ELSEVIER Renal Mortality Associated With Non-Insulin-Dependent Diabetes Mellitus Prasad Kilaru George L. Bakris INTRODUCTION D iabetic nephropathy is the most common cause of end-stage renal disease in the United States. Patients with insulin-dependent diabetes mellitus (IDDM) have twice the chance of developing renal failure compared to those with non-insulin-dependent diabetes mellitus (NIDDM).l Since the prevalence of NIDDM is ten times that of IDDM, most of the patients that progress to endstage renal disease (ESRD) are those with NIDDM.’ It is estimated that greater than 3% of the nearly 300,000 patients on dialysis have diabetes as an etiology; 90% of these diabetics have NlDDM associated nephropathy.’ Since the prevalence of NIDDM is higher in certain ethnic groups, i.e., 59.5% for nonHispanic whites, 92.8% for Mexican-Americans, and 84.3% for African-Americans, it is associated with a higher rate of ESRD.2 This is exemplified by a greater than six fold higher incidence of ESRD in Mexican- and African-Americans compared to non-Hispanic whites.* The paper will provide a brief overview of factors that predispose patients with NIDDM to develop nephropathy. It will also discuss specific antihypertensive strategies that may provide additional benefit to these patients. Department of Medicine (P.K.) Division of Endocrinology, Cook County Hospital and Department of Medicine, Division of Endocrinology, RushPresbyterian/St. Luke’s Medical Center and Division of Nephrology (G.L.B.), University of Illinois Medical Center, Chicago, Illinois, USA Reprint requests to be sent to: Dr. George Bakris, Rush University Hypertension, Rush Presbyterian/St. Luke’s Medical Center, 1725 West Harrison Street, Suite 117, Chicago, IL 60612, USA. ]ournal of Diabetes and Its Complications 11:104-111 0 Elsevier Science Inc., 1997 655 Avenue of the Americas, New York, NY 10010 RISK FACTORS FOR NEPHROPATHY Not every patient with diabetes, regardless of whether it is IDDM or NIDDM develops nephropathy. Thus, the 35%, on average, that develop nephropathy from either IDDM or NIDDM must have some genetic predisposition. Factors that increase the risk of nephropathy from diabetes are listed in Table 1. Diabetic nephropathy is known to occur in familial clusters. Eighty-three percent of diabetic siblings of IDDM patients with nephropathy also have nephropathy.3 Among subgroups with NIDDM, such as the Pima Indians, the risk of developing nephropathy is significantly higher among diabetic offspring if the patient has a parent with diabetic nephropathy.4 Diabetic subjects with a family history of hypertension also have an increased risk of nephropathy from diabetes5 Thus, a genetic predisposition for this process exists, yet is undefined, currently. To further support the notion of a genetic predisposition to nephropathy from diabetes, presence of microalbuminuria, a well-known marker of progressive renal failure in diabetes only occurs and increases in those destined to develop endstage renal disease.@ Microalbuminuria occurred among 14.3% of the diabetic offspring if neither parent had microalbuminuria, and in 22.9% if at least one diabetic parent had microalbuminuria.4 It was present in 45.9% of offspring if both parents had diabetes and microalbuminuria.5 One purposed genetically influenced marker that correlates with nephropathy is erythrocyte sodiumlithium countertransport activity. Increased activity of this transport system is observed in essential hypertension and in diabetics with hyperfiltration, i.e., elevated glomerular filtration rate.+12 This marker, however, is only reflective of those who already have microalbuminuria. Because microalbuminuria is cheaper and easier 1056-8727/97/$17.00 PI1 S1056-8727(96)00102-X J Diub Comp 1997; 11:104-211 RENAL TABLE 1. RISK FACTORS FOR DEVELOPMENT OF NIDDM NEPHROPATHY l l l l Family history Cardiovascular disease Hypertension Diabetic nephropathy Microalbuminuria Ethnicity Mexican-American Asian/Pacific Islander African-American Mauratian American-Indian Genes ACE gene polymorphism Insulin resistance Others MORTALITY ASSOCIATED WITH NIDDM 105 TABLE 2. SIMILARITIES AND DIFFERENCES BETWEEN NIDDM AND IDDM NEPHROPATHY IDDM IncreasedGFR Microalbuminuria prior to HTN l Progressionto ESRD . HTN antedating diabetes l l l Obesity Yes Yes 35%40% Rare Rare NIDDM Yes Occasionally 25%-30% Commonly Commonly NlDDM, non-insulin-dependent diabetes mellifus; IDDM, insulin-dependent diabetes mellifus; GFR, glomerularfilfrafion rate; HTN, kyperfension; ESRD, endsfage renal disease. acterize the early course of NIDDM. These studies have led to the observation that there are a number of simienzyme. larities between the two forms of diabetes. These are summarized in Table 2. This paper will review some of these similarities but to measure and correlates strongly as a predictor of focus on how specific therapeutic interventions can nephropathy development, the sodium-lithium countalter the natural history