Mark B. Adams

Recurrent and de novo glomerular disease after renal transplantation : A report from renal allograft disease registry (RADR)

INTRODUCTION Short-term and long-term results of renal transplantation have improved over the past 15 years. However, there has been no change in the prevalence of recurrent and de novo diseases. A retrospective study was initiated through the Renal Allograft Disease Registry, to evaluate the prevalence and impact of recurrent and de novo diseases after transplantation. MATERIALS AND METHODS From October 1987 to December 1996, a total of 4913 renal transplants were performed on adults at the Medical College of Wisconsin, University of Cincinnati, University of California at San Francisco, University of Louisville, University of Washington, Seattle, and Washington University School of Medicine. The patients were followed for a minimum of 1 year. A total of 167 (3.4%) cases of recurrent and de novo disease were diagnosed by renal biopsy. These patients were compared with other patients who did not have recurrent and de novo disease (n=4746). There were more men (67.7% vs. 59.8%, P<0.035) and a higher number of re-transplants (17% vs. 11.5%, P<0.005) in the recurrent and de novo disease group. There was no difference in the rate of recurrent and de novo disease according to the transplant type (living related donor vs. cadaver, P=NS). Other demographic findings were not significantly different. Common forms of glomerulonephritis seen were focal segmental glomerulosclerosis (FSGS), 57; immunoglobulin A nephritis, 22; membranoproliferative glomerulonephritis (GN), 18; and membranous nephropathy, 16. Other diagnoses include: diabetic nephropathy, 19; immune complex GN, 12; crescentic GN (vasculitis), 6; hemolytic uremic syndrome-thrombotic thrombocytopenic purpura (HUS/TTP), 8; systemic lupus erythematosus, 3; Anti-glomerular basement membrane disease, 2; oxalosis, 2; and miscellaneous, 2. The diagnosis of recurrent and de novo disease was made after a mean period of 678 days after the transplant. During the follow-up period, there were significantly more graft failures in the recurrent disease group, 55% vs. 25%, P<0.001. The actuarial 1-, 2-, 3-, 4, and 5-year kidney survival rates for patients with recurrent and de novo disease was 86.5%, 78.5%, 65%, 47.7%, and 39.8%. The corresponding survival rates for patients without recurrent and de novo disease were 85.2%, 81.2%, 76.5%, 72%, and 67.6%, respectively (Log-rank test, P<0.0001). The median kidney survival rate for patients with and without recurrent and de novo disease was 1360 vs. 3382 days (P<0.0001). Multivariate analysis using the Cox proportional hazard model for graft failure was performed to identify various risk factors. Cadaveric transplants, prolonged cold ischemia time, elevated panel reactive antibody, and recurrent disease were identified as risk factors for allograft failure. The relative risk (95% confidence interval) for graft failure because of recurrent and de novo disease was 1.9 (1.57-2.40), P<0.0001. The relative risk for graft failure because of posttransplant FSGS was 2.25 (1.6-3.1), P<0.0001, for membranoprolifera. tive glomerulonephritis was 2.37 (1.3-4.2), P<0.003, and for HUS/TTP was 5.36 (2.2-12.9), P<0.0002. There was higher graft failure (64.9%) and shorter half-life (1244 days) in patients with recurrent FSGS. CONCLUSION In conclusion, recurrent and de novo disease are associated with poorer long-term survival, and the relative risk of allograft loss is double. Significant impact on graft survival was seen with recurrent and de novo FSGS, membranoproliferative glomerulonephritis, and HUS/TTP.

