Recurrent or de novo glomerular disease is an important cause of graft dysfunction and eventual loss. Cyclosporine A (CyA) has improved short-term renal allograft outcome but has not altered long-term graft survival. The purpose of the current study is to determine the prevalence of such disease and its impact on graft function in the CyA era. From 1984 to 1994, 1,557 renal allografts were performed at the Medical College of Wisconsin and the University of Cincinnati. Patients were followed up for an average of 7.2 years (minimum, 1 year). Recurrent disease was diagnosed by renal biopsy in 98 (6.3%) patients after an average of 36 months. Demographic characteristics of patients with and without recurrent disease were similar. Glomerulonephritis was the most common finding, occurring in 73 patients, and included focal segmental glomerulosclerosis (FSGS), 25; IgA nephropathy (IgAN), 11; membranous (MN), 11; proliferative, 11; membranoproliferative glomerulonephritis (MPGN), 10; glomerular basement membrane (anti-GBM), 3; and systemic lupus erythematosus (SLE), two. Diabetic nephropathy was present in 22, hemolytic uremic syndrome (HUS) in two, and oxalosis in one. Graft loss occurred in 60 of 98 (61%) recipients. Half-life of the allograft was diminished in patients with recurrent disease, 2,038 +/- 225 versus 3,135 +/- 385 days, P = 0.002. The actuarial allograft survival at 1, 3, 5, and 8 years posttransplantation with recurrence was 88%, 74%, 57%, and 34%, respectively; and the corresponding graft survival for patients without recurrent disease was 80%, 70%, 64%, and 53%, respectively (P = 0.003). The risk of recurrent disease increased with length of graft survival from 2.8% at 2 years to 9.8% and 18.5% at 5 and 8 years, respectively. We conclude that recurrent disease is a significant problem after renal transplantation and is associated with decreased graft survival.

Actuarial Analysis↗

PubMed1998

Importance of allograft biopsy in renal transplant recipients: correlation between clinical and histological diagnosis.

Renal allograft dysfunction after transplantation may be caused by acute rejection (AR), chronic rejection (CR), cyclosporine (CyA) or tacrolimus (FK) toxicity, and other causes such as recurrence of renal disease. Allograft biopsy is the "gold standard" to establish the correct diagnosis. However, many transplant centers routinely do not consider graft biopsy at the onset of renal dysfunction; instead, empirical steroid therapy or CyA dose reduction is the initial response to graft dysfunction. In this study, we prospectively predicted the histological findings prior to renal biopsy and correlated the clinical and histological diagnoses after the final report was issued by the pathologist. Patients with renal dysfunction after transplantation (increased serum creatinine >20% from baseline) were submitted to allograft biopsy. Three clinicians (C1, C2, and C3) involved in the care of these patients independently predicted the histological findings prior to the biopsy. A total of 100 cases (62 men, 38 women; 71 whites, 29 blacks) with a mean age of 41 years (21 to 70 years) were included in this study. Biopsy samples were taken after a mean period of 1.6 +/- 0.32 years (median, 0.25 years; range, 4 days to 17 years) after transplantation. Two patients with en bloc pediatric kidneys required postbiopsy blood transfusions for self-limiting bleeding; all other patients had no complications. All patients received azathioprine and prednisone; additionally, 74 received CyA and 19 FK. Final histopathologic diagnoses were AR (30), CyA/FK toxicity (36), AR plus CyA/FK toxicity (17), CR (11), recurrent disease (11), and other (6). In 28 cases (28%), the results of the biopsies showed more than one diagnosis. A completely correct diagnosis was predicted by C1, C2, and C3 in 47%, 42%, and 41% (mean, 43%) of the cases, incorrect diagnosis in 25%, 27%, and 25% (mean, 26%) of the cases, and partially correct diagnosis in 28%, 31%, and 34% (mean, 31%) of the cases, respectively. AR was confirmed histologically in 26 of 47 cases (55%) in the presence of therapeutic or high CyA/FK blood levels, whereas in 41 of 53 cases (77%), the histology showed CyA/FK toxicity in the presence of therapeutic or low CyA/FK blood levels. The mean serum creatinine at the time of the biopsy was 2.92 +/- 0.30 mg/dL, compared with the baseline of 1.76 +/- 0.10 mg/dL (P < 0.0001). After appropriate treatment, mean serum creatinine was 2.38 +/- 0.33 mg/dL (P < 0.0001). These data show that clinical prediction was poor, with totally correct diagnosis in only 43% of the cases. In 26%, the diagnosis was incorrect. We conclude that the renal biopsy is essential for establishing the correct diagnosis of renal allograft dysfunction and the appropriate management thereof.

Adult↗

PubMed1998

Proposed consensus for definitions and endpoints for clinical trials of acute kidney transplant rejection.

