Mysore S. Anil Kumar

Safety and efficacy of steroid withdrawal two days after kidney transplantation: Analysis of results at three years

Background. Chronic steroid therapy in spite of myriad side effects is widely used in kidney transplantation. This prospective controlled study evaluated safety and efficacy of steroid withdrawal at 2 days in kidney recipients monitored by surveillance biopsy. Methods. In all, 300 kidney recipients were studied; 150 in second-day steroid withdrawal group and 150 in steroid treated group (control group). Immunosuppression was basiliximab induction and maintenance was a calcineurin inhibitor and mycophenolate mofetil or sirolimus. Biopsy-proven acute rejection (BPAR) was treated by methylpredisolone. Surveillance biopsies were completed to evaluate subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Primary end point was acute rejection. Three-year patient and graft survival, new onset diabetes mellitus (NODM), serum creatinine and creatinine clearance were evaluated. Results. Acute rejection was diagnosed in 14% in control group and 16% in steroid withdrawal group. Three-year patient and graft survival was 89% and 79% in control and 91% and 78% in steroid withdrawal group. Serum creatinine and creatinine clearance was 1.9±0.8 and 59±11 in control group and 1.8±0.9 mg/dl and 61±10 mls/minute in steroid withdrawal group. Incidence of SCAR and progression of CAN were comparable in the 2 groups. At 3-years NODM was diagnosed in 21% in control group and 4% in steroid withdrawal group (P<0.01). Conclusions. Two-day steroid withdrawal in kidney transplant recipients did not affect BPAR, SCAR, CAN, graft function and patient and graft survival compared to control group up to 3 years. NODM was significantly less in steroid withdrawal group. Two-day steroid withdrawal is safe and beneficial in kidney transplant recipients.

Comparison of steroid avoidance in tacrolimus/mycophenolate mofetil and tacrolimus/ sirolimus combination in kidney transplantation monitored by surveillance biopsy

Background. Chronic steroid therapy in kidney transplantation has myriad side effects and steroid avoidance has become feasible. This prospective study compared the safety and efficacy of steroid avoidance in tacrolimus (TAC)/mycophenolate mofetil (MMF) and TAC/sirolimus (SRL) combinations in kidney transplantation. Methods. In all, 150 kidney recipients were analyzed: 75 each in TAC/MMF and TAC/SRL groups. The primary endpoint was acute rejection. Surveillance biopsies were completed to analyze subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Acute rejection and SCAR were treated by methylprednisolone. Two-year patient and graft survival, renal function, and adverse effects were monitored. Results. Acute rejection was seen in 12% of TAC/MMF and 8% of TAC/SRL patients. Two-year actuarial patient survival was 95% and 97%, and graft survival 90% and 90% in TAC/MMF and TAC/SRL groups, respectively. Surveillance biopsy showed cumulative incidence of SCAR was 27 % in TAC/MMF and 16 % in TAC/SRL groups at 2 years (P=0.04). Overall, 33% of recipients in TAC/MMF and 20% in TAC/SRL received methylprednisolone for acute rejection/SCAR. Moderate/severe CAN was 10% in TAC/SRL group and 22% in TAC/MMF group(P=0.06). New-onset diabetes mellitus (NODM) was 4% each in both groups. All recipients remain free of maintenance steroid therapy. Conclusions. Steroid avoidance in tacrolimus-based immunosuppression with MMF or SRL provides equivalent 2-year patient and graft survival with a low incidence of acute rejection and NODM. SCAR and CAN are lower in TAC/SRL compared to TAC/MMF group. The impact of decreased SCAR and CAN in TAC/SRL group on longer-term graft survival and function is to be evaluated.

Association of Metabolic Syndrome with Development of New Onset Diabetes After Transplantation