Monitoring functional patency of in situ saphenous vein bypasses: The impact of a surveillance protocol and elective revision

Implementation of a protocol that monitored in situ saphenous vein bypass hemodynamics for low-flow states provided insight into the pathophysiologic characteristics and time course of graft failure. From 1981 to 1988, 250 in situ bypasses to popliteal (n = 83) or tibial (n = 167) arteries were performed in 231 patients. Indications for operation included critical limb ischemia in 232 cases (93%), popliteal aneurysm in 11 cases (4%), and disabling claudication in seven cases (3%). Arterial pressure measurements, continuous-wave Doppler spectral analysis, and duplex ultrasonography were used to assess patency, detect hemodynamic changes indicative of graft stenosis, and localize anatomic hemodynamic changes indicative of graft stenosis. Seventy grafts with correctable anatomic lesions (retained venous valves, graft stenosis, arteriovenous fistula, native vessel atherosclerosis) that decreased graft blood flow or ankle arterial pressure or both were identified. Correction of vein conduit or anastomotic lesions comprised 73 (77%) of the 95 revisions performed. Vein-patch angioplasty of a stenosis was the most common secondary operation performed. Graft revision was highest in the perioperative period (10% at 30 days), decreased to 7% per 6-month interval until 18 months, and was 3% per year thereafter. The primary patency rate of grafts not identified to have a correctable lesion was 86% at 4 years, a level similar to the secondary patency of 81% for grafts requiring one or multiple revisions. The surveillance protocol identified grafts with correctable lesions before thrombosis thereby permitting elective revision of patent grafts. Hemodynamic studies confirmed that a frequent mechanism of late failure of grafts was the development of a low-flow state produced by lesions not amenable to revision.

Factors influencing weight gain after renal transplantation.

Weight gain following renal transplantation occurs frequently but has not been investigated quantitatively. A retrospective chart review of 115 adult renal transplant recipients was used to describe patterns of weight gain during the first 5 years after transplantation. Only 23 subjects (21%) were overweight before their transplant. Sixty-six subjects (57%) experienced a weight gain of greater than or equal to 10%, and 49 subjects (43%) were overweight according to Metropolitan relative weight criteria at 1 year after transplantation. There was an inverse correlation between advancing age and weight gain, with the youngest patients (18–29 years) having a 13.3% weight gain and the oldest patients (age greater than 50 years) having the lowest gain of 8.3% at 1 year (P =0.047). Black recipients experienced a greater weight gain than whites during the first posttransplant year (14.6% vs. 9.0%; P =0.043), and maintained or increased this difference over the 5-year period. Men and women experienced comparable weight gain during the first year (9.5% vs. 12.1%), but women continued to gain weight throughout the 5-year study (21.0% total weight gain). The men remained stable after the first year (10.8% total weight gain). Recipients who experienced at least a 10% weight gain also increased their serum cholesterol (mean 261 vs. 219) and triglyceride (mean 277 vs. 159) levels significantly, whereas those without weight gain did not. Weight gain did not correlate with cumulative steroid dose, donor source (living-related versus cadaver), rejection history, pre-existing obesity, the number of months on dialysis before transplantation, or posttransplant renal function. Posttransplant weight gain is related mainly to demographic factors, not to treatment factors associated with the transplant. The average weight gain during the first year after renal transplantation is approximately 10%. This increased weight, coupled with changes in lipid metabolism, may be significant in terms of altering risk from cardiovascular morbidity.

Peroxidative stress in diabetic blood vessels. Reversal by pancreatic islet transplantation.

Diabetic complications are believed to arise, in part, through an increase in oxidative stress. We characterized antioxidant status in vascular tissue in untreated diabetic rats and in diabetic rats rendered euglycemic by pancreatic islet transplantation. Three key endogenous antioxidant enzymes (e.g., superoxide dismutase, catalase, and glutathione peroxidase) were measured. Sprague-Dawley rats with streptozotocin-induced diabetes were killed after 8 weeks of untreated hyperglycemia and compared with age-matched controls. Eight weeks of untreated diabetes resulted in a significant increase of tissue catalase in aorta, iliac artery, and femoral artery as compared with controls. No significant changes in either superoxide dismutase or glutathione peroxidase were observed in aorta, iliac artery, or femoral artery of diabetic animals. This increase in catalase in diabetic vascular tissue suggests increased oxidative stress due to chronic exposure to H2O2 in vivo. To assess the impact of islet transplantation on oxidative stress in vascular tissue, inbred Lewis strain rats were rendered diabetic with streptozotocin. After 8 weeks of untreated diabetes, rats received an intraportal islet isograft and were monitored for 4 subsequent weeks of euglycemia. Islet transplantation improved weight gain and normalized blood glucose and total glycosylated hemoglobin. While catalase was significantly increased in aorta and iliac artery at 8 and 12 weeks of diabetes, vascular catalase was restored to normal by islet transplantation. These data suggest that islet transplantation is an effective treatment strategy to minimize increased oxidative stress in diabetic vasculature.

