Diabetic Nephropathy: Can the Natural History Be Modified? 1 ROBERT

G. NARINS, M.D. Ph//ade$hia,

Pennsyivania

Those diabetic patients who progress to advanced kidney disease constitute a subpopulation that is particularly vulnerable to the angiotoxic effects of the insulin-dependent disorder. Until the predisposing factors are identified, the most effective way to arrest renal deterioration is by controlling those currently recognized risk factors that accelerate the glomerulopathy. Treatments that normalize blood pressure, reduce dietary protein intake, and control hyperglycemia have been shown to retard the progression of diabetic nephropathy.

pproximately 30% of patients with insulin-dependent diabetes mellitus (IDDM) ultimately die of A renal disease or require dialysis or kidney transplan-

1

From Temple University, Philadelphia, Pennsylvania. Requests for reprints should be addressed to Robert G. Narins, M.D., Temple University Health Science Center, Room 580 PP, 3401 North Broad Street, Philadelphia, Pennsylvania 19140.

2A-70s

February 21, 1991

The American Journal of Medicine

tation [l]. The remaining 70% never develop clinically significant renal disease, even if followed for 30 to 40 years. In contrast to diabetic retinopathy, for which the incidence increases progressively with time, if the nephropathy has not occurred within approximately 20 years of diagnosing IDDM, it is unlikely ever to develop [l]. Thus, it appears that there is a vulnerable subpopulation of IDDM patients, but. the constituent forces underlying the vulnerability remain undefined. If, however, the factor(s) rendering certain patients vulnerable to the angiotoxic effects of IDDM could be identified, it might then be possible to craft therapies aimed directly at the inciting cause and thereby slow or halt the progression of the nephropathy. Short of identifying the root cause, the physician must restrict efforts to those associated risk factors currently known to modify the progression of established diabetic nephropathy (Table I). Recent studies [2,3] have identified the genetic nature of this vulnerability. IDDM patients with a family history of hypertension or with a parent or sibling with diabetic nephropathy have a much greater chance of developing the renal lesion. Blacks have a slightly greater incidence of diabetes and an even greater chance of developing the nephropathy as compared with diabetic whites [4]. Again, the transmitted vulnerability has not been clearly identified. Li et al [5] may have brought us a step closer by suggesting that increased sensitivity to various growth factors may be critically related to the nephropathy. Cultured skin fibroblasts from diabetic patients with nephropathy manifested a substantially greater growth response to a variety of added growth factors than did the cells from diabetic patients without the nephropathy [5]. It is tempting to speculate that any noxious damage to the kidney that releases growth factors might then excessively stimulate mesangial proliferation and matrix formation in this vulnerable subpopulation. Such pernicious stimuli as hypertension and hypercholesterolemia may injure the kidney enough to allow release of growth factors that, in turn, set the glomerular changes in motion. The increase in blood pressure that constitutes “damaging” hypertension in a vulnerable diabetic patient might require redefinition. What might otherwise be mild, inconsequential hypertension may, in a sensitive diabetic patient, elicit a mesangial response that sustains and accelerates the nephropathy. If the potential importance of growth factors to the nephropathy is proven and if the sensitivity of certain diabetic patients to them is also proven, new therapies directed at the synthesis and release of these chemicals and perhaps at their tissue receptors could be developed.

Volume 90 (suppl 2A)

SYMPOSIUM

The following discussion summarizes the effects of the key risk factors amenable to therapy that are known to modify the rate of progression of diabetic nephropathy.

Therapeutic Options in Diabetic Nephropathy Modifiers of Glomerular

Figure 1. Effects of antihypertensive

therapy on nephropathy in diabetic rats. C = control; DM = dlabetic; 0 = no therapy; TRX = triple therapy (hydralazine, hydrochlorothiazide, and reserpine); CAPT = captropril; MAP = mean arterial pressure (mean and standard error); SBP = systolic blood pressure; UAlbV = albumin excretion; FGS = focal glomerular sclerosis. (Reproduced with permlssion from Kidney Int. [8].)