of NIDDM-associated renal ertransport system has a role only in the research arena. disease. The renin-angiotensin system may also play a role The interval between the diagnosis and onset of renal in the pathogenesis of diabetic nephropathy. Japanese failure associated with diabetes ranges from 5 to 25 patients with NIDDM and nephropathy had an excess years. A small retrospective study from New Zealand, frequency of the genotype insertion/deletion (ID) com- found that nephropathy progressed more rapidly in pared to diabetic patients without nephropathy and patients with NIDDM compared to those with IDDM, less than expected frequency of the insertion (II) geno- even though diabetic control was worse and blood type compared to healthy controls.13This has also been pressure reduction was greater in the IDDM patients described, however, among African-Americans with (1.7 ml/mm/month versus 1.1 mL/min/month, p = renal injury from hypertension without diabetes. Thus, 0.017.15Similarly increased rates of decline in glomeruit is probably not a unique marker of nephropathy lar filtration rate (GFR) were reported in Pima Indians from diabetes. with NIDDM. The rate of decline was 2 to 3 times the Plasma anigiotensin-converting enzyme (ACE) lev- rates reported for IDDM.16 els correlate with specific genotypes that may also conMicroalbuminuria is known to be an early marker fer risk for nephropathy development. Patients with of nephropathy in both IDDM and NIDDM patients. the insertion (II) genotype have the lowest and deletion Moreover, several studies have documented that mi(DD) genotype the highest level of serum ACE activcroalbuminuria is associated with increased risk of carity. I3 The increased frequency of D allele has been diovascular deaths among patients with NIDDM.@,17.1s tauted as another risk factor for the development of Microalbuminuria is also associated with increased nephropathy in NIDDM. This might explain why ACE mortality and development of vascular disease, even inhibitors are so useful in the treatment of nephropaamong nondiabetic patients.19*20 thy. Additional discussions about the genetics of diabeIn the initial stages of diabetes, glomerular hyperfiltes is beyond the scope of this paper. Several collaboratration and microalbuminuria were thought not to be tive studies, however, are seeking a specific genotype present in NIDDM. However, these findings were rethat may predispose diabetic patients to develop ne- corded in patients with established nephropathy from phropathy. NIDDM.21,23 Among newly diagnosed patients with NIDDM, microalbuminuria was noted to be prevalent NATURAL HISTORY OF NIDDM in up to 37%.24-25 Microalbuminuria, however, is not a NEPHROPATHY universal finding among those with NIDDM. MoreThe natural history nephropathy is better defined in over, some patients continue to have normal albuminIDDM than in NIDDM. This is primarily due to the uria even after several years of NIDDM.26 timing of NIDDM onset, which is often uncertain.6,*4 Unlike patients with IDDM, who only rarely develop Several studies, however, have carefully tried to char- proteinuria during the early years of their disease, paNIDDM, converting non-insulin-dependent diabetes mellifus; ACE, angiofensin- 106 KILARU AND BAKRIS 1 Dizb Comp tients with NIDDM frequently have proteinuria. Note that, like IDDM, microalbuminuria may actually precede the diagnosis of NIDDM. This is not completely surprising, because we are often uncertain of the duration of NIDDM. Up to one-half the subjects that would qualify for a diagnosis of NIDDM are not clinically symptomatic.27 On average, at the time of diagnosis, a person with NIDDM has had the diseasefor more than 4 years.‘” Among newly diagnosed NIDDM patients, in the Rochester study, the prevalence of persistent microalbuminuria was only 2.7% among the 3049 years old patients (with presumably shorter duration of diabetes), and this prevalence raises to 12.5% in the group aged over 70 years old (presumably with longer duration prior to diagnosis) at diagnosis.28 In the 3049 years old group, the incidence of persistent microalbuminuria was lO/lOOO per year in the first 5 years of follow-up, and this rate is much higher (25/1000 per year) in the over 70 years old group.