The kidney in diabetes

The Kidney in Diabetes

S. MICHAEL MICHAEL DAVID

MAIJER. W.

M.

M.D.

STEFFES,

BROWN.

M.D..

Ph.D.

M.U.

Mlnnc:onnlis. %llinnrsotcr

From the Departments

of Pediatrics.

and Labo-

ratorv Medicine and Pathology, the University of Minnesota School of Medicine. Minneapolis. Minnesota. This work was supported by NIH Grants HL 23749 and AM 17697 and Grant 79R251 from the juvenile Diahetcs Foundation. Requests for reprints should he addressed to Dr. S. Michael Mauer. Mayo Box 491,420 Dclawarc Street, Minneapolis. Minnesota 55455.

The kidneys as a target organ for secondary microvascular complications of diabetes mellitus represents a health problem of enormous social cost. Recent studies in man and animals strongly support the concept that the primary responsibility for diabetic nephropathy rests with the metabolic derangements of the diabetic state. However, these metabolic derangements have complex biological effects; it is unlikely that hyperglycemia, per se, produces all of the nephropathic influences of diabetes. Alterations in microvascular hemodynamics in diabetes probably contribute to glomerular pathology. These alterations may be based upon disturbed vasoactive control mechanisms regulating angiotensin and prostaglandin secretion and metabolism. Although much remains to be learned about the pathogenesis of glomerular basement membrane and mesangial thickening in diabetes, these central structural abnormalities appear separable. Mesangial thickening is reversible by cure of the diabetic state in rats whereas glomerular basement membrane thickening is not. Treatment for the diabetic patient with end-stage renal failure has recently improved markedly. Although presently, kidney transplants from living related donors appear best, cadaver transplants and long-term hemodialysis are reasonable options. The kidney as a target organ for clinically important manifestations of the secondary microvascular complications of diabetes mellitus represents a vast problem. It is estimated that in the United States the cost of caring for the diabetic patient in end-stage renal failure will exceed one billion dollars by 1982[l]. In the main this reflects the fact that, in approximately 50 percent of the children with juvenile-onset insulin-dependent diabetes, renal failure will develop within an average of 20 years after its onset 12). Herein we review information, gleaned from studies of the kidney, pertaining to the controversey regarding the role of the metabolic disturbances of diabetes in causing microvasculopathy. We discuss the pathology of diabetic nephropathy with emphasis upon possible pathogenetic mechanisms. Present approaches to the treatment of diabetic nephropathy are evaluated. Finally, we submit our view of the future of this area. The Diabetic State and Diabetic Nephropathy. The argument that diabetic microvasculopathy develops independently of hyperglycemia has its strongest origins in the study of muscle capillary basement membrane (MCBM] thickness in subjects classified as “prediabetic” based upon both their parents being diabetic. Siperstein and coworkers (31 reported that MCBM thickness was increased in about 50 percent of these subjects despite the absence of demonstrable glucose intolerance. The controversey raised by these studies still rages today

