Antiphospholipid antibody syndrome in renal transplantation: occurrence of clinical events in 96 consecutive patients with systemic lupus erythematosus.

We report the results of a detailed examination of clinical events associated with the antiphospholipid antibody (aPL) syndrome in 96 consecutive patients with systemic lupus erythematosus (SLE) who underwent renal transplantation between January 1, 1984, and September 1, 1996. Because of the retrospective nature of our study, we developed strict definitions of clinical events considered to be associated with the aPL syndrome. We reviewed all available hospital, clinic, and outside records of the patients with SLE who underwent transplantation at our center during this time period and noted the results of three standard serological tests for aPLs, when available. Mean follow-up of the 96 patients was 62.6 months. Eighty-five of the 96 patients (88.5%) had at least one test for aPLs performed, and 25 patients (29.4%) had at least one abnormal test result. Among these 25 patients, 15 patients (60%) had clinical events associated with aPL syndrome. Ten patients (10.4%) either died of the aPL syndrome or had an aPL-associated clinical event within 3 months of transplantation. Other morbidity from the aPL syndrome in these 15 patients included: thrombotic arteriolar microangiopathy (2 patients), stroke (4 patients), ocular ischemia (7 patients), deep vein thrombosis or pulmonary embolism (6 patients), renal artery or vein thrombosis (4 patients), peripheral ischemia (1 patient), and fetal wastage (3 patients). By comparison, among the 60 patients with normal aPL test results, only 5 patients had clinical events compatible with the aPL syndrome (P < 0.0001 by chi-squared test). aPLs may be associated with significant morbidity and mortality in patients with SLE undergoing renal transplantation. This study is the first attempt to quantify the impact of aPLs on renal transplantation in a large population of patients with SLE. Further investigation of aPLs in SLE patients with end-stage renal disease is required to clarify the risks, benefits, and optimal clinical management of renal transplantation for these patients.

Outcome of renal transplantation in ninety-seven cyclosporine-era patients with systemic lupus erythematosus and matched controls.

OBJECTIVE: To evaluate the effectiveness of renal transplantation in systemic lupus erythematosus (SLE). METHODS: A total of 97 SLE patients who underwent renal transplantation between January 1984 and September 1996 were selected for study and were matched with a group of non-SLE controls (1 control for each SLE patient) who also received transplants during that period. SLE patients and controls were matched on 6 covariates: age, sex, race, type of allograft (cadaveric versus living-related), number of previous transplants, and year of transplantation. All study subjects received either cyclosporine or FK-506/tacrolimus as part of their immunosuppressive regimen. In a rigorous medical records review, the status of each allograft and the cause of each graft loss was determined. Using a stratified Cox proportional hazards model, the transplantation outcomes of the SLE patients were compared with those of the controls. The effects of 9 individual variables on transplantation outcomes were also examined, and the statistically significant variables were compared in a stratified, multivariate Cox proportional hazards model. RESULTS: The control group included patients with 20 different causes of end-stage renal disease (ESRD). The mean followup times for the SLE patients and controls were 323 weeks and 320 weeks, respectively. During the followup period, 52 SLE patients and 37 controls lost their allografts. The 1-, 2-, 5-, and 10-year allograft survival probabilities for the 2 groups (SLE versus controls) were as follows: 81.7% versus 88.2% (1-year); 74.7% versus 84.4% (2-year); 45.9% versus 75.0% (5-year); and 18.5% versus 34.8% (10-year). In the multivariate model, the relative hazard of allograft loss associated with SLE as the cause of ESRD was 2.1 (95% confidence interval 1.06-4.06, P = 0.0328). The total number of HLA mismatches, smoking status, and delayed allograft function were also associated with allograft loss in the multivariate model. CONCLUSION: Compared with matched controls, renal transplant patients with SLE had inferior transplantation outcomes, with more than twice the risk of allograft loss.

Acute renal allograft dysfunction secondary to suprarenal arterial stenosis: a case series and review of the literature.

Stenosis of vessels proximal to the renal artery is an unusual cause of allograft ischemia. We report four patients who had such 'suprarenal' arterial stenoses leading to graft dysfunction that was reversed with revascularization. We additionally review the existing literature on this entity, outline the etiologies of such stenoses, as well as discuss the surgical and non-surgical therapeutic options in patients with this uncommon cause of allograft dysfunction.