** Also, unlike in IDDM where the incidence of persistent microalbuminuria gradually increases with the duration of the diabetes, in NIDDM, there is no increase in this incidence rate.Z8In the same study, the cumulative incidence of persistent microalbuminuria correlated with the severity of diabetes at diagnosis. Please note that nephrotic range proteinuria was reported in eight of the original patients reported by Kimmelsteil and Wilson, seven of whom had NIDDM.29 PATHOGENESIS OF NIDDM The pathogenesis of NIDDM is not as well understood as IDDM. This is largely due to the fact that the animal models used to study this disease are models of insulinopenia. However, studies in animal models of both IDDM and NIDDM demonstrate the following commonalities: (1) increased glomerular capillary pressure, (2) albuminuria early in the course of the disease, (3) mesangial matrix expansion, and (4) development of glomerulosclerosis. Metabolic as well as hemodynamic factors play major roles in the pathogenesis of the diabetic nephropathy. It is clear that metabolic abnormalities such as hyperglycemia result in changes in glomerular morphology. These changes are further worsened by increases in intraglomerular pressure. Each of these factors is discussed below, and their interaction is represented in Figure 1. Hyperglycemia. Hyperglycemia, in the genetically susceptible individual, is the principal metabolic factor responsible for the development of diabetic nephropathy.30 The earliest morphologic changes seen in the diabetic kidney is mesangial volume increases as well as glomerular basement membrane thickening.31,32The Diabetes 4 i Morphologic Hemodynamic I I + --Stretch -1 mechanical 1 ACE-I L 1997; 11:104-111 kate efferent arteriole + NDCCB + c, 1Nephropathy I 4 mes&ial volume expansion Progression 1 FIGURE 1 The eflects of angiotensin-converting enzyme ACE inhibitors (ACE-l) and nondihydropyridine calcium antagonists (NDCCB) on progression of diabetic nephropathy. Abbreviations: PGC, glomerular capillary pressure; TGF-/3, transforming growth factor p. reasons for these effects of glucose lie in its osmotic effect as well as its effect on cell function. Glucose is transported across the endothelial and mesangial cells by an unregulated and insulin independent facilitated diffusion mechanism raising intracellular glucose levels to those of the elevated ambient glucose concentration33X High intracellular glucose also activates protein kinase C, which stimulates increased synthesis of matrix proteins such as fibronectin, laminin, and type IV collagen 35J6 Fibroblasts from diabetic mice also synthesize increased amounts of fibronectin and incorporate it into extracellular matrix (ECM) at an increased rate.37This excess amount of fibronectin combined with an already increased amounts of ECM proteins leads to mesangial volume expansion. In the streptozotocin-induced diabetic rat kidney, mesangial expansion is noted after 7 months of diabetes, and this expansion was largely reversed after pancreatic transplantation.38 In humans receiving allografts for diabetic nephropathy, tighter control of blood sugar results in less than one-half the mesangial volume expansion. 39 Arteriolar hyalinosis, glomerular ] Diab Camp 1997; 11:104-122 RENAL basement membrane thickness, and volume fraction of the total mesangium all showed significantly lower values when compared to patients maintained on standard insulin therapy. This indicates that hyperglycemia was contributory to the development of these adthat these verse changes, 39 It should be emphasized effects of glucose on morphology are independent of blood pressure. Another way glucose may cause renal morphologic change is through the increased generation of glycosylation endproducts. Glucose reacts with proteins (both structural as well as circulating) without the benefit of the enzymes, producing glycosylation products.40 Initially, the reaction produces compounds with a short half-life. These compounds undergo Amadori rearrangement producing more stable but still reversible sugar-protein adducts. These Amadori products then bind to structural proteins such as collagen and elastin on the glomerular basement membrane as well as other matrix components and produce chemically irreversible reactions that lead to altered morphology.41,Q Glycosylation of the basement membrane enhances the ability to bind to circulating proteins. As a result of this glycosylation, these proteins become resistant to the normal degradation processes leading to accumulation and expansion of the mesangium as well as the basement membrane thickening.43 Last, albumin is also glycosylated as part of this previously described process. The subsequently generated glycated albumin molecules are directly toxic to both mesangial and endothelial cells4 The mechanisms for this are beyond the scope of this paper but are reviewed elsewhere.44,45 Thus, microalbuminuria in the diabetic patient has different prognostic implications compared to a nondiabetic hypertensive patient.