IF The National Kidney Foundation The Official Journal of

Atnerican Journal of Kidney Diseases

VOL XX, NO 6, DECEMBER 1992

IN-DEPTH REVIEW

Diabetic Nephropathy in Insulin-Dependent Patients Julia A. Breyer, MD • Oiabetic nephropathy is a serious complication of insulin-dependent diabetes mellitus (100M) that affects 30% to 40% of 100M patients with a predictable time of onset. Epidemiologic data suggest that either a genetic susceptibility, perhaps for hypertension (HTN), or an environmental exposure selects out that subset of 100M patients and destines them to develop diabetic nephropathy. Hopefully, assessing glomerular hyperfiltration, urinary albumin excretion rate (AER), glycemic control, mean arterial pressure (MAP), and perhaps early morphologic changes will allow early identification of this high-risk group of 100M patients before overt nephropathy is present. Once nephropathy appears, renal function inexorably declines, although the natural history of this progression may be changing with earlier therapeutic intervention. 100M patients with nephropathy suffer a high mortality rate compared with 100M patients without nephropathy or with nondiabetic end-stage renal disease patients. This is primarily due to malignant atherosclerotic disease manifested as coronary, peripheral, and cerebral arterial disease. Therapeutic interventions of demonstrated benefit in slowing the rate of decline of glomerular filtration rate (GFR) include blood pressure control and low-protein diets. Strict blood sugar control or treatment with aldose reductase inhibitors, converting enzyme inhibitors (eEls), or inhibitors of advanced glycosylation end-product formation are of possible benefit, but are awaiting clinical trial results. © 1992 by the National Kidney Foundation, Inc. INOEX WOROS: Oiabetic nephropathy; insulin-dependent diabetes; kidney failure.

D

IABETIC NEPHROPATHY is the single most common cause of end-stage renal disease (ESRO) in the United States, with diabetic patients accounting for 35% of all the patients enrolled in the Medicare ESRO program. 1 Patients with diabetes will soon account for nearly 50% of all renal failure patients if the current rate of increase continues. 2 In 1988, the cost to Medicare for ESRO patients with diabetes exceeded $1 billion dollars per year, while the amount spent in 1990 is projected to exceed $2 billion dollars per year.3 These Medicare ESRO data includes both patients with insulin-dependent diabetes (100M; type I) and those patients with non-insulin-dependent diabetes (NIOOM; type II). This review will focus on patients with 100M. More striking than the cost in dollars, is the cost in morbidity and mortality for patients with diabetic nephropathy. Patients with 100M and diabetic nephropathy as manifested by proteinuria (>0.5 g protein/24 h) have a 100-fold greater risk of dying relative to a nondiabetic population

(Fig 1).4,5 100M patients without proteinuria have only a twofold increase in their relative mortality. Of 1,475 patients diagnosed with diabetes before 1953, only 10% with nephropathy were alive 40 years after the onset of diabetes, while greater than 70% of the patients without renal disease were alive. 6 Although the overall mortality rate for patients with diabetic nephropathy is improving, death is just as likely to occur from macrovascular disease as from renal failure. 4 ,5,7-9 Oespite the impact of diabetic nephropathy on society and the individual, the epideFrom the Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN. Received May 21, 1992; accepted in revised form July 23, 1992. Address reprint requests to Julia A. Breyer, MD, Assistant Professor of Medicine, Division of Nephrology, Vanderbilt University Medical Center, S-3223 MCN, Nashville, TN 37232-2372. © 1992 by the National Kidney Foundation, Inc. 0272-6386/92/2006-0001$3.00/0

American Journal of Kidney Diseases, Vol XX. No 6 (December), 1992: pp 533-547

533

JULIA A. BREYER

534 125

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30 10 20 Duration of diabetes (years)

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60

80

Fig 1. Relative mortality in IDDM patients with proteinuria (-) and without proteinuria (- - -). (Modified with permission.·)

miology, natural history, pathogenesis, and potential therapeutic interventions have only begun to be elucidated, leaving many basic questions unanswered. EPIDEMIOLOGY

