Diabetes and nephropathy: progression, regression, and the effect of therapy.
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Biomedical subjects
Publications and source records attributed to S M Mauer.
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One hundred fifteen consecutive patients received first transplants from cadaver donors at the University of Minnesota between January 1, 1968, and May 31, 1973. All patients have been followed for at least two years. The two-year survival rate is 70 per cent and the two-year transplant function rate is 58 per cent. Considerable improvement in both patient survival and transplant function has been noted since 1971. The success of transplantation appears to depend to a large degree on the age of the transplant recipient, the number of HLA antigens matched between donor and recipient, and the dose of antilymphoblast globulin (ALG) administered to the recipient during the first two weeks after transplantation. Each of these factors appears to be important even when the other factors are controlled, and when patients with diabetes, suffering technical failure or hyperacute rejection, are excluded. The results utilizing well-matched cadaver kidneys plus large doses of ALG appear to be equivalent to those obtained with the use of mismatched kidneys from relatives, but further analysis will be required to draw a definite conclusion. Patients receiving poorly-matched cadaver kidneys do far less well than patients receiving mismatched related grafts, however, even when ALG is utilized.
From January 1, 1968 to May 31, 1973, 100 patients received first kidney transplants from sibling donors. All recipients have been followed for at least two years and several as long as 7.5 years. One hundred per cent follow-up information is available. The absolute two-year patient survival is 85% and the absolute two-year kidney function survival is 76%. Patients with diabetes (especially males) have less success following transplantation than do patients without diabetes. When diabetic patients are excluded, older patients appear to do slightly less well than younger patients. Patients with phenotypically identical HL-A matches with the donor do better than patients without such matches. In the nondiabetic technically perfect transplant recepient, better than 90% long-term transplant function can be expectedwith no kidney losses after the first few months. In contrast, the less well-matched transplant demonstrated both an increased early rejection rate and a high rate of loss after the third to fifth year. Increasing doses of anti-lymphoblast globulin (ALG) had beneficial results in HL-A mismatched sibling transplants, but were slightly detrimental in phenotypically identical HL-A donor-recipient pairs because of an increased rate of infection. The results are compared with the results of transplants from other related donors and from cadavers performed during the same period.
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Although the diabetic patient is at high risk for transplantation and the progression of cardiovascular disease continues, results of our experience indicate that kidney transplantation can be performed with only slightly less favorable results than in the nondiabetic patients. We have found that the survival rate achieved by diabetics who receive a kidney graft is superior to that achieved by diabetic patients who receive dialysis. We also believe that some of the secondary complications of diabetes, which are aggravated by uremia, will be improved and that successful vocational rehabilitation is possible in the majority of diabetic patients.
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.
A sustained decrease of plasma bilirubin concentrations occurred in homozygous recessive Gunn rats lacking the enzyme uridine diphosphate glucuronyltransferase following infusion into the portal vein of hepatocytes from heterozygous nonjaundiced Gunn rats possessing the enzyme. Transplantation of cells capable of continuous enzyme production could be an effective mode of therapy for congenital enzyme deficiency diseases.
101 first transplants were done in patients with end-stage renal disease using kidneys from parents or offspring. All patients were followed up for at least two years, and the absolute two-year patient-survival rate was 88% and the two-year functional-kidney rate was 79%. Actuarial statistics at four years were 82% for survival and 67% for function in the parent-to-child group. In the child-to-parent group absolute patient survival was 83% and transplant function was 79% at two years; these results were unchanged at four years. Thus, transplants from parents to children or from children to parents are much the same despite differences in age. There is some advantage in parent-to-child transplants from being female but no advantage in being diabetic, receiving higher or lower doses of antilymphocyte globulin, or sharing more than two HLA antigens with the donor. Mismatched sibling transplants survived approximately as well as did grafts from parents to children and children to parents. These results, taken in concert with the poor results of cadaver transplantation, the relative safety of donation, the high personal motivation to donate in these groups, and the personal satisfaction derived by the donor, strongly support the policy of informing potential recipients of the benefits of parental or offspring kidney donation.
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Although the renal allograft represents only a single-functioning kidney, it lends itself readily to biopsy from a percutaneous approach. Previous contraindications to percutaneous biopsy of a single normally situated kidney do not apply to the renal allograft because of its altered extraperitoneal and superficial location. The transplant operative note and palpation serve to adequately localize the kidney without the need of fluoroscopy, metal tagging or other X-ray techniques. The cortex may be safely approached through a perpendicular plane directed toward the lower pole or a tangential plane directed toward the lateral curvature of the allograft. The fibrous capsule's resistance to the neddle passage helps localize the periphery of the kidney. Hemostasis is augmented through manual pressure and subsequent pressure dressing. The technique was used in 62 renal biopsies in 62 different patients. Adequate material for microscopic and bacteriologic evaluation was obtained in all cases. There were three episodes of gross hematuria, but no prolonged bleeding, significant perirenal hematoma formation, infection or decreasing renal function after the biopsy procedure.