Single-center long-term results of renal transplantation for IgA nephropathy.

BACKGROUND: Previous reports with short-term follow-up after renal transplantation for IgA nephropathy (IgAN) have suggested an incidence of recurrence up to 50%, an increased recurrence with living-related donors, and the rarity of graft loss due to recurrence. In this study, the long-term results of renal transplantation for IgAN were examined. METHODS: Between June 1980 and December 1994, 54 patients (61 renal transplants) with end-stage renal disease due to IgA nephropathy were performed at the University of California San Francisco. Actuarial patient and graft survival were compared with a matched reference group. Correlates of recurrent disease (biopsy confirmed) and graft loss were determined. RESULTS: Patient and graft survival for IgA patients were good (100% and 75%, respectively, at 5 years after transplant). Graft survival was lower in IgA recipients with living-related compared with cadaveric renal allografts (P<0.09) and also with renal allografts well matched at HLA-AB (< or =2 AB mismatches) (P<0.09) or HLA-DR (< or =1 mismatch) (P<0.01). Recurrence was not correlated with donor status, recipient age, race, gender, or immunosuppression. Recurrence (18 of 61) resulted in substantial graft loss (6 of 18) or deteriorating renal function (4 of 18) at a mean follow-up of 61 months. Mean time to diagnosis of recurrence and subsequent graft loss was 31 and 63 months, respectively. Despite re-recurrence of IgAN in three of five patients who were retransplanted, all have good long-term renal function. CONCLUSIONS: Substantial graft loss due to recurrent disease after renal transplantation for IgAN occurs with long-term follow-up. Living-related transplantation and HLA matching do not appear to confer an advantage for graft survival in patients with IgAN. Despite the potential for recurrence, IgAN patients enjoy good long-term graft survival.

Frequency of recurrent lupus nephritis among ninety-seven renal transplant patients during the cyclosporine era.

OBJECTIVE: To determine the frequency of recurrent lupus nephritis (LN) in patients with systemic lupus erythematosus (SLE) who underwent renal transplantation. METHODS: We reviewed the posttransplant clinical course and renal biopsy results in 97 consecutive SLE patients who underwent a total of 106 renal transplantation procedures at our center from January 1984 to September 1996. RESULTS: There were 81 female and 16 male patients, with a mean age of 35 years. Mean duration of dialysis prior to transplantation was 33.5 months; 9 patients were never dialyzed. In all patients, the disease was clinically and serologically quiescent at the time of transplantation. The mean posttransplantation followup period was 62.6 months. Patients underwent a total of 143 posttransplant biopsies. Nine patients had pathologic evidence of recurrent LN. Six of the patients with recurrence had cadaveric grafts, 2 had living-related grafts, and 1 had a living-unrelated graft. Recurrence occurred an average of 3.1 years after transplantation; the longest interval was 9.3 years and the shortest, 5 days. Histopathologic diagnoses on recurrence included diffuse proliferative glomerulonephritis, focal proliferative glomerulonephritis, membranous glomerulonephritis, and mesangial glomerulonephritis. In 4 patients, recurrent LN contributed to graft loss. Three of the patients with recurrence had serologic evidence of active lupus, but only 1 had symptoms of active lupus (arthritis). Three patients who lost their grafts secondary to recurrent LN underwent second renal transplantation procedures and had functioning grafts at 7, 30, and 35 months, respectively. CONCLUSION: In the largest single medical center series of renal transplant patients with SLE, recurrent LN was more common than reported in the literature, but was not always associated with allograft loss. Recurrent LN was often present in the absence of clinical and serologic evidence of active SLE.

Outcome of renal transplantation in systemic lupus erythematosus.