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[4-6]and will not be fully reviewed here. Suffice it to say that the MCBM abnormalities described in the “prediabetic” are, if present at all, indeed subtle when compared with the gross abnormalities in this pathologic parameter which are correlated with clinically significant nephropathy and retinopathy [4]. One cannot, at present, preclude the possibility that there are genetic derminants to the susceptibility of a person or a species to diabetic microangiopathy [7]; and differing rates of progression of diabetic nephropathy in man may reflect different levels of susceptibility [8]. However, we would argue that in the absence of overt glucose intolerance this susceptibility rarely, if ever, leads to significant vital organ destruction. Recent reviews of the sparse reports of advanced diabetic nephropathy in patients with minimal glucose intolerance have led to the conclusion that, in most instances, the renal lesions described are not specific for diabetes mellitus in human subjects [7]. Thus, clinically significant diabetic nephropathy in the absence of overt diabetes is exceedingly rare [i’].In our center in which we have performed kidney transplants in more than 1,300patients, including more than 400 diabetic patients, we have yet to discover a single patient with diabetic nephropathy who has not had a history of severe long-standing hyperglycemia. Further, the prospective studies of Takazakura et al. [9] strongly indicate that patients.with poorly controlled diabetes have more rapidly progressive nephropathy than those with well controlled diabetes. Evidence that the primary responsibility for diabetic nephropathy rests with the metabolic derangements of the diabetic state is derived from a number of studies in man and animals. The elegant work of Osterby [lo] repTesented the first applications of sophisticated technology of morphometric analysjs to electron microscopy of kidneys of diabetic subjects. She showed that glomerular basement membrane thickening and expansion of the glomerular mesangium, both hallmarks of diabetic glomerular pathology, are absent in young people shortly after the onset of juvenile-onset insulin-dependent diabetes. However, within one and a half to two and a half years, evidence of these glomerular changes was discernible and, within five years of onset, was clear cut. Further information came from the study of normal kidney transplants in diabetic patients. Within two years, most of these kidneys demonstrate hyaline arteriolar lesions characteristic of diabetic nephropathy [ll]. Within four years, all kidney transplants in diabetic patients showed these changes [ll]. In addition, obvious mesangial thickening, including nodular glomerulosclerosis (Figure l), was noted in several of these kidneys [ll]. Immunofluorescent microscopic studies of these transplanted kidneys showed increased linear renal extracellular membrane staining for albumin and immunoglobulin G (IgG) [12]-changes highly specific for diabetes [13]. These pathologic developments in normal kidneys occurred whether the donor was related to the recipient or was a cadaver with no personal or family

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history of diabetes. Thus, it cannot be argued that there existed, in the transplanted kidneys, a genetically determined predisposition to pathologic changes. Rather, these studies strongly support the concept that the diabetic metabolic milieu alone can cause diabetic nephropathy. Recently, a diabetic patient received a successful simultaneous pancreas and kidney transplant from the same donor (Dr. Harold Rifkin, personal communication]. No longer metabolically diabetic, this patient had no evidence of diabetic nephropathy in the graft four years after the transplant. Since all of our diabetic recipients of normal kidneys have pathologic changes of diabetic nephropathy within four years of transplantation, this patient provides further evidence that the diabetic state is a critical prerequisite for these changes. Animal studies supplement this argument. In rats made diabetic by the administration of p cell toxins (alloxan or streptozotocin) or by pancreatectomy, glomerular lesions develop that are remarkably similar to those seen in diabetic human subjects [14-161. In normal kidneys transplanted into rats made diabetic with alloxan, glomerulopathy develops typical of diabetes in the rat [17]. Finally, transplantation of pancreatic islets [18]orinstitution of meticulous control of hyperglycemia in these diabetic rats with insulin therapy early in the

Figure 1. Glomerulus from a normal cadaver kidney four and a half years after its transplaotation into an insulin-dependent diabetic patient. Diffuse mesangial and glomerular basement membrane thickening are present. KimqelstielWilson nodular change (upper arrow) and arteriolar hyalinosis (lower arrow) are evident. From Mauer SM et al. [ 1I].

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TABLE I

Animal Rat

Mouse Dog Monkey

Animal Models of Diabetes in Which Glomerular Basement Membrane and Mesangial Thickening Have Been Demonstrated ModelSystem Alloxan Streptozotocin Pancreatectomy High sucrose diet (genetic) KK (genetic) C57/BLKsJdb/db (genetic) Alloxan Growth hormone Alloxan

