Bruce G. Sommer

Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes?

BACKGROUND Despite use of lower doses of corticosteroid hormones after renal allotransplantation in the era of cyclosporine and tacrolimus, posttransplant diabetes mellitus remains a common clinical problem. METHODS We prospectively investigated the effect of posttransplant diabetes on long-term (mean follow-up, 9.3+/-1.5 years) graft and patient survival in the 11.8% of our renal transplant population (n = 40) who developed diabetes after kidney transplantation, and we compared outcome in 38 randomly chosen nondiabetic control patients who had received transplants concurrently. RESULTS Twelve-year graft survival in diabetic patients was 48%, compared with 70% in control patients (P = 0.04), and Coxs regression analysis revealed diabetes to be a significant predictor of graft loss (P = 0.04, relative risk = 3.72) independent of age, sex, and race. Renal function at 5 years as assessed by serum creatinine level was inferior in diabetic patients compared to control patients (2.9+/-2.6 vs. 2.0+/-0.07 mg/dl, P = 0.05). Two diabetic patient who experienced graft loss had a clinical course and histological features consistent with diabetic nephropathy; other diabetes-related morbidity in patients with posttransplant diabetes included ketoacidosis, hyperosmolar coma or precoma, and sensorimotor peripheral neuropathy. Patient survival at 12 years was similar in diabetic and control patients (71% vs. 74%). CONCLUSIONS Posttransplant diabetes mellitus is associated with impaired long-term renal allograft survival and function, complications similar to those in non-transplant-associated diabetes may occur in posttransplant diabetes, and, hence, as in non-transplant-associated diabetes, tight glycemic control may also be warranted in patients with posttransplant diabetes.

Cyclosporine-associated renal arteriopathy resulting in loss of allograft function

Cyclosporine-associated arteriopathy was the cause of graft loss in 40 percent of all allografts that failed in a series of 200 consecutive cadaveric renal transplants. Arteriopathy was diagnosed by biopsy and renal uptake of indium 111m labeled platelets in the face of acute renal deterioration. A moderate thrombocytopenia and microangiopathic picture of hemolytic uremia was also present on peripheral blood smear. Immunofluorescence and histologic characteristics of the allograft biopsy specimens failed to show evidence for acute rejection: immunoglobulin M, immunoglobulin A, immunoglobulin G, C1q, C3, and C4 were not present, and there was no evidence of an interstitial or vascular mononuclear cellular infiltrate. Two clinical presentations have been described. In Group I (seven patients), anuria occurred rapidly within the first 2 weeks after transplantation. In Group II (nine patients) renal function gradually diminished 1 to 5 months after starting cyclosporine therapy. Fifteen of the 16 recipients had progressive and irreversible loss of renal function which was pathologically associated with fibrin deposition, intimal proliferation, and thrombotic occlusion of the cortical interlobular and arcuate arteries, with subsequent focal glomerular ischemia and cortical infarction. One recipient with rapid loss of renal function received an intraarterial allograft infusion of streptokinase and subsequent systemic heparinization, which resulted in return of normal allograft function. The syndrome of cyclosporine-associated arteriopathy has been linked to a lack of or reduced amounts of prostacyclin-stimulating factor or prostacyclin.

The influence of nephrectomy of the primary allograft on retransplant graft outcome in the cyclosporine era

The present analysis was undertaken to evaluate the influence of primary allograft nephrectomies on the early function, incidence of rejection, and short-term graft survival of subsequent renal retransplants. Among 95 consecutive cyclosporine treated retransplant recipients, 52 were retransplanted without primary allograft nephrectomy; 35 had removal of their primary grafts prior to retransplantation for fever and graft tenderness (30 patients) and persistent hematuria (5 patients); and 8 patients had an elective primary graft nephrectomy at the time of retransplantation. Demographic characteristics and immunosuppressive regimens were otherwise similar in all three groups. Nephrectomy of the primary allograft prior to retransplantation was associated with a significant subsequent rise in preformed cytotoxic antibody levels (57% having PRA > 30% compared with 33% in those with retention of primary grafts), a significantly higher incidence of delayed graft function among retransplants (63% compared with 30% in those who did not undergo primary allograft nephrectomy) and a trend toward decreased allograft survival in the subgroup who lost their primary allografts in the first year poattranaplant. The incidence of acute rejection and 3-year posttransplant renal function in retransplants were not, however, influenced by nephrectomy of the primary allograft.