-6 8= EiE 52 22 a3 Et? Gal c7&

Injury

Therapies

Growth factors Glomerular hypertension Dietary protein Hyperglycemia Hyperlipidemia Miscellaneous Coagulation Sorbitol pathway Thromboxane

Experimental diabetes is associated with asymmetric dilatation of afferent and efferent arterioles [61. The dilatation of the afferent vessel allows greater flow and a greater fraction of systemic pressure to reach fragile glomerular capillaries. Failure of the efferent arteriole to dilate as much as the afferent vessel sustains the elevation of the glomerular blood pressure. Glomerular hyperperfusion and glomerular hypertension are intrinsic components of the diabetic syndrome, at least in experimental animals [6]. Reducing the glomerular pressure has been shown in most series to improve the natural history of diabetic nephropathy in rats [7,8]. Anderson et al [8] compared the effects of triple antihypertensive therapy (hydralazine, hydrochlorothiazide, and reserpine) with that of monotherapy with captopril on nephropathy in diabetic rats to determine whether the choice of the antihypertensive agent influenced the course of the disease. A control group of nondiabetic rats and a group of untreated diabetic rats were also studied. Measurements were made after 6 to 10 weeks of diabetes and again after 16 months. Figure 1 summarizes the principal findings. By 6 to 10 weeks, the untreated diabetic rats had glomerular hypertension with normal mean systemic arterial pressure. As previously noted, afferent arteriolar dilatation allowed access to the glomerular capillaries of a greater fraction of systemic pressure. The control rats had normal glomerular and mean arterial pressures, as did the diabetic animals given either form of antihypertensive therapy (Figure 1). After 16 months, the untreated diabetic rats had become modestly hypertensive, whereas the systolic blood pressure was maintained at a normal level by the use of both antihypertensive regimens. Albumin excretion was obviously elevated in the untreated diabetic rats and was abnormal in the diabetic animals receiving triple therapy. However, proteinuria was virtually eliminated in the group of animals treated with captopril. Similarly, focal glomerular scarring had greatly increased in the untreated, hypertensive, proteinuric

Antibody to growth factor or receptor Antihypertensive agents tow-protein diet Tight glycemic control tipld4owering agents Heparin, antiplateletdrugs Aldose reductase inhibitors Thromboxane synthetase inhibitors

diabetic rats and was increased, though less severely, in the rats given the three-drug combination. Despite maintenance of normal systemic blood pressure, triple therapy was unable to prevent glomerular hypertension from occurring by 16 weeks. In contrast, treatment with captopril sustained normal glomerular and systemic pressures, prevented proteinuria, and precluded glomerular scarring. The investigators thus concluded that glomerular pressure plays an important role in the pathogenesis and development of glomerular scarring and that normalization of glomerular pressure affords protection against proteinuria and sclerosis. The triple drug regimen did not sustain glomerular capillary decompression in the long term and thus permitted the progressive deterioration of renal anatomy and function. In humans, a large and growing body of published reports has clearly established that reduction of elevated blood pressure retards the progression of nephropathy in patients with IDDM [9,10]. The three studies illustrated in Figure 2 are representative of the published studies. Mogensen [9] observed six patients for 24 months before treatment and then for an additional 73 months after initiating antihypertensive therapy with various combinations and doses of beta blockers, hydralazine, and furosemide. Mogensen determined whether blood pressure reduction altered the rate at which glomerular filtration was declining. The drugs effectively normalized systolic and diastolic blood pressures and clearly slowed the rate of loss of renal function from 1.2 ml/minute per month to 0.5 muminute per month.

to Ten Weeks

MAP

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117

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Diabetic nephropathy: can the natural history be modified?

Those diabetic patients who progress to advanced kidney disease constitute a subpopulation that is particularly vulnerable to the angiotoxic effects o...
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