Diabetic nephropathy rarely develops before 10 years' duration of diabetes. Approximately 40% ofIDDM patients have proteinuria after 40 years' duration of diabetes. The cumulative incidence of diabetic nephropathy in relation to duration of diabetes is depicted in Fig 2, and similar incidence patterns have been reported. 6,10-13 Interestingly, in two clinical cohorts of patients with IDDM, the cumulative incidence of proteinuria declined for patients whose diabetes was diagnosed in the 1950s compared with those diagnosed in the 1930s.4,10,11 The annual incidence of diabetic nephropathy peaks just before 20 years' duration of diabetes and thereafter declines (Fig 3).6,11 This pattern of increasing and decreasing annual incidence suggests the risk of developing diabetic nephropathy is not constant over the duration of diabetes and that a pool of susceptible patients becomes exhausted. While it is known that approximately 40% of IDDM patients will develop diabetic nephropathy, those patients who survive 35 years of diabetes without developing nephropathy are at extremely low risk of doing so in the future. These data suggest that either a genetic susceptibility or an environmental exposure may influence the risk of developing nephropathy, The reported familial clustering of

40

Fig 2. Cumulative incidence of diabetic nephropathy in relation to duration of diabetes in 907 IDDM patients. (Reprinted with permission. 5 Copyrlght © 1984 by American Diabetes Association, Inc.)

diabetic nephropathy is consistent with a genetically determined susceptibility.14,15 An increased incidence of albuminuria and end-stage renal disease (ESRD) secondary to diabetic nephropathy occurs in diabetic siblings of probands with diabetic nephropathy. Diabetic siblings of duration-matched probands without nephropathy have few renal complications. Although these data support a shared genetic susceptibility, the influence of common environmental factors has not been evaluated. In reviewing data reported to ESRD Network 17, blacks with diabetes (type I and type II) were found to have a 3.6-fold greater risk of developing ESRD than whites with diabetes. 16 This is comparable to the black to white incidence ratio of 2.6 reported in a Michigan study.17 Similarly, Mexican Americans and American Indians with diabetes have higher rates of diabetic nephropathy 4.0

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Fig 3. Annual incidence of diabetic nephropathy in relation to duration of diabetes in 907 IDDM patients. (Reprinted with permission. 5 Copyright © 1984 by American Diabetes Association, Inc.)

535

DIABETIC NEPHROPATHY

than whites?,18 It is not known whether these racial differences are due to genetic, environmental, or other factors.

IDDM patients with GFR less than 125 mLI min and a 53% positive predictive value occurred in patients with GFR greater than 125 mL/min.22 However, the overlap occurring in the GFR of the patients who later develop nephropathy with those who do not, indicates an early measurement ofGFR alone cannot be the sole predictor of the development of renal disease. In contrast, in a small retrospective study and in a study where renal function was estimated only by serum creatinine, hyperfiltration was not found to predict the onset of nephropathy.23,24 Increases in GFR in patients with nephropathy seem to correlate with elevated erythrocyte sodium-lithium countertransport rates and increased glomerular surface areas (renal hypertrophy).25,26 Also, IDDM 'patients appear to have a much greater increase in GFR after amino acid infusions than normal subjects. 27 In animal models of diabetes, glomerular hyperfiltration is associated with increments in renal plasma flow , due to renal vasodilatation, and increases in the glomerular transcapillary hydraulic pressure gradient, which lead to glomerular sderosis?S The pathogenesis of the hyperfiltration is not clearly established, but the presence of the following conditions may contribute: hyperglycemia, insulin deficiency, augmented glucagon and growth hormone levels, increased ketone bodies, dietary protein excess, an altered renin angiotensin axis, altered prostaglandin production, glomerulopressin secretion, elevated kinin production, elevated atrial natriuretic factor levels, and volume expansion. 22 ,29-33