Progress in transplantation therapeutics requires validation from multicenter trials in which enrollment criteria and endpoint definitions have been standardized. A database of acute rejection was established from 19 North American, European, and Australian transplant centers and included parameters on rejection diagnosis and treatment of 50 consecutive rejection episodes from each center. Patient demographics, induction and maintenance immunosuppressive therapies, antirejection agents (drug, dose, duration), clinical signs (decrease in urine volume, presence of fever of > or =38.5 degrees C), serum creatinine concentration (nadir, at rejection, daily during antirejection therapy to 15 days, and days 30, 90, 180, and 365 after rejection date), rejection biopsy findings, morbidity, recurrence of rejection, and renal function at 1 year were recorded for 953 rejection episodes. From these data, three definitions were proposed. Acute rejection was defined as an immunologic process resulting in a serum creatinine increase of > or =0.4 mg/dL, with or without clinical signs, and should include a biopsy confirmation that has been standardized to the Banff criteria. Corticosteroid-resistant rejection was defined as a rejection episode in which a minimum of 250 to 1000 mg of methylprednisolone administered as initial therapy fails to result in stabilization or reduction of the serum creatinine after 3 days of corticosteroid treatment. Successful response to therapy was defined as a serum creatinine level < or =110% of the serum creatinine on the day of the rejection diagnosis and a return of the serum creatinine to or below the rejection creatinine level by 5 days of therapy with maintenance of this response for a minimum of 30 days. The work represented in the Efficacy Endpoints Database provides a step toward improving definitions in clinical trials. Continuity in clinical trial design should lead to improvements in evaluation of outcomes and, thereby have an effect on clinical practice.

Acute Disease↗

PubMed1998

Characteristics of long-term renal transplant survivors.

Despite the high rates of rejection, allograft failure, and patient death in the early years of renal transplantation, some patients have done remarkably well. Forty-three (17 living related donor and 26 cadaver donor recipients) such patients with an allograft that functioned for 19 years or more (range, 19 to 29 years) were followed up at this center. The patients included 24 men and 19 women, with a mean age at transplantation of 29 years, of whom 39 were white and four were black. At most recent follow-up, the mean daily dose of azathioprine was 104 mg (range, 50 to 175 mg) and that of prednisone was 10 mg (range, 5 to 20 mg). Mean serum creatinine level was 1.6 mg/dL (range, 0.7 to 5.4 mg/dL). Acute rejection occurred in 14 (33%) patients. Nine patients had one episode and five patients had two episodes of acute rejection. Long-term risks to the recipients appeared in the form of coronary artery disease in 10 (23%) patients; malignancy in 13 (30%) patients, which included nine patients with skin malignancy; and chronic hepatitis C virus (HCV) infection in four patients, two of whom died of complications of liver failure. Other complications included avascular bone necrosis in five patients, which required total hip replacement in two patients; hyperlipidemia requiring treatment in 16 (37%) patients; posttransplantation diabetes mellitus in 10 (23%) patients after a median of 17.5 years (range, 1 to 23 years); and hypertension in 23 (53%) patients. There were seven deaths (three of coronary artery disease, two of liver failure, one each of sepsis and malignancy) and eight graft losses (five to death with function, two to chronic rejection, and one to focal and segmental glomerulosclerosis). Although long-term allograft success results in patients receiving minimal amounts of immunosuppression and having good renal function, long-term renal transplant survivors are at risk for significant morbidity even in the third decade posttransplantation.

Adolescent↗

PubMed1998

Use of tacrolimus eliminates acute rejection as a major complication following simultaneous kidney and pancreas transplantation.

This retrospective study illustrates the efficacy of tracrolimus-based immunosuppression following simultaneous kidney and pancreas transplantation. Between March 1995 and December 1996, 24 simultaneous kidney and pancreas transplant recipients received tacrolimus-based maintenance immunosuppression. All patients received sequential therapy with an antilymphocyte agent, azathioprine, prednisone and tacrolimus. The dose of tacrolimus was adjusted to achieve a whole blood trough level of 8-15 ng/mL (IMx). The mean follow-up was 25 months with a median of 26 months (range 12-33 months). A rise in serum creatinine of > 20% over baseline was investigated with a renal biopsy, after mechanical causes for renal dysfunction had been excluded. Mean serum creatinine concentrations at 3, 6, 12, 18 and 24 months post-transplantation were 1.1, 1.2, 1.3, 1.3 and 1.3 mg/dL respectively. The blood glucose concentrations at the corresponding time period were 115, 94, 95, 93 and 95 mg/dL. Four pancreas allografts were lost (three in the immediate post-transplant period due to thrombosis, and one following iliac artery repair for aneurysm). Transient hyperglycemia requiring treatment was seen in 3 patients. There were four (17%) acute rejection episodes--one of the pancreas allograft alone and three involving the kidney. At a mean follow-up of 25 months, the patient survival and renal allograft survival were 100%, with pancreas allograft survival rate of 78.4% (Kaplan-Meier analysis). Nine (37.5%) patients had evidence of tacrolimus toxicity on renal histology. In conclusion, tacrolimus-based maintenance immunosuppression is associated with stable renal and pancreas allograft function, with freedom from acute rejection in 83% of patients.