of the disease [I%-21] obviates the development of diabetic glomerular changes. Interestingly, rats treated with insulin in an effort to diminish but not normalize hyperglycemia demonstrate a substantial decrease in the rate of development of diabeiic glomerulopathy compared to untreated diabetic rats [22]. Thus, in this animal model system, a clear inverse relationship between glucose homeostasis and renal damage has been established. Along these lines Wehner et al. [23] have shown direct relationship between the level of hyperglycemia and the degree of glomerular mesangial thickening in the genetically diabetic KK mouse. Similar conclusions were reached by Reddi et al. [24] following sulfonylurea treatment in KK mice and by Bloodworth (personal communication) following insulin treatment of dogs with alloxan-induced diabetes. The pathology of diabetic nephropathy will be discussed in detail subsequently. Suffice it to say here that glomerular basement membrane thickening and expansion of the glomerular mesangium, primarily due to expansion of mesangial matrix (basement membranelike material) is a constant finding in all human subjects with diabetic nephropathy [10,25]. In each instance in the diabetic animal model systems listed in Table I, glomerular basement membrane and mesangial changes similar to those in man have been documented. The clear implication of these data is that these changes are independent of the cause of diabetes and depend upon the metabolic consequences of the disease. The Pathology of Diabetes: Pathogenic Implications. Structural and functional relationships: The patient with juvenile-onset insulin-dependent diabetes of recent onset has structural and functional changes in the kidney which appear to be interrelated. Kidney size [33], and glomerular and tubular size [34] are very significantly enlarged. Further, the glomerular capillary filtration surface area towards the urinary space is increased [35,36]. Virtually identical changes occur very shortly after onset of streptozotocin-induced diabetes in the rat [19]. If plasma glucose levels are normalized by insulin administration begun shortly after the induction of diabetes in rats, these structural alterations

course

ET AL.

do not develop [19]. In man these structural changes, especially filtration surface area, are closely correlated with the increased glomerular filtration rate which accompanies recent onset juvenile-onset insulin-dependent diabetes [37]. Similarly, single nephron glomerular filtration rate, measured by elegant micropuncture studies, is increased in rats shortly after the induction of streptozotocin diabetes (381. This was secondary to increased glomerular plasma flow and transcapillary hydraulic pressure. The finding of increased glomerular capillary pressure by micropuncture studies in partially pancreatectomized rats (Azar S, personal communication] show that this change is independent of the cause of diabetes. Calculations indicate that these increases in glomerular capillary pressure are secondary to alterations in the balance of afferent and efferent glomerular arteriolar resistances [38]. Interestingly, increased glomerular filtration rate as well as increased urinary albumin excretion in patients with newly diagnosed juvenile-onset insulin-dependent diabetes under poor control are largely reversible by insulin treatment [33,36,39,40] but are unrelated to plasma glucose levels measured at the time the clearance studies are performed. Further, increased kidney size returns towards normal as control is improved [33]. Residual albuminuria, present when glucose homeostasis is improved by intermittent insulin injection is further normalized by continuous subcutaneous insulin infusion [41]. The increase in glomerular filtration rate persists for many years in the patient with juvenile-onset insulindependent diabetes [33,36]. During this time increased urinary excretion of albumin can be demonstrated in the basal state [41] or with exercise [40], but proteinuria by routine clinical tests is usually absent [40]. When overt proteinuria ultimately supervenes, the glomerular filtration rate begins to decrease at the rate of approximately 1 ml/min/month [36,42]. It is during the initial “silent” years that the pathology of human diabetic nephropathy develops. The pathogenesis of these lesions (Figure 1, Table II] is unclear. The argument that the abnormal metabolic milieu of diabetes is a necessary precondition for the development of these lesions has already been presented herein. There is evidence that the rate at which pathologic progression occurs is, at least in part, dependent upon the microvascular hemodynamic disturbances present in the diabetic state. These disturbances, reflected in the renal physiologic abnormalities already mentioned, have been hypothesized as secondary to autoregulatory increases in tissue perfusion as a response to the diminished capacity of the red blood cell to deliver oxygen resulting from increased levels of glycosylated hemoglobin and decreased red blood cell 2-3-diphosphoglycerate levels shifting the oxygen dissociation curve to the left [43]. However, the potential physiologic significance of these shifts in oxygen dissociation in diabetes has recently been disputed [44]. Further hypothesized to contribute to mi-

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TABLE II

ET AL.