NATURAL HISTORY

At the time of diagnosis of diabetes, functional changes in the kidney are present in virtually all patients (Fig 4). Within a few years, morphologic changes occur in the kidneys of most IDDM patients. During this "silent period" when no overt disease is present, predictors of the development of diabetic renal disease such as hyperfiltration, microalbuminuria, hypertension (HTN), and poor glycemic control frequently occur. Approximately 17 years after the onset of IDDM, frank proteinuria is manifested in those 40% ofIDDM patients destined to develop overt diabetic nephropathy. Once proteinuria is established, renal function inexorably declines, with 50% of patients reaching ESRD within 7 years of the onset of proteinuria. Functional Changes

At the onset of diabetes, virtually all patients experience functional changes such as increased kidney size, albuminuria, which reverses with blood sugar control, and dramatically elevated glomerular filtration rates (GFR), which decrease with the initiation of insulin therapy. 19-21 In a retrospective study and a larger prospective study, IDDM patients had increased GFR long before the onset of incipient or overt nephropathy and the increased GFR predicted the later development of nephropathy.2o,22 A negative predictive value of 95% occurred in

r---INCIPIENT NEPHROPATHY----, Predictors? • Hyperfiltration • MicroaJbuminuria • Rising Blood Pressure

HTN

• Poor Glycemic Control

o I

2

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5

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Onset of

Fig 4_ The natural history of diabetic nephropathy.

Y

Time (years)

11-23

Onset of Proteinuria

FUNCTIONAL CHANGES

STRUCTURAL CHANGES

· i GFR

•

• Reversible Albuminuria

· i Kidney Size

i Glomerular Basement Memb. Thickening

• Mesangial Expansion

I

13-25

I

Rising Creatinine

15-27

I

End Stage Renal Failure

536

Morphologic Changes

At the onset of diabetes, renal biopsies are normal. However, within 1.5 to 2.5 years, glomerular basement membrane (GBM) thickening begins in virtually all patients with diabetes. 34 Five distinctive lesions can be recognized in the glomeruli of 100M patients in addition to GBM thickening: nodular (Kimmelstiel-Wilson) and diffuse forms of intercapillary glomerulosclerosis, the capsular drop lesion, the fibrin cap lesion, and mesangial expansion. 35 These changes, along with afferent and efferent arteriolar hyalinosis, increased renal extracellular membrane albumin, and IgG localization in the glomeruli, are diagnostic of diabetic nephropathy.36 Although, no correlation exists between the GBM thickening and clinical renal function, mesangial expansion does correlate with creatinine clearance as evidenced by decreased renal function associated with increased mesangial expansion. 34.37 100M patients with nephropathy demonstrate larger mean glomerular volumes and a greater percentage of sclerosed glomeruli than subjects with normal kidney function. 38 Although diabetes is predominantly a glomerular disease, altered structure and function of the renal tubulointerstitium are present. The degree of interstitial fibrosis correlates with the development of reduced GFR. Also, with the tubulointerstitium comprising the bulk of the kidney, the hypertrophy of the kidney in diabetes is contributed to by the expansion of the tubulointerstitium. 39 A variety of important tubular functional defects have been described, including impaired tubular reabsorption of low-molecular weight proteins (N-acetyliJ-D-glucosamidase) and albumin; increased sodium reabsorption leading to a volume expanded state; hypercalciuria; and impaired hydrogen and potassium excretion. 4o Oespite all the tubular and glomerular changes described, no one has yet demonstrated, in humans, that either a single renal biopsy or a series of renal biopsies can predict who will develop clinically significant diabetic nephropathy. The genesis of the morphological changes is not clearly established, yet transplant data do provide some clues. Normal kidneys transplanted into 100M patients develop diabetic morphologic changes, while diabetic kidneys transplanted into nondiabetic ESRO patients resolve their di-