Renal transplantation for end-stage renal disease following bone marrow transplantation: a report of six cases, with and without immunosuppression.

Background. Over 12 000 bone marrow transplantations (BMT) are performed in the USA each year. This procedure is associated with significant morbidity including acute and chronic renal failure (CRF). CRF after BMT is usually secondary to radiation nephropathy and/or cyclosporine (CsA) toxicity. Survival on dialysis therapy for patients with radiation nephropathy is poor and renal transplantation may be a preferable form of renal‐replacement therapy.Methods. We report our experience with renal transplantation in 6 patients with end‐stage renal disease (ESRD) following BMT: 4 as a result of radiation nephropathy; one secondary to hemolytic–uremic syndrome; and 1 as a result of antitubular basement membrane nephritis. Ages at the time of BMT ranged from 26 to 40 yr. ESRD developed after a mean period of 94 months (range 42–140 months) after BMT. The kidney source was from a living donor in 5 patients, and a cadaveric donor (CAD) in 1 patient. In 3 recipients, the bone marrow and kidney were from the same donor. They are managed without any immunosuppressive therapy. The other 3 were initiated on triple therapy (prednisone, mycophenolate mofetil/azathioprine and cyclosporine/tacrolimus).Results. These patients have been followed for up to 31 months (range 3–30 months) after kidney transplant, and 5 out of 6 are alive with functioning bone marrow and renal transplants. Their plasma creatinines range from 70 to 160 μmol/L (mean 97 μmol/L). One patient died following metastatic squamous cell cancer of the genital tract.Conclusions. 1) Renal transplant is a feasible alternative for patients with ESRD following BMT; 2) if bone marrow and kidney are from the same donor, the recipient requires little or no maintenance immunosuppression; 3) short‐term results show good survival, but long‐term follow‐up is needed; 4) infections and malignancy post‐renal transplantation were seen in recipients who needed immunosuppression; and 5) reduction in immunosuppression may be needed in such post‐BMT patients who undergo kidney transplants.

Turbulence occurring after carotid bifurcation endarterectomy: A harbinger of residual and recurrent carotid stenosis

The goal of carotid endarterectomy is to remove an obstructing or embologenic lesion and reconstruct a durable arterial segment free of flow abnormality. The technical adequacy of 250 endarterectomy sites in 235 patients was assessed at operation by pulsed Doppler spectral analysis and arteriography and was correlated with postoperative patency, the incidence of residual and recurrent stenosis, and clinical outcome. Duplex scanning was used after operation to categorize disease severity. At operation, 10 patients (4%) had angiographic and Doppler flow abnormalities identified in the internal carotid artery. Vessel exploration identified intimal flaps, platelet aggregation, or stricture. Residual flow disturbances at the endarterectomy site correlated with perioperative thrombosis and stroke, angiographic abnormalities, primary closure of the arteriotomy, and a postoperative duplex scan consistent with stenosis. In 175 patients (182 sites) with normal arterial flow after carotid bifurcation endarterectomy, no thrombotic events occurred and the incidence of recurrent stenosis (life-table analysis) was zero at 3 months, 5% at 1 year, and 9% at 2 years. The incidence of occlusion and recurrent stenosis was increased (8% at 3 months, 18% at 1 year, and 21% at 2 years) in 68 arteries with residual flow disturbance identified at operation. Assessment of endarterectomy sites for turbulence identifies anatomic lesions that threaten patency and increase the incidence of residual and recurrent stenosis.

