent presence of comorbid conditions, the management of diabetic patients is more complex and the outcome worse than for nondiabetic patients. Thus, it is especially important in diabetic patients that renal involvement be detected early and that an intensive, multidisciplinary approach be applied to prevent the development and progression of renal disease and other complications of diabetes. In a recent study in which patients with type 2 diabetes and microalbuminuria were followed for an average of 8 years, it was shown that long-term, target-driven, intensified intervention aimed at multiple risk factors reduced the risk of cardiovascular and microvascular events -- including nephropathy -- by ~50%[40]. CME Information The print version of this article was originally certified for CME credit. For accreditation details, contact the publisher. Clinical Cornerstone, 105 Raider Boulevard, Suite 101, Hillsborough, NJ 08844-1528. Table I. Clinical Stages of Diabetic Nephropathy in Type I Diabetes
BP = blood pressure; ESRD = end-stage renal disease; GFR = glomerular filtration rate; RBF = renal blood flow. Table II. Characteristic Morphologic Changes in the Diabetic Kidney
Table III. Pathogenic Factors Mediating Functional and Structural Changes in the Diabetic Kidney
AII = angiotensin II; AGEs = advanced glycation endproducts; CTGF = connective tissue growth factor; IGF-I = insulin-like growth factor-I; PDGF = platelet-derived growth factor; PKC = protein kinase C; TGF-b = transforming growth factor-b.
Sidebar: Key Points
Sidebar: Dialogue Box Editorial Board: Would you start an ACE inhibitor (ACEI) or an ARB in a diabetic patient with microalbuminuria even if the patient were normotensive? |
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