JULIA A. BREYER

abetic lesions. 41 This strongly suggests that an intrinsic defect in the kidney is not the predisposing factor in the development of diabetic nephropathy, but rather something occurring in the diabetic milieu. Glomerular hemodynamic changes also appear to be critical for the development of diabetic nephropathy, since both in diabetic rats who have had their renal artery clipped and in humans with unilateral renal artery stenosis, the kidney distal to the blocked renal artery is protected from developing the morphologic changes of diabetes, while the contralateral unblocked kidney does develop diabetic nephropathy.42,43 Studies in animal models of diabetic nephropathy have demonstrated that maneuvers which alter glomerular hemodynamics affect the progression of the renal disease. 28 Although the diabetic milieu and exposure to the systemic circulation appear necessary for the development of the morphologic changes in the kidney, the pathogenesis of these changes on the molecular level is not clearly established and is beyond the scope of this review. Candidate defects include abnormal regulation of glycosaminoglycans, alteration of extracellular matrix, accumulation of advance glycosylation end-products, disturbed platelet functions, abnormal cytokine or growth factor production, abnormal aldose reductase activity, abnormal glomerular eicosanoid production, and inhibition of glomerular N-deacetylase and, hence, heparan sulfate biosynthesis. 39,44-50 Predictors

Renal hypertrophy, glomerular hyperfiltration, and specific morphologic changes are seen in many, if not most diabetic patients (Fig 4). However, none of these indicators alone identify the subset of 30% to 40% of 100M patients destined to develop clinical diabetic nephropathy. Being able to predict that subset of 100M patients would be an important tool and allow early preventive intervention. In an attempt to develop an early predictor of diabetic nephropathy, a sensitive radioimmunoassay for urinary albumin was developed to determine if subclinical elevations of urinary albumin excretion, in diabetic patients without frank proteinuria, would predict later development of proteinuria and diabetic ESRO. 51 There are currently multiple methods for determining albumin excretion rates (AERs) in a va-

537

DIABETIC NEPHROPATHY

riety of types of urine collections. Normal albumin excretion in the urine is less than 30 mg/24 h. Microalbuminuria is defined as an AER of 20 to 200 f.lg/min or 30 to 300 mg/24 h. Patients with microalbuminuria have a negative urine dipstick for protein and a normal 24-hour urine protein excretion measured in the usual manner. Overt dipstick proteinuria is defined as greater than 300 mg/24 h of albumin excretion. As shown in Table 1, transient causes of microalbuminuria such as hyperglycemia, HTN, congestive heart failure, urinary tract infection, and excessive physical exercise must be considered. If the AER is elevated in a single collection, persistent microalbuminuria needs to be documented by the occurrence of three elevated collections over 3 to 6 months. A single elevated collection is not adequate documentation. The reported prevalence of microalbuminuria in patients with 100M varies widely (3.7% to 23.0%), depending, at least in part, on how the population is selected in terms of the duration of diabetes or degree of microalbuminuria. 52·55 Duration of diabetes, glycemic control, and elevations in the mean arterial pressure (MAP) correlate with the presence of microalbuminuria. The presence of microalbuminuria in 100M patients is highly predictive of progression to clinical diabetic nephropathy during the next 10 to 15 years (Table 2).8,20,56,57 The lower level of microalbuminuria at which risk for diabetic nephropathy begins to increase has varied. GFRs in patients with microalbuminuria are well preserved or increased, but may begin to decrease once the AER exceeds 70 f.lg/min. The excretion of iJ2-microglobulin, a marker of tubular damage, does not increase until the AER exceeds 1,000 f.lg/min.58 Two studies have attempted to correlate micro albuminuria with the morphologic changes seen on biopsy, with conflicting reTable 1. Evaluation of Microalbuminuria

1. Test 100M patients of greater than 5 years' duration every 2 years. 2. Rule out causes of transient microalbuminuria: hyperglycemia, urinary tract infection, physical exercise, essential HTN, congestive heart failure, water loading. 3. If AER is elevated, repeat three times over 3 to 6 months to define persistent microalbuminuria.