Pathology of Established Diabetic Nephropathy in Human Subjects AlwaysPresent’

OftenPresent

Glomerular basement membrane thickening, especially lamina densa Mesangial widening with increased matrix material predominating (diffuse glomerulosclerosis) Intense glomerular basement membrane, tubular basement membrane and Bowman’s capsular immunofluorescent staining for albumin

Kimmelsteil-Wilson+ nodules (nodular glomerulosclerosis) Afferent and efferentt glomerular arteriolar hyalinization Tubular basement membrane thickening

SometimesPresent Hyaline “exudative” lesions, subendothelial Parietal Bowman’s capsular surface+ “capsular drop”

In combination, diagnostic of diabetic nephropathy. + Highly characteristic of diabetic nephropathy. l

crovascular disease are increased microvascular pressures and shear forces based upon the known increases in plasma viscosity and decreases in red blood cell deformability which occur in diabetic patients [45,46]. A fascinating experiment of nature dramatized the p?tential impact of hemodynamic perturbations on renal lesions in diabetes. Berkman and Rifkin [47] reported autopsy findings in a patient with long-standing diabetes and unilateral renal artery stenosis. The kidney with the stenotic artery had only mild ischemic changes whereas the contralateral kidney exposed both to hypertension and diabetes had advanced diabetic nephropathy. Interestingly, Mogensen [42] has reported, in patients with long-standing juvenile-onset insulin-dependent diabetes, that untreated hypertension is associated with an accelerated rate of decline in the glomerular filtration rate compared to that in treated hypertension.

In order to expand upon these observations we induced diabetes in rats following the surgical creation of unilateral renal artery stenosis [48]. We found that the “clipped” kidney, protected from hypertension, was strikingly protected from diabetic glomerular changes of mesangial thickening, and mesangial immunoglobulin and complement deposition. In the contralateral kidney, exposed to hypertension and diabetes, development of these glomerular lesions was accelerated compared to that in normotensive diabetic animals. These glomerular changes were not seen in nondiabetic hypertensive rats [48]. We further studied rats uninephrectomized following the induction of diabetes and found accelerated diabetic glomerulopathy in these animals but no such changes in nondiabetic uninephrectomized animals [49]. It is known that one kidney Goldblatt hypertension in rats is associated with in-

Figure 2. Artist’s line drawing conceptuahztng mesanglum in diabetes (left figure) expanding into the subendothelial space and lengtheningthe rnesangial-glomerularbaserrjent membransepithelial interface. The right figure depicts reversal of mesangial expansion following pancreatic islet transplantation and persistant glomerular basement membrane thickening.

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creased glomerular capillary pressures [50], and uninephrectomy in rats results in increased glomerular blood flow and glomerular capillary pressures [50]. We concluded that manipulation of these physiologic parameters in diabetic rats very markedly influences the rate at which glomerulopathy progresses without major influence upon severity of the diabetic state. However, these studies indicated that diabetes was a necessary precondition for the development of these glomerular lesions in that they did not occur in nondiabetic animals that were experimentally manipulated to induce increased glomerular capillary pressures and flows. The dramatic influence of hemodynamic perturbations on glomerular changes in diabetes might help to explain the lack of precision in predicting individual rates of progression of microangiopathy in human subjects

[71. Although hyaline arteriolar degenerative change [51] may ultimately reduce glomerular blood flow and renal function in man, in species such as the rat renal failure can develop secondary to diabetes without these arteriolar lesions. It is our view, shared by Kimmelsteil [25], that mesangial expansion encroaching on the subendothelial space [52] (Figure 2), and eventually compromising the glomerular capillary lumen and blood flow, ultimately leads to glomerular obsolescence. Indeed, Gundersen and asterby [53] have found a relationship between the number of glomeruli with capillary occlusion and both duration of disease and degree of renal insufficiency in autopsy studies of patients with long-standing diabetes. Interestingly, the nonoccluded glomeruli were very large, and there was an inverse relationship between their size and the fraction of solid material within them [53]. This indicates that the functioning glomeruli in advanced diabetic nephropathy represent residual nephron units manifesting compensatory hypertrophy. One might deduce that this residual functioning nephron population represents glomeruli relatively spared from the glomerular nephropathic process. The glomerular mesangium: Since a major contribution to the increased glomerular “solid material” in diabetes appears to be mesangial expansion, understanding of mesangial structure and function is of great importance [54,55]. This glomerular intercapillary system of cells and matrix has its peripheral branches join centrally towards the hilum forming the axial pole of the glomerulus (Figure 3). At the hilum the mesangium extends outside the glomerulus (the extraglomerular mesangium); its cells become continuous with the granular and agranular cells of the juxtaglomerular apparatus and intimate contact with the distal tubular macula densa cells develops [56]. This anatomic relationship, the presence .of angiotensin II receptors in mesangial cells [57], the finding of nerve endings [58] and smooth muscle antigens [56] in the mesangium, suggest a role for the mesangium in renin release and response mechanisms and in regulation of glomerular