OBJECTIVES: (1) To provide an overview of the world's experience with renal transplantation in systemic lupus erythematosus (SLE), and to consider the most important studies in detail. (2) To examine four specific questions raised by the review, including (a) the frequency of recurrent lupus glomerulonephritis (GN); (b) the effect of pretransplantation dialysis on transplantation outcome; (c) the method of monitoring lupus activity in transplant patients; and (d) the frequency of early graft loss among lupus patients. METHODS: We performed a MEDLINE search of the world's literature from 1975 to 1997 on the subject of renal transplantation in SLE, using the search terms "lupus," "SLE," "kidney," "renal transplantation," and "outcome." We included in this review 20 original reports that devoted significant attention to the outcome of renal transplantation among patients with lupus. RESULTS: Of the nine studies that compared the transplantation outcomes of lupus patients with those of transplant patients with other causes of end-stage renal disease, the allograft survival rates were superior in the comparison groups in six, and approximately equivalent in three. The 1-year allograft survival rate of lupus patients with cadaveric renal transplants (CRTs) was 67% in the largest multicenter study, significantly lower than the rate for the other 14 diseases examined (77%; P = .009). In most studies, the lupus groups were significantly younger than their comparison groups, but they frequently included larger percentages of black patients. Lupus patients who received living-related renal transplants (LRRTs) generally had superior graft survival rates compared with those who received CRTs. In the largest single-center report, the 5-year graft survival rate in the cyclosporine era was 89% for LRRTs, compared with 41% for CRTs. Recurrence of lupus nephritis in the allograft is relatively rare, approximately 2%; this estimate is probably low. However, recurrent lupus glomerular nephritis (GN) did not invariably result in allograft failure. Short length of pretransplantation dialysis (i.e., less than 6 months) had no adverse effect on transplantation outcome in 10 of 11 studies that examined the relationship. Pretransplantation serological parameters, such as complement and anti-double-stranded DNA antibody levels, appear to be unreliable predictors of the likelihood of recurrence, and also may be inaccurate measures of disease activity in the posttransplantation period. Finally, 9 of the 20 studies reviewed noted an increased risk of early graft loss among lupus transplant patients, possibly because of an increased frequency of acute injection reactions and thrombotic events associated with antiphospholipid antibodies. CONCLUSIONS: Despite the fact that many lupus patients have excellent renal transplantation outcomes, substantial evidence indicates that renal transplant patients with lupus do not fare as well as patients with other causes of end-stage renal disease. Lupus patients may be particularly susceptible to adverse events occurring in the first year after transplantation. Further investigation is needed to improve renal transplantation outcomes for patients with lupus.

Immunologic and patient selection strategies for successful utilization of less than 15 kg pediatric donor kidneys--long term experiences with 40 transplants.

Renal transplantation using infant donors is associated with significantly less graft survival (GS) and increased morbidity, especially from very young and small donors. We report our results using specific strategies to determine which age and size donor require en bloc renal transplant reconstruction and associated immunologic protocols for optimization of subsequent GS. Forty cadaveric pediatric en bloc renal transplants were performed. Mean donor age was 23.6+/-18.4 months with subgroups: 2-12 months, n=14; 13-24 months, n=19; and 25-60 months, n=7. Mean donor weight was 14.4+/-4.5 kg. All kidneys were placed in primary, nonsensitized (peak PRA = 7.9+/-5.6%) adult (41.6+/-16 years) recipients. Low weight was preferred (62.4+/-12.8 kg). Mean cold ischemia time was 26.9+/-8.6 hr. Immunosuppression consisted of quadruple immunosuppression (QI) with OKT3 induction. All patients had ureteral stents placed intraoperatively. Mean follow-up was 16.9 months. Actuarial GS at 12, 24, and 33 months were 100% (n=13), 85% (n=20), and 71% (n=7), respectively. Total GS was 35/40=88%. All grafts functioned immediately and there were no technical losses. Biopsy proven rejections occurred in 12 (30%) patients, developing at 16-167 days postoperatively (mean = 50.3 days). Mean serum creatinine at one week and 1, 6, 12, and 18 months were 2.1+/-2.0, 1.5+/-0.8, 1.3+/-0.5, 1.1+/-0.4, and 0.9+/-0.4 mg/dl, respectively. Functional isotopic renography, as well as sonographic monitoring reflected rapid initial and continued growth in these kidneys. Mean BP at 12 and 24 months postoperatively were 145/83+/-18/13 and 122/76+/-20/10 mmHg, respectively, with no significant proteinuria noted. Excellent results with minimal complications utilizing very small and young infant donors can be achieved with QI immunosuppression, and selection of low immune reactive and noncomplicated adult recipients. Additionally, maximal renal dosing by minimizing recipient weight may prevent future hyperfiltration damage.