Background. New-onset diabetes after transplantation (NODAT) is a major posttransplant complication associated with lower allograft and recipient survival. Our objective was to determine whether metabolic syndrome pretransplant is independently associated with NODAT development. Methods. We recruited 640 consecutive incident nondiabetic renal transplant recipients from three academic centers between 1999 and 2004. NODAT was defined as the use of hypoglycemic medication, a random plasma glucose level more than 200 mg/dL, or two fasting glucose levels more than or equal to 126 mg/dL beyond 30 days posttransplant. Results. Metabolic syndrome was common pretransplant (57.2%). NODAT developed in 31.4% of recipients 1 year posttransplant. Participants with metabolic syndrome were more likely to develop NODAT compared with recipients without metabolic syndrome (34.4% vs. 27.4%, P=0.057). Recipients with increasing number of positive metabolic syndrome components were more likely to develop NODAT (metabolic syndrome score prevalence at 1 year: 0 components-0.0%, 1-24.2%, 2-29.3%, 3-31.0%, 4-34.8%, and 5-73.7%, P=0.001). After adjustment for demographics, age by decade (hazard ratio [HR] 1.34 [1.20-1.50], P<0.0001), African American race (HR 1.35 [1.01-1.82], P=0.043), cumulative prednisone dosage (HR 1.18 [1.07-1.30], P=0.001), and metabolic syndrome (HR 1.34 [1.00-1.79], P=0.047) were independent predictors of development of NODAT at 1 year posttransplant. In a multivariable analysis incorporating the individual metabolic syndrome components themselves as covariates, the only pretransplant metabolic syndrome component to remain an independent predictor of NODAT was low high-density lipoprotein (hazard ratio [HR] 1.37 [1.01-1.85], P=0.042). Conclusions. Metabolic syndrome is an independent predictor for NODAT and is a possible target for intervention to prevent NODAT. Future studies to evaluate whether modification of metabolic syndrome factors pretransplant reduces NODAT development are needed.

Successful Transplantation of Kidneys from Deceased Donors with Acute Renal Failure: Three-year Results

Background. Kidneys from deceased donors with acute renal failure (ARF) are generally not accepted for transplantation because of the expected poor outcome. This prospective study examined the utilization of kidneys from donors with ARF for transplantation and the outcomes. Methods. Fifty-five kidneys from donors with ARF were transplanted. The outcome was compared with concurrent and matched 55 recipients of standard criteria donor (SCD) kidneys and 55 expanded criteria donor (ECD) kidneys. ARF kidneys were accepted from donors aged <50 years, a negative history for kidney disease, and a negative pretransplant biopsy for chronic structural changes. The immunosuppression was similar in all three groups. The outcome measurements included three-year patient and graft survival, biopsy-proven acute rejection (BPAR), subclinical acute rejection (SCAR), and chronic allograft nephropathy (CAN), serum creatinine, and creatinine clearance. Results. Three-year patient and graft survival was 90% and 90% in ARF group, 100% and 89% in SCD group and 83% and 66% in ECD group. BPAR and SCAR were comparable in the groups but CAN was significantly higher in ECD group. Mean serum creatinine levels were 1.9±1.1, 1.9±0.9, and 2.2±1.3 mg/dl and mean creatinine clearances were 66±15, 68±14, and 58±10 mls/minute in ARF, SCD, and ECD groups, respectively (SCD and ARF vs. ECD P=0.04). Conclusions. Transplantation of kidneys from selected deceased donors with ARF provides comparable survival and function compared to kidneys from non-ARF donors and may be considered for transplantation to expand the donor pool to overcome the current acute shortage of kidneys.

Long-term function and survival of elderly donor kidneys transplanted into young adults.

BACKGROUND Traditionally, elderly donor kidneys have not been widely accepted for transplantation on the assumption of inferior performance. However, the United Network for Organ Sharing reports an increase in the number of elderly donors from less than 2% in 1982 to 24% in 1995. This trend is commensurate with the increase of older dialysis patients and an overall increase in the elderly population in the United States (1). Optimal utilization of these kidneys is essential to overcome the acute organ shortage. METHODS In this study, we transplanted 25 kidneys from elderly donors (ages 56-72 years) into young adult recipients (ages 20-50 years) (group 1) over a 4-year period. We compared the results with matched recipients of young adult donor kidneys (group 2) with regard to long-term kidney function and graft survival. A pretransplant biopsy of elderly donor kidneys was carried out and a frozen section report was obtained. Only those kidneys showing glomerulosclerosis of less than 20% were accepted for transplantation. All cadaveric kidneys were preserved in University of Wisconsin solution. RESULTS Pretransplant biopsies of elderly donor kidneys showed structural deficits, which included glomerulosclerosis in 85%, arteriolar and/or mesangial thickening in 75%, and interstitial lymphocyte infiltration in 30%. The mean serum creatinine was 2.4+/-0.74, 2.2+/-0.56, and 2.9+/-0.76 mg/100 ml in group 1 and 1.5+/-0.55, 2.3+/-2.24, and 1.7+/-0.62 in group 2 at 1, 3, and 5 years, respectively. The patient survival was 92%, 92%, and 88% in group 1, and 100%, 100%, and 100% in group 2 at 1, 3, and 5 years, respectively. The graft survival was 80%, 64%, and 56% in group 1 and 100%, 96%, and 88% in group 2 at similar time intervals. The differences in the serum creatinine and graft survival between the two groups were statistically significant (P < 0.05). CONCLUSIONS Most of the elderly donor kidneys with structural deficits transplanted into young adults provided suboptimal function and inferior long-term graft survival. To maximize the utilization and optimize the survival of elderly donor kidneys, we propose transplantation of these kidneys into age-matched recipients with similar physiological requirements as those of donors, with regard to kidney function.