ET AL.

blood flow. Interestingly, the intensity of immunofluorescent staining for smooth muscle staining is markedly increased in diabetic nephropathy in man [59] and animals [60], an abnormality not yet noted in any other renal diseases. These immunohistochemical studies suggest that contractile properties of glomeruli are altered in diabetes It is possible that both functional and hemodynamic aberrations in diabetes may be effected by specific contractile control factors. One may speculate that these changes may be attributable to altered vasoactive control mechanisms regulating angiotensin and prostaglandin secretion and metabolism. For example, Christlieb et al. have shown that in human subjects with diabetic neuropathy [61] and in diabetic rats [62], renin secretion is decreased. Since renin secretion is controlled by prostaglandins, most specifically prostacyclin [63], it is possible that decreased renin secretion in the diabetic state is related to altered secretion and/or responses to prostaglandin metabolites. Increased synthesis of thromboxane, a potent vasoconstrictor and platelet-aggregating prostaglandin metabolite, occurs in platelets in diabetic patients [64]. Further. decreased

I-

igure 3. Schematic drawing of a glomerulus depicting the relationships between the axial mesangial region and the juxtaglomerular apparatus. The arrows indicate the probable direction of macromolecular movement through the mesangial system towards the extraglomerular mesangium and the distal tubule (DT). AA, afferent arteriole; EA, efferent arteriole; P, mesangial cell cytoplasmic processes projecting into the subendothelial space. From Hamberger et al. (eds) In: Advances in Nephrology. Vol 1. Chicago: Year Book Medical Publishers, Inc. 1971; 93.

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amounts of the potent vasodilator and platelet aggregation inhibitory substance, prostacyclin, are produced by blood vessels from human subjects with diabetes [65]. Comparable studies in experimentally-induced diabetes in rats have shown similar alterations of thromboxane and prostacyclin relationships in platelets and blood vessels [66-681. The observations that cycle-oxygenase, a pivotal enzyme to the formation of prostaglandins, is found in the mesangium as well as in endothelial cells of arteries and arterioles of the kidney [69] suggests a key role of these compounds in regulating smooth muscle functions and, perhaps, cellular contractility and permeability in the glomerulus. Other studies have demonstrated prostaglandin synthesis in isolated rat kidney glomeruli [70,71]. Significant increases in prostacyclin synthesis by glomeruli of diabetic rats may provide an important clue that some aspects of glomerular dysfunction in diabetes may result from the increased vasodilatory effects of that substance [72]. The mesangium has been demonstrated to have the capacity to take up and process macromolecules from the circulation [73]. The macromolecules appear to traffic through intercellular channels from the periphery of the mesangium to the JGA and may leave this area via the distal tubular cells at the level of the macula densa [30,74] (Figure 3). The mesangium may also be involved in the processing of products of glomerular basement membrane turnover [75]. Recently, we demonstrated in diabetic rats that in those areas of the mesangium most thickened secondary to long-standing diabetes the capacity to clear macromolecules, which have been made to localize therein, is impaired [76]. Relatively normal-appearing mesangial areas had no such abnormality [76]. Thus, we concluded that dysfunction of the mesangial efferent (clearing) limb was secondary to disruption of mesa&al architecture rather than to the diabetic state per se [76]. It is imaginable that this dysfunction could lead to further mesangial injury. The glomerular basement membrane: osterby [lo] initially showed parallel thickening of the glomerular basement membrane and of the mesangium in the first few years after the onset of juvenile-onset insulindependent diabetes. More recently, she and her colleagues [35] have hypothesized, based on morphometric studies in animals and man, that “increased synthesis of the peripheral basement membrane triggered by the metabolic aberrations characterizing diabetes mellitus, constitutes the earliest phase in the development of diabetic microangiopathy.” Argument exists as to the changes, if any, in the fundamental biochemical structure of glomerular basement membrane in diabetes in man [77-791. However, there is evidence, based upon in vivo studies of hydroxylation of tritiated proline, that in alloxan diabetic rats glomerular basement membrane production is twice normal as soon as nine days after the onset of disease [80]. Further confirming the aforementioned morphometric studies, Cohen and Klein [81] found, by quantitative analysis, that rats diabetic for six