Histopathological concordance of paired renal allograft biopsy cores. Effect on the diagnosis and management of acute rejection.

To assess the effect of sampling error on renal allograft biopsies, we determined the concordance of diagnoses between 2 biopsy samples from the same renal allograft and the frequency with which 1 biopsy sample would underdiagnose or lead to the undertreatment of acute rejection. Two core samples from the same allograft biopsy procedure were labeled as core A and core B and presented to both unblinded and blinded pathologists, and each pathologist independently assigned an acute and a chronic rejection grade. A set of clinical data with pertinent prebiopsy information was combined with either the core A or core B histopathological diagnosis and presented to 3 transplant nephrologists who made treatment recommendations for each combination. Two cores were obtained in 79 allograft biopsies. Core pairs differed by > or = 1 grade of acute rejection in 30% and 50% of cases for unblinded and blinded pathologist readings, respectively. Moderate or severe acute rejection would have been missed with a 1 core in 9.5% of cases, increasing to 25.6% if only biopsy pairs containing at least 1 reading of moderate or severe acute rejection are included. Therapy would have failed to be increased with a single core in 7.5% of cases, increasing to 10.5% if only pairs containing at least one recommendation of an increase in therapy are included. The use of 2 cores of renal allograft tissue provides better diagnostic information and thereby leads to appropriate increases in antirejection therapy without increasing the complication rate of the procedure.

Long-term outcome in kidney transplant patients with hepatitis C (HCV) infection.

To assess the prevalence and long-term impact of HCV on kidney transplant recipients, we assayed 716 pre-transplant sera using a first-generation ELISA. The anti-HCV positive sera were confirmed by a 6-antigen radioimmunoassay (RIA). Patients were followed up for 5 years. Graft survival, function, evidence of chemical hepatitis (AST > 2x normal), patient mortality and cause of death were evaluated. The prevalence of anti-HCV antibody was 10.3%. In the 638 patients who were followed up for 5 years, there were no differences in graft function, graft survival, overall mortality, or death from sepsis or liver disease. Peak AST levels were significantly higher in anti-HCV positive patients compared to anti-HCV negative patients. At 5 years, the AST levels remained significantly higher in the anti-HCV positive group, however, this was only 6 U/1 > normal. Liver biopsies performed 3 to 7 years post-transplant in 80% of anti-HCV positive patients with chemical hepatitis showed 12% CAH, 50% mild hepatitis and 38% normal histology. Six (9.7%) patients seroconverted from anti-HCV positive to anti-HCV negative 2 to 5 years post-transplant. The presence of anti-HCV does not appear to alter long-term patient or graft survival, and histologic evidence of severe chronic liver disease was rare in anti-HCV positive patients with chemical hepatitis. From these results, the presence of anti-HCV antibody should not preclude kidney transplantation.

The risk of transmission of hepatitis B from HBsAg(-), HBcAb(+), HBIgM(-) organ donors.

Liver allografts from HBcAb(+), IgM(-), HBsAg(-) donors can transmit HBV to uninfected recipients. We currently no longer accept these livers for transplantation while continuing to accept the kidneys. The purpose of this study is to determine the risk of donor-transmitted HBV infections from HBcAb(+), HBIgM(-), HBsAg(-) organ donors and determine if the risk of donor-transmitted HBV infections and their severity is dependent on the organ being transplanted. This study consists of a retrospective review of the posttransplant course of recipients of HBcAb(+), HBIgM(-), HBsAg(-) donors accepted at UCSF from 6/85 to 12/93. Transmitted HBV infection was defined as one in which the recipient changed from HBsAg(-) prior to transplantation to HBsAg(+) posttransplant, with no other source. There were 25 of 1190 donors who were HBcAb(+), HBIgM(-), HBsAg(-); 1/42 kidney, 3/6 liver, and 0/7 heart HBsAg(-) transplant recipients of organs from these donors became HBsAg(+) after transplantation. This difference in infection rate (liver vs. kidney and heart) is statistically significant. The clinical course of the liver recipients was also more severe. All of the patients who became infected were HBsAb(-) and HBcAb(-) prior to transplant. We conclude that (1) HBV can be transmitted from HBcAb(+), HBIgM(-), HBsAg(-) organ donors, (2) the rate of transmission is highest and severity of infection is worst in the liver recipients; and (3) we will continue to transplant kidneys from these donors, preferably into immunized recipients.