@ Moreover, it may cause renal injury.45,46 Thus, reduction of microalbuminuria theoretically should prevent injury.” Hemodynamic Factor. The two major hemodynamic processes that occur in the diabetic kidney are loss of renal autoregulation and increased efferent arteriolar tone 47,49 both of which cause an increase in glomerular capmary pressure (PGc). A discussion of these topics is beyond the scope of this paper but the reader is referred to several recent reviews on the topic.50,51The interaction between metabolic and hemodynamic factors is depicted in Figure 1. TREATMENT OF NEPHROPATHY While it is clear from long-term follow-up studies, like the Diabetes Control and Complication Trial, that aggressive control of blood glucose to fasting levels less than 120 mg/dL prevents progression of renal disease, this is not true once nephropathy is established.51 In such patients, only normalization of blood pressure has been shown to alter the natural history of disease MORTALITY ASSOCIATED WITH NIDDM 107 and reduce mortality in advanced diabetic nephropathy.52-56 Effective blood pressure control may be achieved with combinations of diuretics, B blockers, vasodilators, calcium-channel blockers (CCBs), or ACE inhibitors. All these agents have been reported to attenuate the progression of nephropathy. This is exemplified by a study utilizing metoprolol, hydralazine, and furosemide that showed a reduction in the rate of the fall of the glomerular filtration role (GFR) by as much as 6O%-75%.57-58 These agents also improved survival from 48% to 87% in such patients.59 Newer classes of agents, however, have been shown to have unique properties on progression of diabetic nephropathy. The remainder of this paper will concentrate on those agents. ACE Inhibitors. Several studies document that ACE inhibitors are clearly more effective in decreasing albuminuria as well as improving renal survival in patients with IDDM associated nephropathy. ACE inhibitors reduce urinary albumin excretory rates and slow progression of disease even in normotensive diabetics.“)-62 In a randomized controlled study, IDDM patients with overt nephropathy, were given either captopril or placebo for a median period of 2.7 years.@ Captopril treatment was associated with a 50% reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small disparity in blood pressure between the groups.63 In a subgroup analysis of the above study, when patients with nephropathy range proteinuria at the time of entry in to the study were analyzed, it was found that ACE inhibitors are still effective even if the patients have nephrotic range proteinuria.U The remission rate was 16.7% in the captopril group compared to 1.5% in the placebo group. One important difference between the groups was that the captopril group had significantly lower blood pressure (126 +- 8/81 2 8 mm Hg) and more reduction from baseline than the placebo group (140 + 13/85 + 8 mm Hg), and this blood pressure reduction may have played an important role in this reduction. In a recent meta-analysisof 104 published studies, involving more than 2000: patients, Weidmann et a1.56 have identified that ACE inhibitors have reduced the proteinuria by 37% and nondihydropyridine CCBs (NDCCBs) by 33%, whereas nifedipine has actually worsened the proteinuria by 5%56. The change in the blood pressure was comparable in all the treatment groups. Nifedipine also had the maximum decline in the GFR at 48%/year, compared to 1% for ACE inhibitors and 8% to placebo and 9% to the combination of diuretics and B blockers. It was also noted that ACE inhibitors are the only drugs that reduced the proteinuria, even if no reduction in blood pressure was 108 KILARU AND BAKRIS achieved. The achieve the same degree of proteinuria as the ACE inhibitors, the non-ACE inhibitors have to reduce the blood pressure by 20% more.56In another meta-analysis, Maki et al. also noted similar findings.55 In 14 randomized controlled trials, ACE inhibitors caused a greater decrease in proteinuria, improvement in glomerular filtration rate, and decline in mean arterial pressure. 55In a multivariate analysis of controlled and uncontrolled trials, each 10 mm Hg reduction in blood pressure decreased proteinuria, but ACE inhibitors and nondihydropyridine CCBs were associated with additional declines in proteinuria independent of blood pressure changes and diabetes.55,56 Last, in animal models of diabetes, ACE inhibitors are the only class of antihypertensive agent, thus far, shown to prevent mesangial volume expansion in the absence of blood sugar contro13’ This further supports a protective role of these agents, independent of blood pressure reduction. 1 Diab Cornp 1997; 21:104-211 nifedipine group started dialysis at the end of 3 years compared to captopril group.69 However, in a separate study with nitrendipine, there was a reduction in proteinuria and slowed decline in renal function70 This later study is the only one to show any long-term benefit on renal function in diabetic nephropathy patients. Thus, dihdropyridine CCBs in general, do not seem to protect against progression of nephropathy to the same extent as do nondihydropyridine CCBs. Reductions in proteinuria correlate with a slowed progression of renal disease and time to dialysis.5*,““* There are clear differences between the two subclasses of CCBs on proteinuria. In an early, small study that compared the effects of diltiazem with those of a sustained release nifedipine in 14 hypertensive NIDDM patients with renal insufficiency, both drugs reduced blood pressure to a similar level. However, the nifedipine group had an mcrease in proteinuria at the end of the 6-week study period. 