Sundaram Hariharan

Improved Graft Survival after Renal Transplantation in the United States, 1988 to 1996

BACKGROUND The introduction of cyclosporine has resulted in improvement in the short-term outcome of renal transplantation, but its effect on the long-term survival of kidney transplants is not known. METHODS We analyzed the influence of demographic characteristics (age, sex, and race), transplant-related variables (living or cadaveric donor, panel-reactive antibody titer, extent of HLA matching, and cold-ischemia time), and post-transplantation variables (presence or absence of acute rejection, delayed graft function, and therapy with mycophenolate mofetil and tacrolimus) on graft survival for all 93,934 renal transplantations performed in the United States between 1988 and 1996. A regression analysis adjusted for these variables was used to estimate the risk of graft failure within the first year and more than one year after transplantation. RESULTS From 1988 to 1996, the one-year survival rate for grafts from living donors increased from 88.8 to 93.9 percent, and the rate for cadaveric grafts increased from 75.7 to 87.7 percent. The half-life for grafts from living donors increased steadily from 12.7 to 21.6 years, and that for cadaveric grafts increased from 7.9 to 13.8 years. After censoring of data for patients who died with functioning grafts, the half-life for grafts from living donors increased from 16.9 years to 35.9 years, and that for cadaveric grafts increased from 11.0 years to 19.5 years. The average yearly reduction in the relative hazard of graft failure after one year was 4.2 percent for all recipients (P<0.001), 0.4 percent for those who had acute rejection (P=0.57), and 6.3 percent for those who did not have acute rejection (P<0.001). CONCLUSIONS Since 1988, there has been a substantial increase in short-term and long-term survival of kidney grafts from both living and cadaveric donors.

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.

Calcineurin‐Inhibitor‐Free Immunosuppression Based on the JAK Inhibitor CP‐690,550: A Pilot Study in De Novo Kidney Allograft Recipients

This randomized, pilot study compared the Janus kinase inhibitor CP‐690,550 (15 mg BID [CP15] and 30 mg BID [CP30], n = 20 each) with tacrolimus (n = 21) in de novo kidney allograft recipients. Patients received an IL‐2 receptor antagonist, concomitant mycophenolate mofetil (MMF) and corticosteroids. CP‐690,550 doses were reduced after 6 months. Due to a high incidence of BK virus nephropathy (BKN) in CP30, MMF was discontinued in this group. The 6‐month biopsy‐proven acute rejection rates were 1 of 20, 4 of 20 and 1 of 21 for CP15, CP30 and tacrolimus groups, respectively. BKN developed in 4 of 20 patients in CP30 group. The 6‐month rates of cytomegalovirus disease were 2 of 20, 4 of 20 and none of 21 for CP15, CP30 and tacrolimus groups, respectively. Estimated glomerular filtration rate was >70 mL/min at 6 and 12 months (all groups). NK cells were reduced by ≤77% in CP‐690,550‐treated patients. In the CP‐690,550 arms, there were modest lipid elevations and a trend toward more frequent anemia and neutropenia during the first 6 months. These data suggest that coadministration of CP‐690,550 30 mg BID with MMF is associated with overimmunosuppression. At 15 mg BID, the efficacy/safety profile was comparable to the tacrolimus control group, excepting a higher rate of viral infection. Further dose‐ranging evaluation of CP‐690,550 is warranted.

Risk factors for renal allograft survival from older cadaver donors

BACKGROUND The shortage of cadaver donors for kidney transplantation has prompted many centers to use kidneys from older donors. The use of older donor kidneys has been associated with lower graft survival. METHODS United Network for Organ Sharing data of all adult cadaveric renal transplant recipients receiving kidneys from adult donors between 1988 and 1994 (transplants, n=35,621) were analyzed to further study this issue. All patients were followed for a minimum of 1 year after transplantation. The recipients were classified according to donor age: group 1, 19-50 years; group 2, 51-60 years; and group 3, >60 years. RESULTS The actuarial kidney survival estimates for group 1: (n=27,999) at 1, 3, and 5 years were 82.7%, 72.2%, and 61.4%. The corresponding values for group 2 (n=5,367) and group 3 (n=2,255) were 77.3%, 63.3%, and 51.3%; and 71.7%, 55.3%, and 42.7%, respectively (P<0.0001). Logistic regression analysis for 1-year graft survival was performed, and odds ratios (ORs) were computed for various risk factors. Increased odds of graft failure were seen with increasing donor age, previous transplantation, and elevated panel-reactive antibody. In the older donor group, lower ORs were observed if the recipients were Hispanic or Asian. In addition, kidneys from African-American or Asian donors had a poorer graft outcome. A similar analysis for 3-year graft survival for those grafts functioning at 1 year revealed poorer survival with older African-American donors (OR=1.78, P<0.02), whereas improved survival rates were seen when older kidneys were used for older (OR=0.635, P<0.01) and female (OR=0.733, P < 0.01) recipients. Statistically significant factors such as HLA mismatch, cold ischemia time, and African-American or diabetic recipients differ in their impact on graft survival across the donor age groups. CONCLUSION In conclusion, kidneys from older donors are associated with poorer graft survival rates with African-American and Asian donors and African-American recipients, and no detrimental effects when used for older, Hispanic, Asian, or female recipients.