Primary disease effects and associations in patients without early posttransplant events.

Many patients receiving primary cadaver renal transplants have complications in their early post-transplant courses which can affect and possibly confound long-term outcome analyses. Forty-four percent of primary cadaver recipients in the present study were excluded because of early events: delayed graft function (DGF) and early rejection episodes (ERE). Even with these exclusions, similar conclusions to the previous study (1) were noted: that is, the patients with systemic diseases (NS, HTN and IDDM) had the lowest 5-year graft survivals (57-62%) compared to those with diseases that were primarily renal (ALP, IGA and PC) which had better 5-year graft survival results (76-81%). Long-term half-life calculations also demonstrated improved graft survival prognoses in patients with primarily renal diseases (15-18 years in ALP, IGA and PC vs 6-8 years in IDDM, HTN and NS). Again, with the exclusions of patients with early events, Black recipients with HTN did not fare as well as non-Blacks (5-year graft survival of only 52% vs 69%). Many long-term graft losses were due to deaths, oftentimes from cardiovascular diseases. This was especially prominent in disease states with the greatest potential for arteriosclerosis (IDDM, HTN and NS). When patients with early events were excluded, the percent of graft losses attributable to patient death ranged from 21-58%, but were the highest with HTN, PC (age related) and IDDM: 41%, 45% and 58%. A similar analysis in IDDM patients receiving either a LD, SPK or KAT-type transplant revealed that although there was a 10% reduction in 5-year graft survival for KAT patients, most of these graft losses were owing to patient death. Outcomes in SPK and LD in IDDM patients were similar, suggesting selection bias and center effects with the latter two types of transplants going to healthier IDDM patients. It is too soon to conclude whether FK506 has a particularly beneficial role in one primary disease or another as compared to CsA. Combined kidney transplantation with a liver or heart transplant appears to be a reasonable risk. When graft losses due to patient deaths are accounted for, kidney graft survival was approximately that of kidney alone transplantation, suggesting again that graft loss due to patient death must be accounted for when analyzing transplant graft survival.

Chronic immunosuppression of the renal transplant patient.

The advent of potent immunosuppressive drugs to prevent rejection has led to a phenomenal improvement in renal transplant results increasing spectacularly the number of transplant recipients to arrive in the transplant clinic who remain for many years. This has engendered a series of questions about the most appropriate cyclosporine dosing for these patients that prevents rejection while avoiding toxicity. Three separate issues were analyzed: the most appropriate combination strategy with cyclosporine as a base "double" or "triple" therapy; the possibility of conversion from regimens containing cyclosporine to those devoid of it; and the optimal cyclosporine dose for a maintenance regimen. A meta-analysis of seven individual prospective and randomized trials of double versus triple therapy encompassing 1,080 patients revealed no statistical difference between the two regimens in terms of graft survival at 1 or 5 yr, patient survival, the rejection rate per patient, or the infection rate. In an analysis of 17 separate studies in which conversion away from cyclosporine was attempted, in 629 individuals with 702 individuals left on cyclosporine as controls, a significant risk of acute rejection (P < 0.001) was found in the withdrawn group without evidence of improved graft survival. Certain factors such as previous rejection, race, and degree of reactivity predicted even more rejection in the withdrawn group. Analyzing six separate studies of renal transplant recipients maintained on cyclosporine for up to 5 yr with renal functional stability, one can conclude that a dose of approximately 4.0 mg/kg per day is optimal. Because of variant pharmacokinetics or concomitant medicines, blood levels can confirm a therapeutic concentration with this target dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Recurrent focal glomerulosclerosis: natural history and response to therapy.

