S. Michael Mauer

The kidney in diabetes

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.

Association of Renal Allograft Rejection with Virus Infections

Abstract Sixty-one immunosuppressed renal transplant recipients were systematically screened for virus infections and the findings correlated with their clinical course. Only herpesvirus (cytomegalovirus, herpes simplex and herpes zoster) were consistently isolated. The onset of virus infections could usually be associated with clinical syndromes. Patients without virus infections were usually asymptomatic. The clinical syndrome associated with virus infection consisted of fever, leukopenia and renal allograft rejection. Renal biopsy, performed at the time serum creatinine levels were elevated, revealed classic rejection; most rejections were reversed by increasing the dose of steroids. Patients continued to excrete virus even after antibody response and clinical recovery. Virus infections do not appear to be incidental findings in transplant patients except after recovery when the virus persists in the immune patient. The clear-cut association between virus infection and rejection episodes suggests a pathogenic relationship. The two mechanisms which seem to best explain the relationship are (1) the virus infection acting as an adjuvant and triggering the rejection of the allograft or (2) the allograft rejection activating a latent virus infection.

Development of Diabetic Vascular Lesions in Normal Kidneys Transplanted into Patients with Diabetes Mellitus

We examined renal-transplant tissue from 12 diabetic and 28 nondiabetic patients who had had a renal graft for at least two years. In 10 diabetic patients arteriolar hyalinosis lesions developed in the graft. In six these lesions involved both afferent and efferent limbs of glomerular arterioles - a pathological finding virtually diagnostic of diabetes mellitus. In all cases these lesions were present within five years of transplantation. Only three of the 28 nondiabetic patients had hyaline vascular changes (P less than 0.001), which occurred only in rare vessels, did not appear within the first five years after transplantation and did not involve both afferent and efferent arterioles, One diabetic patient had nodular glomerulosclerosis. Thus, the first clearly distinguishable lesion of diabetes to occur with frequency in normal kidneys transplanted into diabetic patients is arteriolar hyalinosis.

The glomerular mesangium: I. Kinetic studies of macromolecular uptake in normal and nephrotic rats

This study was designed to define quantitatively the function of the rat glomerular mesangium in the uptake and processing of intravenously administered protein macromolecules (radiolabeled aggregated human IgG, AHIgG-(125)I), to relate this function to that of the general reticuloendothelial system, and to examine the effects of increased glomerular permeability to protein on the mesangial cell system.Mesangial localization of human IgG as demonstrated by immunofluorescent microscopy showed good correlation with concentrations of AHIgG-(125)I in preparations of isolated glomeruli. In normal rats the concentrations of AHIgG-(125)I in glomeruli were similar to those of lung, liver, and spleen and demonstrated a rapid decrease with increasing time intervals after aggregate administration. In rats given aminonucleoside of puromycin a marked increase in mesangial uptake of aggregates was found while studies of nephrotic lungs, liver, spleen, and blood showed no such differences. Glomerular levels of AHIgG-(125)I in aminonucleoside animals could not be correlated with the quantity of proteinuria. Nephrotic and control animals given unaggregated human IgG showed little glomerular localization by immunofluorescent microscopy; no difference in the concentration of this protein in nephrotic as compared to control glomerular isolates was found.Thus, the mesangium in normal animals functions in a manner analogous to that of the general reticuloendothelial system. In nephrotic rats the mesangial uptake of macromolecules is makedly increased, a finding not observed in other tissues.

Varicella in children with renal transplants

Nineteen of 160 children developed varicella between eight days and 6.4 years following renal transplantation. Eight had severe varicella characterized by prolonged fever and new vesicle formation with rash involving mucous membranes. The severe group had an increased incidence of thrombocytopenia and markedly elevated liver enzyme values. Two patients of this group had bladder paralysis and another died. In three children post-transplant varicella represented a second attack of the disease. Children maintained on azathioprine therapy for three days or more after onset tended to have severe varicella. No graft loss occurred consequent to stopping azathioprine. Children with transplants at risk should have zoster immune plasma or globulin upon exposure, and azathioprine therapy should be stopped at onset of varicella. Corticosteroid therapy should be continued in order to avoid stress-induced Addisonian crisis.