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weeks have an accumulation of glomerular basement membrane. Further, by gel filtration, they did not find any qualitative abnormalities of over-all glomerular basement membrane protein chain patterns in glomerular basement membrane from diabetic rats [81]. Thus, glomerular basement membrane production appears to increase early after the onset of severe hyperglycemia. Spiro and Spiro [82] have also shown that glycosyl transferase enzyme, involved in the synthesis of glomerular basement membrane is increased in diabetic rats and that this increase can be reversed by insulin therapy. There is no evidence that the degradation of glomerular basement membrane is diminished in diabetes, but studies adequate to answer this question have not been performed. If the half-life of glomerular basement membrane is, as has been reported, very long, studies of glomerular basement membrane degradation in diabetic rats may be difficult to carry out [80]. If recent evidence that the half-life of glomerular basement membrane in the rat is only on the order of several weeks [83], studies of glomerular basement membrane breakdown in diabetic rats would be feasible and should be carried out. We found that uninephrectomy, which does accelerate mesangial thickening, smooth muscle antigen accumulation, and increased immunoglobulin and complement localization, does not result in accelerated glomerular basement membrane thickening in chronically diabetic rats (Steffes MW, Brown DM, Basgen JM, Mauer SM: Manuscript in preparation). Thus, the pathogenesis of glomerular basement membrane and mesangial changes in diabetes may be different. This point will be expanded upon subsequently. Increased linear renal extracellular basement membrane localization of plasma proteins, especially of albumin, is characteristic of diabetic nephropathy in man [13] but has not yet been documented in other species with diabetes. The pathogenesis of this abnormality, which also occurs in muscle, skin and perhaps other tissues, is unknown. Studies of nondiabetic family members of subjects with juvenile-onset insulin-dependent diabetes demonstrate that these immunohistochemical abnormalities are present in muscle [8] and skin (Chavers B, Michael AF: Personal communication). The relationship of these findings to glucose intolerance has not been completely worked out, but it is clear that overt diabetes is not a necessary precondition for these basement membrane changes to occur. It is further clear that these immunohistochemical changes occur independent of changes in basement membrane thickness [8]. The pathogenesis and significance of these abnormalities is presently unknown, but the described phenomena do indicate that the spectrum of basement membrane changes in diabetic families is very wide. In summary, the onset of severe diabetes seems to rapidly result in increased glomerular basement membrane production and, ultimately, glomerular basement membrane thickening. Although clearly re-

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lated to the metabolic perturbations of diabetes, the pathogenesis of this process is poorly understood. We do not even know what role glomerular basement membrane thickening in diabetes has in the development of renal functional abnormalities. Much work remains to be carried out. Reversibility of Diabetic Nephropatby. No data exist which would permit an answer to the question as to the reversibility of established diabetic nephropathy in man. The first study addressing this issue was performed in rats. Using highly inbred Lewis rats, in which rejection between animals within this strain does not occur, kidneys from rats diabetic for six months were transplanted into nondiabetic rats [17]. The diabetic kidneys, which had mesangial thickening and increased immunoglobulin and complement localization at the time of transplantation, showed marked improvement in these parameters two months after their placement into normal metabolic environments. These studies were expanded by examination of the effects of the pancreatic islet tissue transplant on diabetic glomerulopathy in the rat. We found that establishment of normoglycemia by this approach resulted in a marked decrease in mesangial thickening by semiquantitative light microscopy, and mesangial immunoglobulin and complement staining by immunofluorescent microscopy compared to that in kidney biopsy specimens obtained from these same animals at the time of pancreatic tissue transplantation and compared to that in untreated rats [15,84]. Quantitative morphometric electron microscopic analysis in rats diabetic for seven months prior to transplantation documented increased relative and absolute mesangial volumes in glomeruli from the diabetic rat, primarily due to a striking increase in mesangial matrix volume and, to a lesser extent, to increased mesangial cell volume [52]. Transplantation of islet tissue resulted in a decrease in these parameters of mesangial structure to near normal values (Figure 21. Further, the mesangial expansion as seen in untreated diabetic rats had produced an increase in the surface area of mesangial-endothelial cell interface thus encroaching on the endothelial-glomerular basement membrane-epithelial “filtering” surface of the glomerulus (Figure 4). Pancreas transplantation returned these altered glomerular filtering surface relationships towards normal [Figure 2) [52]. In sharp contradistinction, glomerular basement membrane thickness, increased in diabetic rats at the time of pancreas transplantation, was completely unaffected by the reestablishment of normoglycemia for a three to four month period of time [85]. Interestingly, the urinary excretion of albumin increased in untreated diabetic rats and returned to normal in animals given pancreas transplants [86]. This indicates that the glomerular basement membrane, thickened by the diabetic process, may function normally in the animal cured of hyperglycemia. Thus, at this stage of diabetic nephropathy in the rat, increased permeability to protein of the glomerular