Myocardial nuclear factor-κB activity and nitric oxide production in rejecting cardiac allografts

BACKGROUND Nuclear factor-kappaB (NF-kappaB) is a rapid response transcription factor for genes whose products are critical for inflammation and immunity. In a rat model of heterotopic cardiac transplantation, we studied NF-kappaB DNA binding activity and nitric oxide (.NO) production in untreated allografts and whether inhibition of NF-kappaB suppresses .NO production and prolongs graft survival. METHODS In allograft recipients and isograft controls, NF-kappaB was assayed by electrophoretic mobility shift assay, daily from transplant until rejection. Myocardial .NO was directly detected in explanted allografts by electron spin resonance spectroscopy on day 6 after transplant. The potent inhibitor of NF-kappaB, pyrrolidine dithiocarbamate (PDTC; 250 mg/kg s.c.) was administered daily from transplant until day of rejection. The extent of graft lymphocytic infiltrate was assessed by routine hematoxylin and eosin staining. Immunohistochemical staining of NF-kappaB was per formed to identify the cell type responsible for NF-kappaB activity. RESULTS A time-dependent increase in myocardial NF-kappaB activity was seen in untreated allografts as compared with isografts as determined by PhosphorImage analysis. Peak NF-kappaB activity occurred in allografts on day 4 with a ninefold increase as compared with isografts (24.0+/-3.7% vs. 2.7+/-0.5; P<0.05). On posttransplant day 6, electron spin resonance spectroscopy analysis of allografts demonstrated .NO identified by a triplet nitrogen signal centered at g=2.012 with hyperfine splitting of 17.5 Gauss, which is consistent with nitrosoheme formation and low-field signals at g=2.08 and g=2.03 consistent with nitrosomyoglobin. These signals were not seen in native hearts of allograft recipients. With PDTC administration, a threefold decrease in NF-kappaB activity within the transplanted heart was observed on posttransplant day 5 as compared with untreated allografts (9.7+/-1.6% vs. 23.5+/-2.5%; P<0.01). PDTC prolonged graft survival as compared with untreated allografts (11.7+/-0.3 vs. 6.6+/-0.2 days; P<0.05) and reduced the intensity of the nitrosoheme and nitrosomyoglobin signals. Allograft mononuclear cell infiltrate correlated with peak NF-kappaB activity with peak infiltrate on posttransplant day 4. PDTC treatment had no effect on the extent of infiltrate. Immunohistochemical staining localized NF-kappaB to the infiltrating mononuclear cells on posttransplant day 5. CONCLUSION These data support a role for NF-kappaB in allograft rejection.

Chronic treatment in vivo with dimethylthiourea, a hydroxyl radical scavenger, prevents diabetes-induced endothelial dysfunction.

Oxidative stress is believed to play a role in diabetes-induced vascular complications. In this study, we tested whether chronic treatment with a known hydroxyl radical scavenger, dimethylthiourea (DMTU), could prevent endothelial dysfunction in diabetes. Lewis strain rats were made diabetic by an intravenous injection of streptozotocin. A subgroup of diabetic animals received daily intraperitoneal injections of 50 mg/kg DMTU beginning at 72 h after streptozotocin and throughout 8 weeks of diabetes. Diabetes caused an increase in aortic catalase activity (an index of compensatory in vivo oxidative stress) that was not prevented by long-term DMTU treatment. Long-term treatment of diabetic animals with DMTU did not alter serum insulin levels, blood glucose concentrations, or total glycosylated hemoglobin. Descending thoracic aortas were isolated, sectioned into rings and suspended in isolated tissue baths, and contracted with a submaximal concentration of norepinephrine. Relaxation to the endothelium-dependent vasodilator, acetylcholine, was impaired in diabetic aortas, whereas relaxation to A23187 and nitroglycerin was unaltered. DMTU treatment prevented the diabetes-induced impairment in endothelium-dependent relaxation to acetylcholine but had no effect on relaxations induced by either A23187 or nitroglycerin. These data suggest that chronic exposure to increased levels of hydroxyl radicals in vivo likely play a significant role in the origin of diabetes-associated endothelial dysfunction.