Comparison of four different immunosuppression protocols without long-term steroid therapy in kidney recipients monitored by surveillance biopsy: five-year outcomes.

Induction and maintenance immunosuppression protocols with or without long-term steroid therapy in kidney transplant recipients are variable and are transplant center-specific. The aim of this prospective randomized pilot study was to compare 5-year outcomes in kidney recipients maintained on 4 different calcineurin inhibitor (CNI)-based immunosuppression protocols without long-term steroid therapy. Two hundred consenting patients who received kidney transplants between June 2000 and October 2004 were enrolled in 4 immunosuppression protocol groups, with 50 patients in each group: cyclosporine (CSA)/mycophenolate mofetil (MMF), CSA/sirolimus (SRL), tacrolimus (TAC)/MMF, and TAC/SRL. Induction therapy was done with basiliximab and methylprednisolone. Steroids were withdrawn on post-transplant day 2, and long-term steroid therapy was not used. Demographic characteristics among the four groups were comparable; approximately 50% of the recipients were African American and > or =80% of the kidneys transplanted were from deceased donors. Clinical acute rejection (CAR) was confirmed by biopsy and treated with intravenous pulse steroid therapy. Steroid-unresponsive CAR was treated with Thymoglobulin. Surveillance biopsies were performed at 1, 6, 12, 24, 36, 48, and 60 months to evaluate subclinical acute rejection (SCAR), chronic allograft injury (CAI), and other pathological changes per the Banff 2005 schema. The primary end point was CAR, and secondary end points were 5-year patient and graft survival rates, renal function, SCAR, CAI, and adverse events. In the first year post-transplant, the incidence of CAR was 18% in the CSA/MMF group, 8% in the CSA/SRL group, 14% in the TAC/MMF group, and 4% in the TAC/SRL group (CSA/MMF vs. TAC/SRL; p=0.05). The incidence of SCAR was 22% in the CSA/MMF group, 8% in the CSA/SRL group, 16% in the TAC/MMF group, and 6% in the TAC/SRL group (CSA/MMF vs. CSA/SRL and TAC/SRL; p=0.05). After the first year, the incidences of CAR and SCAR decreased and were comparable in all 4 groups. At 5 years post-transplant, cumulative CAI due to interstitial fibrosis/tubular atrophy (IF/TA), hypertension (HTN), and chronic calcineurin inhibitor (CNI) toxicity was observed in 54%, 48%, and 8% of the CSA/MMF group vs. 16%, 36%, and 12% of the CSA/SRL group vs. 38%, 24% and 6% of the TAC/MMF group vs. 14%, 25% and 12% of the TAC/SLR group (IF/TA: CSA/MMF vs. CSA/SRL and TAC/SRL; p=0.04, HTN: CSA/MMF vs. TAC/MMF and TAC/SRL; p=0.05, CNI toxicity: TAC/SRL and CSA/SRL vs. TAC/MMF; p=0.05). Five-year patient and graft survival rates were 82% and 60% in the CSA/MMF group, 82% and 60% in the CSA/SRL group, 84% and 62% in the TAC/MMF group, and 82% and 64% in the TAC/SRL group (p=0.9). Serum creatinine levels and creatinine clearances at 5 years were comparable among the groups. Our data show that the rates of CAR and SCAR in the first year post-transplant were significantly lower in the CSA/SRL and TAC/SRL groups and that cumulative CAI rates due to IF/TA and HTN at 5 years were significantly lower in the TAC/MMF, TAC/SRL, and CSA/SRL groups than in the CSA/MMF group. Despite significant differences in the incidences of CAR and SCAR and prevalence of different types of CAI at 5 years, renal function and patient and graft survival rates at 5 years were comparable among kidney recipients maintained on 4 different immunosuppression protocols without long-term steroid therapy.

Steroid avoidance in renal transplantation using basiliximab induction, cyclosporine-based immunosuppression and protocol biopsies

Abstract:  Background:  Reducing chronic steroid exposure is important to minimize steroid‐related morbidity, particularly for susceptible renal transplant recipients. Steroid‐free and steroid‐sparing protocols have shown benefits, but safety has not been established for all populations. We investigated the safety of steroid avoidance (SA) in a population including African‐Americans, using modern immunosuppression with protocol biopsy monitoring.