Polyoma virus infection after renal transplantation. Use of immunostaining as a guide to diagnosis

Division of Nephrology, and Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226 Background. Polyoma virus infection is characterized by lymphocytic interstitial infiltrate in the kidney, and it mimics acute rejection. The purpose of this study is to estimate renal allograft outcome with this infection and characterize the lymphocytic infiltrates in polyoma virus-infected renal allografts. Methods. Patients who had polyoma virus inclusions in renal allograft biopsies were identified. Other viral inclusions were excluded by immunohistochemistry. The lymphocytic infiltrates of six cases of polyoma virus infection were compared with six cases of definite acute rejection by immunostaining for T and B cells. Results. There were 10 cases of polyoma virus infections in renal transplant recipients. Immunosuppressants consisted of mycophenolate mofetil with tacrolimus in eight cases and mycophenolate mofetil with cyclosporine in two. The median time of diagnosis of polyoma virus infection after transplantation was 9.5 months, and the time to graft failure after the diagnosis was 4 months. Reduced allograft survival was seen in patients who had polyoma virus infection. Immunostaining for T and B cells revealed marked increase in the B cells (CD20) in renal allografts with polyoma virus infection of 21% (range, 5‐ 40%) compared with 6% (range, 0 ‐10%) in those with acute rejection (P50.039). Reduced cytotoxic T cells (TIA-1: median, 7%; range, 2‐15%) were seen in polyoma virus-infected allografts compared with 24% (range, 15‐30%) in those patients who had acute rejection (P50.0159). Conclusion. Irreversible graft failure is more prevalent with polyoma virus infection. Enhanced immunosuppressants with mycophenolate mofetil with tacrolimus may play a role in the development of this infection. An increase in CD20 and a decrease in cytotoxic T cells in allografts is characteristic of polyoma virus infection.Background. Polyoma virus infection is characterized by lymphocytic interstitial infiltrate in the kidney, and it mimics acute rejection. The purpose of this study is to estimate renal allograft outcome with this infection and characterize the lymphocytic infiltrates in polyoma virus-infected renal allografts. Methods. Patients who had polyoma virus inclusions in renal allograft biopsies were identified. Other viral inclusions were excluded by immunohistochemistry. The lymphocytic infiltrates of six cases of polyoma virus infection were compared with six cases of definite acute rejection by immunostaining for T and B cells. Results. There were 10 cases of polyoma virus infections in renal transplant recipients. Immunosuppressants consisted of mycophenolate mofetil with tacrolimus in eight cases and mycophenolate mofetil with cyclosporine in two. The median time of diagnosis of polyoma virus infection after transplantation was 9.5 months, and the time to graft failure after the diagnosis was 4 months. Reduced allograft survival was seen in patients who had polyoma virus infection. Immunostaining for T and B cells revealed marked increase in the B cells (CD20) in renal allografts with polyoma virus infection of 21% (range, 5–40%) compared with 6% (range, 0–10%) in those with acute rejection (P =0.039). Reduced cytotoxic T cells (TIA-1: median, 7%; range, 2–15%) were seen in polyoma virus-infected allografts compared with 24% (range, 15–30%) in those patients who had acute rejection (P =0.0159). Conclusion. Irreversible graft failure is more prevalent with polyoma virus infection. Enhanced immunosuppressants with mycophenolate mofetil with tacrolimus may play a role in the development of this infection. An increase in CD20 and a decrease in cytotoxic T cells in allografts is characteristic of polyoma virus infection.

Risk factors for renal allograft survival from pediatric cadaver donors : an analysis of united network for organ sharing data