PURPOSE: Recurrent focal glomerulosclerosis (FGS) has been well documented since it was first reported in 1972. However, the course of the disease after transplantation and the optimal treatment regimen have not been well defined since the introduction of newer treatment modalities. PATIENTS AND METHODS: We reviewed all the charts of patients with biospy-proven FGS who received renal transplants at our institution from January 1980 through December 1990. Case histories consistent with diagnoses other than primary FGS (such as reflux nephropathy or intravenous drug use) were eliminated from the study. During this time period, 78 allografts were received by 71 patients with FGS. Independent variables that were analyzed included sex, race, time in months between the diagnosis of FGS and end-stage disease (dialysis or transplantation), age at time of transplantation, type of dialysis, source of allograft (cadaveric or living related), haplotype matching, donor-specific transfusions, age and sex of the donor, post-transplantation acute tubular necrosis, rejection episodes, immunosuppression regimen, use of plasmapheresis and angiotensin converting enzyme (ACE) inhibitors, and outcome. RESULTS: FGS recurred in 25 allografts (32%) of 21 patients. Biopsy-proven diagnosis of recurrence was made a mean of 7.5 months (range: 0.5 to 44 months) after transplantation. Patients who had rapid progression to end-stage disease tended to experience more frequent recurrences. Of seven patients who received a second transplant, five patients lost the first graft to recurrent FGS, and four of those patients (80%) had a recurrence in the second allograft. Recurrent disease developed in 34% of patients concurrently treated with cyclosporine and in 28% of those treated with prednisone and azathioprine alone (NS). Patients with recurrent FGS who were treated with ACE inhibitors benefited from a significant reduction of proteinuria. Six patients underwent plasmapheresis after diagnosis of the recurrence. Three of five patients in whom the diagnosis was made early in the course of the disease and in whom plasmapheresis was initiated immediately had reversal of epithelial foot process effacement and remission of proteinuria. End-stage disease eventually developed in 14 allografts (56%) an average of 23.7 months (range: 1 to 65 months) after diagnosis of recurrent disease. The cause of failure was chronic rejection in four allografts and recurrent disease in the remaining 10 allografts. CONCLUSIONS: FGS recurs in approximately 30% of allografts and causes graft loss in half of these. Patients who have lost a first allograft to recurrent FGS are at high risk for developing recurrent disease in a second allograft. Prolonged allograft survival is possible in patients with recurrent FGS and may best be obtained with a combination of treatment modalities including cyclosporine (perhaps in higher dosages than are routinely used in clinical renal transplantation), ACE inhibitors, and early use of plasmapheresis. The efficacy of these modalities supports the notion that recurrent FGS is caused by a circulating humoral mediator.

Cytokine and T cell receptor gene expression at the site of allograft rejection.

Intragraft cytokine and T cell receptor gene expression was analyzed in rejecting renal allografts by polymerase chain reaction (PCR). Message for IL-1 beta, IL-6, and TNF-alpha was detected in nephrectomy tissue with pathological evidence of acute or chronic rejection. Similarly, mRNA for both IL-6 and TNF-alpha was present in renal biopsies from acute rejecting kidneys. IL-2R, IL-4, and IL-5 mRNA was present in both rejecting and rejected kidney allografts, indicating that these cytokines may play a role in ongoing renal allograft rejection. Conversely, IL-2, IL-7, and IFN-gamma message was detected infrequently. In order to address the diversity of T cells in rejecting kidneys, we have analyzed the clonality of the TcR present within the allograft tissue. Rearranged TcR genes were identified in all allografts examined (n = 16) indicating the presence of T cells bearing the alpha/beta TcR. We have determined that there is a heterogeneous infiltration of T cells in the rejected allograft with TcR representing x = 7.47 +/- 2.4 families rearranged in samples obtained from nephrectomies, whereas x = 5.33 +/- 0.58 families were detected in samples obtained from biopsy tissue. These data indicate that (1) cytokines are produced locally which may contribute to graft cell destruction, (2) the heterogeneity of intragraft T cells during kidney allograft rejection may exist because nonspecific lymphocytes have been recruited to the site by locally produced cytokines or because T cells are responding to multiple epitopes or multiple donor antigens. Detection of intragraft cytokines and TcR may prove useful in elucidating the mechanism of rejection and therefore lead to improved immunosuppression.