Table 2. Predictive Value of Microalbuminuria

No. of Patients

Study

Parving, 198256

25

Viberti, 198630

63

Mogensen, 1984 Mathiesen, 1984

20

57

43 71

AER (!'g/min) Cutoff

% of Patients Developing Nephropathy

>28 30 15 70 0 (,)0 o

10

2

4 Years after onset of proteinuria

6

Fig 5. Cumulative incidence of coronary heart disease in patients with (e - e) and without (0 - 0) nephropathy. (Reprinted with permission.'02)

540

JULIA A. BREYER

Also, not only are there increased rates of coronary artery events, but also excessive cerebral and peripheral arterial complications in IDDM patients on dialysis or posttransplant. 9,104,105 Last, in addition to advanced atherosclerosis, malnutrition may play an important role in the increased mortality of the diabetic dialysis patient. A retrospective logistic regression of analysis of 12,000 hemodialysis patients found that the relative risk of diabetes fell after adjustment for decreased albumin.106 Thus, despite advances in renal replacement therapies, malnutrition, infection, and arthrosclerotic diseases shortens the life of the IDDM patient with ESRD. THERAPEUTIC INTERVENTION

The major therapeutic interventions that have been evaluated include antihypertensive therapy, improved diabetes control, treatment with aldose reductase inhibitors, treatment with inhibitors of the formation of advanced glycosylation endproducts, and the restriction of dietary proteins.

Antihypertensive Therapy Multiple studies have demonstrated that in IDDM patients with proteinuria and declining GFR, lowering MAP dramatically slows the rate of decline in renal function and improves patient survival (Fig 6.)107-111 Slowing the rate of decline in GFR for example from 0.89 mL/min/mo to 0.22 ml/min/mo delays ESRD by approximately 342 months in patients starting with a GFR of 100 mL/min (Fig 6). This dramatic slowing of the rate of decline in GFR occurs despite relatively modest blood pressure control (Fig 6). IDDM patients with microalbuminuria may be overtly hypertensive or may have MAP values that are not overtly hypertensive, but often are significantly higher than the MAP values in IDDM patients without nephropathy."2 Antihypertensive therapy in IDDM patients with microalbuminuria decreases AERs."2-"7 However, studies have not been completed to determine whether a reduction in microalbuminuria will lead to better-preserved GFR. Data from experiments in diabetic rats not only suggest that blood pressure control improves renal survival, but also that specific antihypertensive agents such as angiotensin converting enzyme inhibitors (CEls) have superior effects to other antihypertensive agents. This may be due

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to their unique effects on glomerular hemodynamics. 1l8 ,119 In diabetic rat models, increased glomerular capillary pressures contribute to the development of diabetic nephropathy, and lowering these glomerular pressures with CEls preserves renal structure and function. 1 19,120 In animal models, CEls have been effective despite the normal or reduced renin levels typically found in diabetic rats and humans. A number of studies in humans with IDDM have examined the effects of CEls on microalbumunirua, proteinuria, or preservation of GFR with conflicting resultS." 3,14,121-126 Many of these studies were hampered by small patient numbers, the absence of an appropriate control group, or the presence of concurrent illnesses in the patients studied. However, a meta-regression analysis of 77 experimental groups including controlled and uncontrolled studies in IDDM and NIDDM patients concluded that CEls had an ability to decrease proteinuria and to preserve GFR in patients with diabetic nephropathy that was uniquely independent of blood pressure changes. '27 In a study in which normotensive, microalbuminuric IDDM patients were given placebo or CEI, the group given CEI had a 5 mm Hg decrease in MAP and a significant decrease in AER. 113 This suggests the possibility that, even in normotensive IDDM patients, specific antihypertensive agents may be of benefit. The Col-

DIABETIC NEPHROPATHY

541

Table 3. Does Control of Hyperglycemia Alter the Course of Diabetic Nephropathy? No. of Subjects