Pericardial drainage via percutaneous catheter placement and local nonabsorbable steroid instillation was employed as definitive therapy for uremic patients who had intractable pericardial effusions. Twelve patients are reported. Prior daily dialysis, and in one case systemic steroids, were not curative. 11 of 12 cases suffered severe tamponade requiring pericardiocentesis. One patient had an organized pericardial effusion, making pericardiocentesis impossible. He required pericardiectomy with prolonged hospitalization (2 weeks) due to postoperative complications. There were no complications in the 11 patients where catheter drainage and local steroid instillation were employed. No patient had recurrence of his pericardial effusion (followed from 2 weeks to 32 months). Instillation of a relatively nonabsorbable steroid through an indwelling pericardial catheter provides immediate and lasting relief without either the inconvenience or postoperative complications and prolonged hospitalization associated with the surgical procedure of pericardial fenestration. This report offers initial evidence that the percutaneous approach may be a safe and effective alternative to pericardial fenestration in most uremic patients with pericardial effusion.
Kidneys of patients with severe diabetic nephropathy demonstrate marked linear immunofluorescent staining of extracellular membranes, including the tubular and glomerular basement membranes (TBM and GBM) and Bowman's capsule. Immunofluorescent studies were carried out on kidney tissue obtained from 12 diabetic and 17 nondiabetic patients from two to 12 years following renal transplantation. The frequency and intensity of SgG and albumin staining of these membranes were significantly greater in the diabetic than in the nondiabetic patients (P less than 0.0005). TBM, GBM, and Bowman's capsule staining did not occur in any of the seven kidneys studies at the time of their transplantation into diabetic recipients. Thus, the abnormalities leading to the deposition or trapping of proteins in renal extracellular membranes occur early after the placement of normal kidneys into the abnormal metabolic environment of the diabetic transplant recipient. The present study supports the concept that basement membrane alterations in diabetes are a consequence of the biochemical perturbations of diabetes rather than a separately inherited genetically linked disorder.
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Animal models of diabetes mellitus allow for the manipulation of the metabolic state and the performance of experiments that may shed light on the pathogenesis of diabetic nephropathy. Rats with long-standing chemically induced diabetes develop glomerular mesangial thickening and immunoglobulin and complement deposition. These glomerular changes are reversible on the transplantation of a kidney from a diabetic rat into a normal host and on cure of the diabetic state by pancreatic islet transplantation. Conversely, diabetic renal changes develop in normal kidneys transplanted into diabetic rats (within tow to four months) and humans (within two years). These studies suggest that nephropathy results from the diabetic state. The mesangium is thickened in diabetic rats, mice, and humans. In rats, mesangial function is the processing of macromolecules localized therein is disturbed in areas of mesangial pathology. The finding that glomerulopathy is accelerated in uninephrectomized diabetic rats and is retarded in rat kidneys "protected" by narrowing of the renal artery suggests that alterations in glomerular blood flow are related to the pathogenesis of diabetic glomerular damage. Marked hyperglycemia in animals and man leads to "glycogen nephrosis," which affects the distal tubule at the level of the macula densa of the juxtaglomerular apparatus (JGA). This could lead to disturbance of JGA blood pressure regulation. Disturned mesangial function may result from failure of macula densa cells to process macromolecules that have reached that site from the mesangium.
Fifteen patients with chronic renal failure had depressed neutrophil chemotactic responsiveness following several hemodialysis treatments. The chemotactic index (C.I.) of these patients was 12.7+/-6.4 as compared with 72.8+/-22.7 for controls (p less than 0.001). Patients with chronic renal failure, not on hemodialysis, had only mildly depressed neutrophil chemotactic responsiveness (42.3+/-15;p less than 0.01). Thus, hemodialysis impairs neutrophil function and may contribute to the increased risk of infection in uremic patients. Chemotactic responsiveness returned to normal in three patients following renal transplantation.
A 10-month-old infant was treated with intensive supportive care and hemodialysis for severe propoxyphene intoxication. Dialysis clearance studies demonstrated that propoxyphene was removed from the serum at approximately 50% of the rate of blood urea nitrogen removal. Possibly because of tissue binding of the drug, the absolute quantity of propoxyphene removed by dialysis was small. The child survived the acute episode of intoxication but died of pulmonary complications several days later. The role of dialysis in propoxyphene intoxication remains to be established.
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