71This observation has been made by a,number of different studies.55s56 The mechanism for this lack of effect on proteinuria lies in the fact that dihydropyridine agents do not alter glomerular permeability at the membrane leve1.72 Calcium-Channel Blockers. Despite their common biological action of blocking the entry of the calcium into the cell, calcium-channel blockers are a biochemically very heterogeneous group and have significantly different therapeutic actions. This is largely due to the Combination Therapy. Despite sharing some of the diversity of different calcium channels present in cells. final pathways in their action sequences, CCBs and Moreover, not all cells contain all calcium channels. ACE inhibitors have several different actions at differThus, partially explaining the diversity of actions; di- ent locations. The potential benefits of combining the hydropyridine (nifedipine-like) primarily vasculosel- two classesof agent is appreciated by viewing Figure ective and nondihydropyridines (verapamil or diltia1. Clinically, it is exemplified by an animal study that zem) affecting cardio-renal functions as well as the combined nitrendipine and enalapril and found the combination to be more effective in reducing proteinvasculature. Hemodynamically, the predominant effect of all uria and preventing development of glomeruloscleroCCBs is dilation of the afferent arterioleem They differ sis.73It should be noted, however, that blood pressure in their actions on the efferent arteriole. The dihydrowas significantly lower in the combination group compyridine CCBs have no effect on the efferent arterioles, pared to either drug alone. A recent study that evaluwhereas the nondihydropyridine group partially di- ated the combination of verapamil and trandolapril on lates these arterioles.e,67 In spite of these differences, proteinuria and renal function found that the combinahowever, efferent arteriolar dilatation is minimal com- tion reduced proteinuria and prevented glomerulosclepared to the predominant afferent dilatation. Thus, rosis in the absence of blood pressure reduction in the systemic blood pressure needs to be significantly lowstroke-prone spontaneously hypertensive rat.74 Moreered to reduce the intraglomerular pressure with all over, a separate study showed a benefit of verapamil types of CCBs. alone on preservation of renal morphology and funcNondihydropyridine CCBs have been documented tion in a remnant kidney model utilizing 24-h blood to reduce proteinuria and slow the progression of the pressure monitoring. 75Taken together, these data sugnephropathy in patients with NIDDM associated ne- gest that verapamil alone or in combination with an phropathy.68 Several long-term follow-up studies dem- ACE inhibitor have effects on renal morphology and onstrate that NDCCBs slow the progression of the ne- function that are, in part, independent of blood presphropathy significantly better than the conventional sure reduction. antihypertensives notably, diuretics and B blockers.56,58 Clinically, combination therapy is useful in reducing Moreover, their efficacy for preserving renal function side effects associated with CCBs. Moreover, ACE inmay be comparable to that of the ACE inhibitors.5658 hibitors and CCBs do not interfere with each other’s An example of differences between dihydropyridine antihypertensive actions, they may have synergistic CCBs and NDCCBs is exemplified by a 3-year study actions.76The combination of an ACE inhibitor-CCB using slow release nifedipine. This small study demon- may also reduce the adverse reactions associated with strated that five times the number of patients in the each other. While on combination therapy, the edema J Diab Comp 2997; 22:204-212 seen in association with nifedipine disappeared in three of four patients. 77In the same study, the combination therapy lowered the blood pressure more than monotherapy with either captopril or nifedipine alone. There are also reports of lesshyperkalemia when fixeddose ACE inhibitors-CCB combinations are used.” In NIDDM patients with proteinuria, the combination of a nondihydropyridine CCB, verapamil with lisinopril clearly demonstrated superiority over either of the respective monotherapies for slowing progression of renal disease.63This occurred despite lowering the blood pressure to a similar level in all three arms of the study. Soon after that, similar results were obtained for the combination of lisinopril with diltiazem.78 Other small studies have been recently reviewed using various ACE inhibitor-CCB combinations to examine changes in proteinuria. These have been recently reviewed, and the results parallel those previously described in this paper.76 In short aggressive blood pressure control, encompassing an ACE inhibitor as part of the armamentarium is critical to slow progression of nephropathy from diabetes. 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