Treatment Duration

Hyperfiltration

12

12 mo

Hyperfiltration with amino acid infusion Microalbuminuria

12

3wk

Jorgensen, 1992'39

Microalbuminuria

45

Feldt-Rasmussen 1986'40 Kroc, 1984'4' Reichard, 1991'42 Bending , 1984144

Microalbuminuria Microalbuminuria Microalbuminuria

Study

Wiseman, 1985'36 Tuttle, 1991'37 Viberti, 197938

Renal Function

Proteinuria

Glucose Control

Outcome

Remarks

HbA,

.j.GFR

None

Blood glucose

.j.GFR

Questionable blood glucose control

.j.AER

Short-term effects

7 yr

Blood glucose HbA,

.j.AER

36

2 yr

HbA,

.j.AER

Poor BS control, tAER ; Fair and good BS control, no change in AER BP different among groups

70 96

8 mo 5 yr

HbA, HbA,

.j.AER .j.AER

2 yr

HbA,

No effect

7

6

24 h

Only 1 AER at entry Changes relate to mean HbA, not treatment group Small number of subjeCts

Abbreviation: BS, blood sugar.

laborative Study Group of Angiotensin Converting Enzyme Inhibition in Oiabetic Nephropathy is performing an ongoing study designed to determine ifCEls are of unique benefit in preserving renal function in 100M patients with overt nephropathy. In this clinical trial, more than 400 100M patients with overt nephropathy (proteinuria > 0.5 g/24 h, serum creatinine < 221 1Lmol/L [2.5 mg/dL]) were randomly assigned to receive either placebo or captopril. Although both normotensive and hypertensive patients were enrolled, blood pressure goals in both the placebo and captopril groups were identical. 128 So few studies have been conducted examining the effects of calcium channel blockers in 100M patients with incipient or overt nephropathy that no firm conclusions can be drawn about the potential beneficial effects independent of blood pressure control. 1 1 6,129, 130 Antihypertensive therapy slows the rate of decline of renal function in 100M patients with overt nephropathy and is currently the therapeutic intervention with the most established and significant benefit. Important unanswered questions remain. Will the initiation of antihypertensive therapy in the early stage of incipient nephropathy prove to have a long-term beneficial impact? What is normal blood pressure in an 100M patient with nephropathy? Are established normotensive goals (140/90 mm Hg) too high for this group of patients? Are specific antihy-

pertensives or combinations of these of added benefit in IDOM patients with nephropathy? Improved Diabetes Control It is intuitively appealing to postulate that hyperglycemia is the cause of renal damage in diabetic patients, and its control will prevent the disease. Tight control of blood glucose prevents the development of and ameliorates established diabetic nephropathy in animal studies. 131 ,132 Multiple retrospective studies show an association between the development of diabetic nephropathy and poor blood sugar control. 11,79,80, 133·135 In 100M patients who have baseline hyperfiltration and renal hypertrophy or who have an abnormal increase in GFR and kidney size in response to amino acid infusions, short-term strict blood sugar control leads to reductions in kidney size and GFR. 136,137 Short-term strict blood sugar control can also decrease microalbuminuria. 138 Several studies suggest that long-term blood sugar control ameliorates microalbuminuria (Table 3).139.1 42 Criticisms of these trials include lack of stratification based on blood pressure, small sample size, inadequate duration of follow-up, inadequate measurement of entry AER, and varying start points in the disease process. The Oiabetes Complications and Control Trial now ongoing with 1,400 subjects is designed to determine if strict blood sugar control will prevent the development or progression of microalbuminu-

542

ria. 143 This trial, in a preliminary report, notes that the patients in the strict control group have a significantly greater number of severe hypoglycemic episodes. Last, once proteinuria and decreasing renal function are established, strict blood glucose coritrol is both difficult to achieve (due to frequent hypoglycemia) and without benefit for preserving renal function . 144 However, in a single uncontrolled study not designed to address this question, hyperglycemia in patients with established nephropathy contributed to their decline in GFR.145 Aldose Reductase Inhibitors