Avoidance of Chronic Steroid Therapy in African American Kidney Transplant Recipients Monitored by Surveillance Biopsy: 1-Year Results

African American (AA) kidney recipients receive chronic steroid therapy to improve outcomes, despite their high susceptibility to side effects, particularly diabetes and hypertension. This study evaluated the safety and efficacy of avoidance of chronic steroid therapy in AA compared to non‐AA kidney recipients. Two hundred and six kidney recipients were studied; 103 AA recipients versus 103 non‐AA recipients. Induction was basiliximab and maintenance was a calcineurin inhibitor plus mycophenolate mofetil or sirolimus. Surveillance biopsies were preformed at 1, 6 and 12 months to assess subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Biopsy‐proven acute rejection (AR) and SCAR were treated by methylprednisolone. The primary end point was AR. Secondary end points were graft function, 1‐year patient and graft survival. AR was observed in 16% of AA and 13% of non‐AA recipients. SCAR at 1 month was significantly higher in the AA group (p = 0.04). One‐year actual patient and graft survival in the AA group was 96% and 88% and in the non‐AA group 97% and 89%, respectively. Avoidance of chronic steroid therapy directed by surveillance biopsies provides equivalent AR, CAN and 1‐year patient and graft survival in AA versus non‐AA recipients and a 5% incidence of new onset diabetes mellitus. All recipients remain free of chronic steroid therapy. Longer‐term follow‐up is ongoing.

Neogenesis of pancreatic endocrine cells in copper-deprived rat models.

Transplantation of progenitor cells for regeneration of islet cells could prove invaluable in the treatment of diabetes mellitus. This study provides evidence that in rats maintained on a copper-deficient diet containing the copper-chelating agent tetraethylenepentamine pentahydrochloride, regeneration of single &agr; and &bgr; endocrine cells in the ductules and acinar tissue of the adult rat pancreata occurred. These regenerated cells both in the ductules and acinar tissue stained positive for glucagon and insulin similar to cells within the islets and in addition to being reactive to proliferative cellular nuclear antigen, an intracellular marker of active proliferation. In contrast, the control group pancreata did not show any evidence of islet regeneration, proliferation, or proliferative cellular nuclear antigen reactivity pre-or posttransplantation. Transplantation of digested pancreatic tissues from the copper-deficient group into the spleen of syngeneic diabetic rats reversed diabetes, and this was confirmed histologically by demonstrating cells within ductules that stained positively for insulin. This study concludes that copper deprivation contributes to the neogenesis of pancreatic &agr; and &bgr; cells in the ductules and acinar tissue of adult pancreas in rat model and that transplanted stem cells maintain their functional capacity in the recipient after transplantation.

Induction immunosuppression in kidney transplant recipients older than 60 years of age : safety and efficacy of ATGAM, OKT3 and Simulect.

BackgroundThe choice of induction immunosuppression for kidney transplantation in elderly recipients is dictated by the consideration of the risk of infection as well as efficacy in the prevention of acute rejection, thus allowing a reduction in subsequent maintenance immunosuppression and its attendant long-term adverse effects.ObjectiveTo compare the efficacy and safety of the antibody induction immunosuppression strategies in elderly recipients of kidney transplants.Patients and methodsWe present retrospective data analysis on 183 kidney transplant recipients ≥60 years of age at Hahnemann University Hospital (Philadelphia, PA, USA) over a 12-year period. We compared four consecutive cohorts of kidney transplant recipients receiving lymphocyte immune globulin, equine antithymocyte globulin (ATGAM®) [n = 29]; muromonab CD3 (OKT3®) [n = 45]; basiliximab (Simulect®) with corticosteroid maintenance [n = 40]; and Simulect® without corticosteroid maintenance (n = 69).ResultsDelayed graft function (DGF) was observed in 48% of patients receiving ATGAM®, 35.6% in the OKT3® group and 35% in the Simulect® group with corticosteroid maintenance and 36.2% in the Simulect® group without corticosteroid maintenance.The rejection rate within the first 3 months was 31% in the ATGAM® and OKT3® groups, 17.5% in the Simulect® group with corticosteroid maintenance and 14.5% in the Simulect® group without corticosteroid maintenance.These differences for DGF and acute rejection were statistically significant between patients receiving ATGAM® and OKT3®, ATGAM® or OKT3® and both groups of Simulect® (all p < 0.05). Patients receiving Simulect® were free of adverse effects typically encountered by patients receiving polyclonal and monoclonal antibodies for induction. Patients receiving Simulect® had much shorter hospital stays and benefited from significant reduction of costs compared with other groups.ConclusionOur data indicate that kidney transplant recipients ≥60 years of age benefit from induction therapy with Simulect® followed by corticosteroid-free maintenance immunosuppression.