Congenital nephrotic syndrome: Evolution of medical management and results of renal transplantation

We analyzed the clinical course, pathologic findings, and results of aggressive medical management and renal transplantation in 41 infants with onset of nephrotic syndrome in the first 3 months of life. All but one infant with congenital onset failed to thrive and had progressive renal insufficiency; 17 were given steroids or cytotoxic drugs or both, without benefit. Severe bacterial infections occurred in 85% of the infants, pyloric stenosis in 12%, gastroesophageal reflux in 8%, and thrombotic events in 10%. All children prior to the era of renal transplantation died before 4 years of age. The last 24 infants received aggressive medical management, which allowed renal transplantation in 17. Two-year patient and graft survival rates were 82% and 71%, respectively. There was no recurrence of the nephrotic syndrome in the children who underwent transplantation. All but one surviving infants has had normal or accelerated growth, although mean height for the group is 3.1 SD below the mean. School and social performance has been normal in 80%. Thus intensive medical therapy combined with renal transplantation offers a very good opportunity for survival with an acceptable quality of life for infants with congenital nephrotic syndrome.

The Outcome of Renal Transplantation in Children with Posterior Urethral Valves

The effect of vesical dysfunction on the survival and function of renal transplants was evaluated by a retrospective study in which 18 children with posterior urethral valves and 18 children with vesicoureteral reflux were randomly matched with 36 children used as controls. There was no statistically significant difference in patient survival among the 3 groups. Five years after transplantation 50 per cent of the grafts in children with posterior urethral valves were functioning, while 73 and 75 per cent, respectively, of the grafts were functioning in children with vesicoureteral reflux and in the control group. Renal function during the 5 years was significantly better in children in the control group and in those with vesicoureteral reflux than in children with posterior urethral valves. We believe that the presence of an abnormal bladder may alter graft survival and adversely affect the function of the transplanted kidney.

Studies of Kidney and Muscle Biopsy Specimens from Identical Twins Discordant for Type I Diabetes Mellitus

To distinguish metabolic from genetic factors in the development of microangiopathy in diabetes, we evaluated biopsy specimens of kidney and quadriceps muscle from seven pairs of identical twins who were discordant for Type I (insulin-dependent) diabetes mellitus. Two of the diabetic patients had clinical diabetic nephropathy, including hypertension, marked albuminuria, and a substantially reduced creatinine clearance; the other five had normal renal function and only minor clinical indications of complications. All the twins of the diabetic patients had normal glomerular basement membrane widths and normal fractional volumes of the glomerular mesangium. Values for glomerular basement membrane width, tubular basement membrane width, and mesangial volume in each diabetic twin exceeded the values in the respective sibling (P less than or equal to 0.0035), even if the value in the diabetic twin lay within established normal ranges. Values for muscle capillary basement membrane width in the diabetic twins did not differ from those in their siblings (P = 0.5). Our observations suggest that the metabolic abnormalities of diabetes are necessary, if not sufficient, for the development of glomerular abnormalities. We also conclude that in diabetic patients, alterations in muscle capillary basement membrane width do not necessarily accompany pathologic lesions in the kidney.

The management of life-threatening hyperammonemia: A comparison of several therapeutic modalities

THE DEVASTATING central nervous @stem effects of marked hyperammonemia are most clearly evident in congenital defects in the activity of each of the five urea cycle enzymes, the most common of which is ornithine transcarbamylase deficiency? Recent advances in the dietary management of patients with these hyperammonemic syndromes have been demonstrated to prolong or preserve life. 2 Further, temporary hyperammonemia has been described in premature infants? Thus treatment of life-threatening hyperammonemia is important since efficient removal of ammonia in a crisis situation, coupled with steps taken to control NH3 reaccumulation, may be life saving. Recently Donn et aP demonstrated the advantages of hemodialysis over exchange transfusion and peritoneal dialysis in the removal of ammonia from a neonate with OCT deficiency. A newborn infant with extreme hyperammonemia due to this enzyme defect provided us the opportunity to compare the relative effectiveness of these treatments, charcoal hemoperfusion, and resin hemoperfusion as means of NH~ removal.

Wegener granulomatosis in pediatric patients

Wegener granulomatosis is more easily recognized as a distinct clinical entity than other vasculitides because the initial clinical features frequently include granulomatous vasculitis of the upper and lower respiratory tract and glomerulonephritis. Although the disease has been lethal in the past, prolonged survival and avoidance of end-stage kidney disease can now be expected when cyclophosphamide therapy is introduced early in the course. We report four children with Wegener granulomatosis in whom the initial clinical findings suggested Henoch-Schönlein purpura. In two of the patients Wegener granulomatosis was not recognized until after end-stage kidney disease had developed. The course in these patients emphasizes the need for attention to even scant evidence of inflammation of the upper or lower respiratory tract in patients with glomerulonephritis. Appropriate diagnostic studies may then lead to recognition of Wegener granulomatosis and the prompt institution of appropriate treatment.