The tissues most affected by the diabetic disease process, including nerves, kidney, retina, and lens, do not require insulin for their uptake of glucose. Substantial evidence indicates that a significant proportion of the excess glucose in these tissues is metabolized via the polyol pathway. The enzymes that form the polyol pathway are aldose reductase and sorbitol dehydrogenase. Aldose reductase reduces the excess glucose to sorbitol, initiating a cascade of biochemical alterations. This leads to decreases of myo-inositol concentration in many tissues, including the glomerulus. It is postulated that inhibition of the aldose reductase enzyme may reverse or prevent progression of diabetic renal disease. In diabetic rats, aldose reductase inhibitors reverse proteinuria and decrease the rate of mesangial expansion.146.147 In diabetic patients, aldose reductase inhibition in preliminary studies decrease urinary albumin excretion rates. 148 Aldose reductase inhibitors are of potential, but clearly not established, benefit and are currently being studied in a multicenter clinical trial. Prevention of the Formation ofAdvanced Glycosylation End-Products

Hyperglycemia accelerates formation of nonenzymatic advanced glycosylation end-products in tissues and may playa major role in the pathogenesis of diabetic complications. Glucose forms chemically reversible early glycosylation products with proteins at a rate proportional to the glucose concentration. However, some of the early glycosylation products on collagen and other longlived proteins of the vessel walls do not dissociate and instead undergo a slow complex series of chemical rearrangements that form irreversible

JULIA A. BREYER

advanced glycosylation end-products. The levels of these products do not return to normal when hyperglycemia is corrected. 49 Glycation of albumin may contribute to its loss across the GBM, and the accumulation of glycosylated proteins in the glomerulus may stimulate mesangial growth and matrix formation. 49,149.1 52 Macrophages have receptors for these advanced glycosylation endproducts and trigger a series of cytokine events. In 100M patients, advanced glycosylation endproducts accumulate at a faster than normal rate. The increase in circulating advanced glycosylation end-product peptides also parallels the severity of renal functional impairment in diabetic nephropathy.153 Aminoguanidine, a nucleophilic hydrazine compound, prevents both the formation of advanced nonenzymatic glycosylation products and the formation of glucose-derived collagen cross-links in vivo and in vitro. 154 This drug inhibits cross-linking in diabetic rats, as well as inhibits the characteristic increase in GBM thickness seen morphologically in the diabetic rat. 49 Aminoguanidine reduces albuminuria and glomerular sclerosis in diabetic rat models. 155 ,156 Interestingly, aminoguanidine is also an inhibitor of nitric oxide formation and, in diabetic rats, it prevents diabetic vascular dysfunction. 157 Low-Protein Diets

In most experimental animal models of renal disease, high-protein intake accelerates the deterioration in renal fun ction. I 58 In diabetic rats, a high-protein diet increases glomerular blood flow and pressure and accelerates glomerular scaring. 159 Low-protein diets reduce glomerular pressures and preserve kidney function and structure. In 100M patients with no or incipient renal disease, low-protein diets reduce glomerular hyperfiltration. 160 In a study of eight 100M patients with microalbuminuria, alow-protein diet decreased the AER.161 The effects of the low-protein diet in 100M patients with overt nephropathy and declining renal function have also been examined.162-166 In the study with the largest group of patients observed for the longest duration, the rate of decline in GFR was 1.01 mL/ min/mo for patients on the high-protein diet and only 0.26 mL/min/mo for those on the low-protein diet. 166 Dietary restriction of protein can slow the progression of chronic renal failure substantially in patients with diabetic nephropathy.

543

DIABETIC NEPHROPATHY

Other Interventions A variety of other interventions have been attempted in small studies in either diabetic rats or humans with different degrees of renal involvement.

These include octreotide, antiplatelet drugs, pentoxyphyline, thromboxane synthetase inhibitors, camostat mesilate, high-linoleic acid diets, and eicosapentaenoic acid ethyl esters. 167-174

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