Pre‐transplant identification of risk factors that adversely affect length of stay and charges for renal transplantation

Background. In the current era of renal transplantation, increasing attention is being focused on resource utilization. The purpose of this study was to identify demographic, medical and immunologic risk factors that are associated with changes in length of stay (LOS) and charges for renal transplantation.Method. The study was a retrospective analysis of 311 consecutive renal transplants performed at a single institution. Univariate and multivariate analyses were used to examine relationships between risk factors, LOS, charges and post‐operative complications.Results. The following pre‐transplant variables were found to be independently significant in predicting increased LOS and/or charges: African–American race, obesity for women, chronic obstructive pulmonary disease (COPD), presence of cardiac disease or previous stroke, pre‐transplant dialysis time ≥1 yr, a 10% increase in panel reactive antibody (PRA), cadaver donor and retransplantation. The analyses were performed with and without adjustment for key outcome variables such as delayed graft function (DGF) and use of induction antibody therapy. Increased LOS or charges for specific risk factors could be attributed to increased complication rates, including delayed graft function seen with various co‐morbidities, or increased immunologic risk and more frequent use of induction antibody therapy.Conclusion. Analysis of linked financial and clinical databases can reveal demographic, medical and immunologic risk factors that correlate with LOS, charges and complications for renal transplantation. Efforts to establish quantitative relationships for various risk factors relative to resource utilization will become important in managed care and/or capitated healthcare delivery systems.

Syngeneic Pancreatic Islet Transplantation Reverses Endothelial Dysfunction in Experimental Diabetes

Diabetes is known to cause impaired endothelium-dependent relaxation of blood vessels. The purpose of this study was to determine whether this endothelial dysfunction is a permanent defect or is reversible after acute arginine supplementation in vitro or by surgical intervention in vivo using syngeneic pancreatic islet transplantation. Lewis rats were injected with streptozotocin to induce diabetes and were studied either 8 or 12 weeks later. Another group received syngeneic islets via intraportal injection at 8 weeks of diabetes and were allowed to become euglycemic for 4 weeksbefore study. Thoracic aortic rings were tethered in isolated muscle baths, contracted with a submaximal concentration of norepinephrine, and challenged with either the endothelium-dependent vasodilator acetylcholine or the endothelium-independent vasodilator nitroglycerin. Relaxation to acetylcholine (but not nitroglycerin) was reduced in both 8- and 12-week diabetic rings compared with age-matched control rings. Preincubation of diabetic rings in vitro with L-arginine (but not D-arginine) restored relaxation to acetylcholine to normal to rings from 8-week but not 12-week diabeticanimals. Plasma basic amino acids (arginine, lysine, and histidine) were reduced by diabetes, whereas other neutral or acidic amino acids were unchanged (phenylalanine, proline, and glutamate), reduced (serine, cysteine, threonine, tyrosine, tryptophan, and aspartate), or elevated (isoleucine,leucine, and valine). Islet transplantation restored to normal the changes in plasma amino acids. Elevation in blood glucose and total glycosylated hemoglobin in diabetic animals was normalized after islet transplantation. Furthermore, islet transplantation completely restored the defective endothelium-dependent relaxation to acetylcholine in diabetic rings. These studies provide evidence for the existence of reversible and irreversible stages of endothelial cell dysfunction that occurin diabetes and that preemptive surgical intervention using pancreatic islet transplantation can completely restore normal endothelial function.