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01 Glomeruiaf Components

and

GBM

1

Intarposrd

of Mesangfum

a =Surface of Peripherul GBM b =Surface of Mesongium-Capillary

interface

c * Surface of Mesongium GBM- Epithefium lnterfoce

Figure 4. Artist’s line drawing depicting the structures and defining the surface relationships in a glomerular tuft. From Steffes et al. [52].

capillary filter system cannot be explained by glomerular basement membrane thickening per se. This observation is in keeping with findings in human subjects with membranous nephropathy that marked glomerular basement membrane thickening may persist despite disappearance of immune deposits, loss of proteinuria and normal renal function [87]. Management of the patient with Diabetic Nephropathy. Unfortunately, at present, the availability of therapeutic technology with widespread applicability to diabetic patients and with proved effectiveness in markedly diminishing the development of nephropathy does not exist. The evidence cited supports careful metabolic control, but it is possible that exogenous intermittent insulin administered with the utmost skill may not materially influence the rate at which the secondary complications develop. Perhaps preventative measures demand precision of metabolic control that only continuous insulin infusion systems or pancreatic islet transplantation can provide. As emphasized, careful control of hypertension can significantly retard the rate of progression of diabetic nephropathy towards uremia. The principles of the medical management of uremia, and their application and modification for the diabetic patient, have recently been enunciated in detail by Goetz and Kjellstrand [88] and will not be repeated here. The advanced technologies of dialysis and transplantation were delayed in their application to diabetic uremic patients because of the a priori assumption that their multisystem organ injuries from micro- and macrovascular disease would be insurmountable despite these technologies. Indeed, initial dialysis experience with these patients was disappointing [89]. More re-

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cently, very significant improvements in survival of diabetic patients undergoing dialysis has been achieved, making this therapy a realistic option [90-931. However, it has been determined that a kidney transplant from a living related donor is a more successful mode of therapy than long-term dialysis for these patients [88,92,94]. Further, although survival with cadaver transplants is approximately equivalent to that of long-term dialysis, the quality of life of the recipient with a successful diabetic cadaver transplant appears superior to that of the diabetic patient undergoing long-term dialysis [94,95]. The most extensive review to date of this subject, involving a 10 year experience and 365 kidney transplant recipients with juvenile onset diabetes has recently been published [96]. This classic paper provides a wealth of information. After a shaky beginning [97] followed by a lo-year hiatus, pancreas transplantation is again being vigorously explored for the diabetic uremic subject. Initial results of partial pancreas transplantation in the patient stabilized for one or two years by successful renal transplantation seems very promising (Sutherland DER, Najarian JS: Personal communication]. The possibility, by this approach, of definitively answering the question of whether complete reversal of the metabolic consequences of the diabetic state will uniformly prevent or reverse the development of diabetic nephropathy in the transplanted kidney is most exciting. Thus, the diabetic uremic patient, initially considered to present a hopeless therapeutic challenge, may point the way to future approaches to the management of all insulin-dependent diabetic patients.