Adult↗

PubMed1998

Development of Sang-35: a cyclosporine formulation bioequivalent to Neoral.

During a research program, SangStat Medical Corporation developed more than 270 oral cyclosporine formulations. On the basis of animal and clinical trials, Sang-35 was chosen for clinical development, and bioequivalence with the cyclosporine microemulsion Neoral was established. In a cross-over study involving 36 healthy male volunteers, single 500 mg cyclosporine doses of Sang-35 (AUC0-infinity: 13,900 +/- 2470 micrograms.h.L-1, mean +/- standard deviation (SD)) and of Neoral (AUC0-infinity: 14,000 +/- 2900 micrograms.h.L-1) resulted in equal areas-under-the-time-concentration curve (AUC0-infinity). Sang-35 and Neoral were also bioequivalent in healthy male subjects after high-fat meals as well as in female and African-American subjects. In stable kidney transplant patients (n = 12) receiving a mean (+/- SD) cyclosporine dose of mg/d (3.6 +/- 1.6 mg/kg/d), AUC0-12 h after Sang-35 was, as expected, significantly higher than that after Sandimmune (4550 +/- 1858 vs 3468 +/- 1402 micrograms.h.L-1, p < 0.01). Sang-35 and Neoral resulted in equivalent cyclosporine AUC0-12 h values (4120 +/- 1508 and 4377 +/- 1579 micrograms.h.L-1, respectively) in stable kidney transplant patients (dose: 293 +/- 114 mg/d or 3.7 +/- 1.5 mg/kg/d, n = 32). In an additional study, 42 stable kidney graft patients were switched from Sandimmune to Sang-35. Based on a conversion strategy targeting AUC equivalence, only one dose adjustment was required in 55% of the patients, and 95% of patients (40 of 42) needed three or fewer dose adjustments. The mean Sang-35 dose was 7% lower than the mean Sandimmune dose. During the studies, Sang-35 and Neoral exhibited similar safety and tolerability profiles. It is concluded that Sang-35 and Neoral are bioequivalent and that patients can safely and easily be switched from Neoral or, in combination with dose adjustment, from Sandimmune to Sang-35.

Administration, Oral↗

PubMed1997

Efficacy of OKT3 as primary therapy for histologically confirmed acute renal allograft rejection.

BACKGROUND: OKT3 is often used as primary treatment for acute renal allograft rejection. In a retrospective study, we sought to determine the efficacy of OKT3 as a first-line agent in reversing histologically confirmed acute renal allograft rejection. METHODS: Patients with mild to moderate, moderate, or severe acute cellular and acute vascular rejection who had not received any other anti-rejection treatment were included in this analysis. A total of 88 patients, who received OKT3 between 1987 and 1995, fulfilled these criteria. RESULT: Seventy of these patients were renal transplant recipients, and 18 were combined kidney and pancreas transplant recipients. The median time to the diagnosis of rejection from transplantation was 32 days (range, 6 days to 13 years). On histology, 6 were graded as mild to moderate, 36 as moderate, 29 as moderate to severe, and 17 as severe rejection. The mean baseline serum creatinine was 1.62 mg/dl (range, 0.7-10.1 mg/dl), and the mean serum creatinine at the time of diagnosis of rejection was 2.60 mg/dl (range, 1.4-12.7 mg/dl) (P=<0.0001). The mean duration of OKT3 treatment was 11.2 days (range, 8-18 days). The mean serum creatinine at the end of OKT3 treatment was 1.73 mg/dl (range, 0.6-5.0 mg/dl; P=0.24 compared with baseline serum creatinine). Rejection was reversed in 86 (98%) patients. Graft survival at 1 year after OKT3 therapy was 87.5% (77 of 88). At a mean follow-up of 38 months, 8 patients had died and 26 grafts were lost. The mean serum creatinine level in the 64 patients with a functioning graft was 1.76 mg/dl (range, 0.8-4.0 mg/dl) at the last follow-up. CONCLUSION: OKT3 when utilized as first-line therapy reversed 98% of the acute rejection episodes, with a 1-year post-OKT3 graft survival of 87.5%.

Acute Disease↗

PubMed1997

Primary care of patients with renal transplants.

The number of renal transplant recipients in the community continues to rise due to improved organ and patient survival. With increasing emphasis on primary care, more organ transplant recipients are being cared for by primary care physicians. This article outlines the management of renal transplant recipients and reviews the problems unique to this group of patients.

Cadaver↗

PubMed1997

Clinical and economic outcomes of expanded criteria donors in renal transplantation.

Although graft and patient survival rates were similar between recipients of kidneys from ECDs and non-ECDs, transplantation with organs from ECDs was significantly more expensive. Multivariate analysis using stepwise linear regression demonstrated length of stay to be a strong proxy for total hospital costs. Inherent tensions between the overall good clinical outcomes associated with the use of ECDs in terms of graft survival and the markedly increased costs seen with these organs are evident.

Age Factors↗

PubMed1997

The donor supply.

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Age Factors↗