Sequential antilymphoblast globulin and cyclosporine for renal transplantation

The nephrotoxic effects of cyclosporine (CsA) seem to be augmented by co-existing renal injury. A high rate of prolonged delayed function (acute tubular necrosis [ATN]) and non-function (NF) has been associated with the use of CsA prior to and following renal transplantation. Cyclosporine has also been associated with a slower recovery of allograft function and poor baseline renal function even in allografts that function immediately compared with conventionally treated recipients. In 1983 we hypothesized that the rate of ATN and NF following renal transplantation could be decreased and more normal kidney function achieved if renal injury was resolved before adding the nephrotoxic effects of CsA. A group of 300 nonsplenectomized, uremic recipients have received 304 renal transplants and have been initially immunosuppressed with azathioprine, prednisone, and Minnesota antilymphoblast globulin (ALG) prior to starting maintenance CsA and prednisone. The incidence of NF has been 1.9% and the development of ATN has been 7.6% following transplantation with sequential use of ALG and CsA. Other benefits to the renal recipient have also occurred with use of this immunotherapy protocol. Renal allograft survival for recipients of first, second, and third renal allografts has been higher than that generally reported with cyclosporine and prednisone alone. Rejection episodes have been infrequent during the first six months posttransplant, as 75% and 62% of first and second renal allograft recipients have remained rejection-free. Clinically significant infectious complications were infrequent. No cadaver recipient has developed a lymphoma. Moreover, the initial hospitalization following transplantation with sequential ALG/CsA has been short and generally uncomplicated. We conclude that sequential ALG/CsA following renal transplantation provides excellent early posttransplant immunosuppression while avoiding the nephrotoxic effects of CsA and also provides the steroid and infection-sparing benefits derived from maintenance CsA therapy.

The effect of kidney size on cadaveric renal allograft outcome

Chronic rejection is the commonest cause of long-term renal allograft loss. Though immunologic factors are thought dominant in its pathogenesis, nonimmunologic factors, in particular, hyperfiltration damage related to reduced renal mass, have also been proposed as factors in the causation of chronic allograft rejection. We assessed the influence of renal size on graft survival and function in all cyclosporine-treated cadaver donor adult renal allograft recipients engrafted at a single center between June 1989 and July 1994, whose grafts functioned for > or = to 3 months (n=169). Patients were divided into 4 groups based on the ratio of kidney volume to recipient body surface area (volume/BSA) (ml/m2), and outcome in groups compared by methods including Coxs proportional hazards and Kaplan-Meier analysis. No significant differences between groups existed for serum creatinine levels, presence of significant proteinuria, or 1- and 5-year graft survival. There was no correlation between volume/BSA and either serum creatinine or degree of proteinuria at 3, 6, 12, 36, and 60 months posttransplant. Volume/BSA was similar in patients with good or poor renal function (58 +/-21 vs. 56 +/- 28 ml/m2), with or without significant proteinuria (57 +/- 24 vs. 60 +/- 25 ml/m2) or in patients who lost their grafts to chronic rejection compared with those with stable allograft function (64 +/- 34 vs. 59 +/- 24 ml/m2). Volume/BSA was not a predictor of graft survival on multivariate regression. We conclude that donor kidney size has no apparent effect on cadaveric renal allograft outcome in the short and intermediate-term, suggesting that close matching of donor kidney size to recipient size is not presently indicated.

Physiological and Pharmacological Stimulation of Pancreatic Islet Hormone Secretion in Type I Diabetic Pancreas Allograft Recipients

Successful heterotopic and denervated pancreas allograft transplantation (PAT) often results in normoglycemia and peripheral hyperinsulinemia in insulin-dependent (type I) diabetic recipients. The contribution of altered hepatic insulin extraction (HIE) to the resulting hyperinsulinemia in such patients remains uncertain. Furthermore, whether the denervated pancreas allografts exhibit β-cell hyperresponsiveness to physiological and pharmacological stimulation is controversial. We evaluated β-cell function and HIE after successful whole cadaveric PAT with systemic venous drainage in 13 type I diabetic patients before and after mixed-meal and intravenous glucose and glucagon administration. The results were compared with those of 5 nondiabetic patients with kidney transplantation only, who had native innervated pancreases with portal insulin delivery and were receiving an equivalent triple immunosuppressive therapy (cyclosporin, azathioprine, and prednisone), and 7 healthy control subjects with no family history of diabetes. After PAT, fasting and poststimulation serum glucose concentrations were normalized. PAT was associated with marked basal hyperinsulinemia (3- to 8-fold) as assessed by immunoreactive insulin (IRI) levels in type I diabetic patients (mean ± SE 345 ± 43 pM) compared with control subjects (43 ± 14 pM) and nondiabetic kidney-transplantation patients (129 ± 38 pM). After mixed-meal ingestion, the mean incremental integrated insulin area was similar in PAT patients (18 ± 3 nM · min) compared with kidneytransplantation patients (20 ± 4 nM · min) and healthy control subjects (21 ± 3 nM · min). Basal serum Cpeptide levels were significantly greater in PAT (1.72 ± 0.13 nM) and kidney-transplantation (2.15 ± 0.33 nM) patients than in healthy control subjects (0.50 ± 0.10 nM; P < 0.01). In contrast, the post-mixed-meal incremental integrated C-peptide area was significantly lower in PAT (95 ± 20 nM · min) than in kidneytransplantation (304 ± 42 nM · min; P < 0.001) patients, but it was similar to that of healthy control subjects (100 ± 14 nM · min). Although the acute first and second phases of insulin response were greater in PAT patients after intravenous glucose, the corresponding C-peptide responses were not different among the three groups. The mean basal steady-state molar ratios of C-peptide and insulin that reflect basal HIE were significantly reduced by 70 and 60% in PAT patients compared with kidney-transplantation patients and healthy control subjects, respectively (P < 0.01). In summary, successful heterotopic PAT results in normalization of glycemic control at basal conditions and after physiological and pharmacological stimulations in type I diabetic patients; however, the normalized glucose concentrations occur at the expense of markedly elevated basal IRI that could be ascribed to severe insulin resistance and decreased HIE caused by direct systemic venous drainage that bypasses the liver rather than β-cell hyperresponsiveness.