A View of the Future. The multifocused research attack on diabetes is advancing at an ever quickening and exciting pace. Studies of the pathogenetic mechanisms involved in the production of the secondary complications of diabetes may provide approaches to the treatment of diabetes which would permit interference with the progression of these secondary complications despite our continued inability to maintain precise glucose homeostasis. It is not unreasonable to expect that within the next five years answers as to the effect of successful pancreas transplantation on diabetic nephropathy in man will be available. A major thrust of this review has been to provide the rationale for this experimental approach, and we would predict that these studies in human subjects will completely confirm the animal experiments described herein. We would also predict that developmental work on technologies of glucose regulation with the artificial pancreas or islet tissue transplantation will be enormously expanded so as to have relevance to the larger population of diabetic patients. Finally we hope that improved understanding of the pathogenesis of the diabetic state would provide preventative approaches to diabetes within the next quarter century. We have no doubt as to the ultimate cost effectiveness of research in these multiple areas. ACKNOWLEDGMENT We thank Ms. Maggie Dashke for her assistance in the preparation of this manuscript and Mr. Marshall Hoff for the illustrations.

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Report of the National Conference on Diabetes. Bethesda, Maryland: National Institutes of Health Publication No. 80-2073. April 1980. Marks HH: Longevity and mortality of diabetics. Am ] Public Health 1965; 55: 416. Sipcrstein MD, Unger RH, Madison LL: Studies of muscle capillary basement membranes in normal subjects, diabetic and pre-diabetic patients, J Clin Invest 1968: 47: 1973. Gundersen HIG. 0stcrbv R. Lundbaek K: The basement membrane controversy. Diabctologia 1978; 15: 361. Sipcrstein MD, Feingold KR, Bcnnctt PH: Hyperglycemia and diabetic microangiopathy. Diabctologia 1978; 15: 365. Williamson JR, Kilo C: A common sense approach resolves the basement controversy and the NIH Pima Indian Study. Diabetolonia 1979: 17: 129. Tchobroutsky G: Prevention and treatment of diabetic nephropathy. In: Hambergcr J, Crosnicr J, Griinfeld J-P, Maxwell MH, eds. Advances in nenhrologv, vol. 9 Chicago: Year Book Medical Publishers, 19’79: 63-86. Barbosa J, Cohn RA, Chavers B, Michael AF, Steffes MW, Mauer SM: Muscle extracellular membrane immunofluorescence and HCA as possible markers of prediabetes. Lancet 1980; 2: 330. Takazakura E, Nakamoto Y, Hayakawa H, et al.: Onset and progression of diabetic glomerulopathy. Diabetes 1975; 24:

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merulopathy. Acta Med Stand 1975; 574 [suppl): 1. Mauer SM, Barbosa J. Vernier RL, et al.: Development of diabetic vascular lesions in normal kidneys transplanted into patients with diabetes mellitus. N Engl J Med 1976;295: 916. Mauer SM, Miller K, Goetz FC, et al.: Immunopathology of renal extracellular mcmbrancs in kidneys transplanted into patients with diabctcs mcllitus. Diabetes 1976; 25: 709. Miller K, Michael AF: Immunopathology of renal extracellular membranes in diabetes mellitus. Specificity of tubular basement membrane immunofluorescence. Diabetes 1976: 25: 701. Mauer SM, Michael AF, Fish A]. Brown DM: Spontaneous immunoglobulin and complement deposition in glomeruli of diabetic rats. Lab Invest 1972: 25: 488. Mauer SM, Sutherland DER, Steffes MW. et al.: Pancreatic islet transplantation. Effects on the glomerular lesions of experimental diabetes in the rat. Diabetes 1974: 23: 748. Foglia VG. Mancini RE, Cardeza AF: Glomerular lesions in the diabetic rat. Arch Pathol Lab Med 1950; 50: 75. Lee CS, Mauer SM. Brown DM, Sutherland DER, Michael AF, Najarian JS: Renal transplantation in diabetes mellitus in rats. J Exp Med 1974; 139: 793. Weil R III, Nozawa M, Koss M. Weber C, Reemtsma K, McIntosh RM: The kidney in streptozotocin diabetic rats. Morphologic, ultrastructure and function studies. Arch Path01 1976: 100: 37. Rasch R: Prevention of diabetic glomerulopathy in strepto-

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