BACKGROUND The shortage of cadaveric donors for kidney transplantation has prompted many centers to use cadaver kidneys from pediatric donors. Use of kidneys from pediatric donors has been shown to have a lower graft survival. METHODS Recipients receiving cadaver kidneys from pediatric and adult donors between 1988 and 1995 were analyzed. The data were obtained from United Network of Organ Sharing database. The actuarial kidney transplant graft survival was estimated by the Kaplan-Meier method. A logistic regression analysis was used to identify various risk factors for 1-year graft failure. Odds ratios (OR) were estimated for various risk factors. RESULTS Kidney transplant survival rates for donor age <18 years (n=12,838) at 1, 2, 3, 4, and 5 years were 81.5%, 76.3%, 71.3%, 66.4%, and 61.7%, respectively. The corresponding results for adult donors from age 18 to 50 years (n=35, 442) were 83.5%, 78.4%, 73.1%, 67.9%, and 62.4%, respectively, Log-rank test P<0.01. Pediatric donors were further divided into three groups according to donor age: group I (0-5 years), group II (6-11 years), and group III (12-17 years). The actuarial survival rates for 1, 3, and 5 years for group I (n=2198) were 73.6%, 63.3%, and 55.6%, respectively. The corresponding values for group II (n=2873) were 78.0%, 67.5%, and 57.8% and for group III (n=7767) were 85%, 75.0%, and 64.8%, respectively, P<0.01. Although the recipients of group I had lower graft survival, en bloc grafts (n=751) had much better 1-, 3-, and 5-year graft survival rates (76.3%, 67.7%, and 60.7%, respectively) compared with single grafts (n=1447; 72.2%, 61.1%, and 53.2%, P=0.02) from donors 0 to 5 years. Graft thrombosis as a cause of graft failure was seen in 10% of group I compared with 6% in group II and 5% in group III. In group I, lower OR were seen when an en bloc transplant was performed (0.688, P<0.01) and when donor body weight was>15 kg (0.547, P<0.01). However, OR were elevated in recipients of previous transplants (1.556, P<0.01), with prolonged cold ischemic time (1.097, P=0.03), for black recipients (1.288, P=0.03), and for recipients with body mass index> or =25 (1.286, P=0.02). Progressive increase in the donor age was associated with lower OR in group II (0.894, P<0.01). CONCLUSIONS (1) Overall, poorer graft survival was seen in pediatric donor transplants, (2) transplant kidney survival with en bloc kidneys was better than a single kidney from donors 0-5 years, (3) progressive increase in donor age was associated with improved graft survival when the donors were 6-11 years, whereas progressive increase in donor weight was associated with improved graft survival when the donors were 0-5 years.

Humanized anti-CD20 monoclonal antibody (Rituximab) treatment for post-transplant lymphoproliferative disorder.

Abstract: Introduction: Post‐transplant lymphoproliferative disorders (PTLD) is a consequence of Epstein–Barr virus (EBV) infection and is a B‐cell hyperplasia with CD‐20 positive lymphocytes. The treatment of PTLD includes reduction/withdrawal of immunosuppression and chemotherapy. This study reports our center experience with humanized monoclonal antibody against CD‐20 (Rituximab) for the treatment of PTLD.

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.

Evolution of Endpoints for Renal Transplant Outcome

Progressive improvement in short‐term kidney transplant survival and reduction in acute rejection rates have restricted our ability to assess newer therapy. Past and present conventional endpoints, such as short‐term graft survival and acute rejection rates, are no longer practical. This has prompted investigators to search for alternative endpoints. Long‐term graft survival is an ideal endpoint. However, this requires a large cohort of patients with longer follow‐up. A simpler approach would be to identify short‐term markers, which can predict long‐term survival. Short‐term potential markers that can predict long‐term survival are: clinical (renal function), histological (renal pathological markers) and immunological (anti‐donor antibody, blood and urine cytokines). Post‐transplant renal function estimated by serum creatinine, cystatin C and creatinine clearance within 1 year, and histological indices, as the Banff chronicity score, have the potential to predict long‐term graft survival. Serum creatinine is limited as a marker by its variability based on recipient age, body weight, race and sex. Histological indices are limited, due to the invasive nature of evaluation. Post‐transplant renal function and histological indices can be used potentially as a composite endpoint, in combination with conventional endpoints, such as graft loss, death and acute rejection. A practical approach for assessing newer therapies in future studies is to use composite endpoints, which combine conventional endpoints (graft loss, death, acute rejection) with newer endpoints (renal function, histological indices).

Successful Treatment of BK Viremia Using Reduction in Immunosuppression Without Antiviral Therapy

Background. Treatment of BK virus (BKV) infection in renal transplant recipients remains controversial. This retrospective analysis evaluated efficacy and safety of reducing immunosuppression without antiviral therapy. Methods. This single center analysis included 24 patients diagnosed with BK viremia between September 2001 and December 2003. Sixteen patients (66%) presented with BKV nephritis and eight patients (34%) presented with viremia without evidence of nephritis on renal biopsy. Results. At time of diagnosis, mean plasma BKV DNA (copies/mL) was 460,409 (range 10,205–1,920,691). Mean doses reduction of mycophenolate mofetil and tacrolimus were 44% and 41%, respectively, from time of diagnosis of BKV infection to complete resolution of viremia. A decline in BK viral load was noticed within 15 to 30 days, with successful elimination of viremia over a mean period of 5.8 months (range, 1–9.5). Mean serum creatinine at time of diagnosis of BK viremia was 1.8 mg/dL (range, 1.2–2.8). Mean follow-up period is 30.9 months postdiagnosis. At the most recent visit, serum creatinine was 2.0 mg/dL (range, 1.0–3.6) (P=0.14). With reduction in immunosuppressive therapy, three patients (13%) developed acute cellular rejection and were treated successfully with intravenous bolus steroids. During follow-up, one patient had a relapse of BKV nephritis during pregnancy and lost her graft. After mean follow-up period of 43.5 months posttransplantation, all 24 patients are alive and 23 have a functioning graft. Seventeen patients (71%) have stable or improved graft function. Conclusion. Our analysis shows that reduction in immunosuppression therapy alone results in clearance of the BK viremia with good long-term outcome.