Improved immediate function of renal allografts with Belzer perfusate.

The charatersistics of 254 cadaveric kidndys were evaluated and the incidence of immediate function identified. The Belzer perfusate was used primarily (n=140) and secondarily (n=14) in conbination with pulsatile machine perfusion. These two groups were compared with a previous group of kindneys machine-perfused with silica gel (cryoprecipitated human plasma). The incidence of immediate function of the group primarily perfused with Belzer perfusate was statistically significantly improved over that of the silica gel. The secondarily perfused Belzer group, “imported” kidneys previously preserved with simple cold storage, had notably longer periods of preservation adn higher resitances on the machine. However, 100% of this group functioned immeidately. Other dindings in this study show that the Belzer perfusate allows for improved parenchymal function posttransplant, as noted by a more rapid clearance of serum creatinine posttransplant. When comkkparing the immediate function group with those suffereing early dysfunction, there is a statistically significant increased resistance on the machine in the latter group. This allows for prediction of immediate function based on perfusion characteristics of the kidney.The Belzer perfusate, comosed of metabolic substrates for high-energy phosphate production, improves the incidence of immediate function in machine-perfused kidneys, as well as improved qualitative function posttransplant. It also is effective as a “rescue” mechaniosm in previously simple cold-stored (ATP-depleted) kidneys.

Cyclosporine in renal transplantation: a single institutional experience.

Cyclosporine (CsA) as immunosuppression in renal transplantation was evaluated in a single institutional experience to answer several controversial questions. CsA was found to be the superior method of immunosuppression for primary cadaveric renal transplantation. Graft survival, with CsA, was improved over that with conventional immunosuppression which included an antilymphocyte preparation. CsA was found to be the immunosuppressive agent of choice in retransplantation for patients who had rejected a previous renal allograft. Also, CsA was indeed the agent of choice for immunosuppression in patients over 50 years of age seeking renal transplantation. The risks of CsA following transplantation were almost exclusively related to the associated nephrotoxicity. The nephrotoxicity, however, was easily manageable through a defined management strategy which titrates the CsA dose to renal function. CsA was also found to be more cost effective when compared to conventional immunosuppression. Morbidity was substantially decreased with CsA as fewer infectious complications and rejection episodes resulted.

Incidence and morbidity of cytomegalovirus disease associated with a seronegative recipient receiving seropositive donor-specific transfusion and living-related donor transplantation: A multicenter evaluation

This retrospective study was conducted to identify the frequency of cytomegalovirus (CMV) disease in seronegative recipients of donor-specific transfusion (DST) and living-related donor (LRD) kidneys from seropositive donors. A total of 151 LRD transplants (TX) were performed at six transplant centers over a 3-year period. A total of 33 patients were identified as having been seronegative (pre-TX) for CMV, yet they had DST and a TX from a seropositive LRD. of these patients, 12 (36.45%) seroconverted within the first 6 months post-TX and developed clinical CMV disease. Additional patients seroconverted, but did not have evidencde of clinical disease and were not tested further. All TX centers, with the exception of one, had seronegative patients that became ill after receiving a seropositive DST/LRD TX. Six patients manifested their disease as a febrile illness with leukopenia and liver enzyme elevations, four had pneumonitis, and two developed CMV ulcerations of the colon (one of whom died from resultant sepsis). Of the 36 seronegative patients who received seronegative DST/LRD TX none became ill with CMV disease. Of the 72 seropositive patients who received DST/LRD TX, only 2 (2.8%) developed CMV illness (one, seropositive into seropositive, the other, seronegative into seropositive). Of the 33 seronegative patients receiving seropositive DST/LRD TX, 17 received antilymphocyte preparations (ALP), and 8 of these became ill (47.1%). Of 16 patients not receiving ALP, 5 (31.3%) developed clinical CMV illness. Of the 33 patients who were identified as having been seronegative for CMV seronegative for CMV yet received seropositive DST/LRD TX, the 12 who did develop CMV illness had two graft losses, one death, and a serum creatinine for the remaining 9 patients of 2.3pL1.6 at last follw-up. the remaining 21 patients who developed no illness had a serum creatining of 1.3pL0.6 with no graft losses at the last follow-up. This evidence suggests that a prospective TX recipient who is seronegative for CMV who received DST/LRD Tx from a seropositive family member has a significant risk for developing morbidity related to clinical CMV illness.

Transluminal balloon angioplasty of infrahepatic caval anastomotic stenosis following liver transplantation: case report

Treatment of an infrahepatic caval anastomotic stenosis with percutaneous transluminal balloon angioplasty is described in a patient 5 weeks after liver transplantation. Pressure measurements confirmed the significance of the obstruction and the success of the dilatation procedure.