770-5 Chamber Specific Regulation of the Sarcoplasmic Reticulum Calcium ATPase Pump In Human Heart Failure

Alterations in the expression of Ca2+ channels have been described in failing human left ventricle, including down regulation of the ryanodine receptor (RyR)/Ca2+ release channel and the sarcoplasmic reticulum Ca2+ ATPase pump (SERCA) which are involved in excitation-contraction coupling and relaxation (Cir Res 71: 18, 1992). We previously reported chamber specific regulation of the RyR during end-stage human heart failure (Clin Res 42(2):166A. 1994). We investigated whether SERCA is also regulated in the other cardiac chambers during human heart failure. Total RNA and protein homogenates were isolated from the left and right atria (LA, RA) and left and right ventricles (LV, RV) obtained prospectively from 32 cardiac transplant patients and 4 normal controls. Messenger RNA (mRNA) levels of SERCA were quantified using Northern and slot blot hybridizations with a 1.6kb rat cardiac SERCA cDNA probe and normalized to 28S ribosomal levels. Protein levels of SERCA were quantified using enzyme-linked immunosorbent assays with monoclonal antibodies directed against dog cardiac SERCA. Northern analyses detected a single ≈4 kb mRNA in all regions. Compared to controls. SERCA mRNA expression in failing hearts was decreased in LV by 39% (p<0.005), unchanged in RV, and increased in LA by 255% (p<0.005) and in RA by 338% (p<0.025). Consistent with the mRNA data. immunodetectable levels of SERCA were also reduced in LV by 30% (p<0.05) and unchanged in RV; however, protein levels appeared unchanged or reduced in both atria in contrast to the mRNA. This is the first study reporting simultaneous measurements of SERCA mRNA and protein levels in the human heart. We conclude that chamber specific regulation of SERCA mRNA occurs during end-stage heart failure. corroborated by protein expression in the ventricles. Down regulations of SERCA may contribute to impaired relaxation and increased diastolic tone during heart failure

Renal Siderosis in Donor Allograft: Pathologic and Clinical Sequelae.

Transplantation of a cadaver kidney with marked siderosis and its outcome has not been reported. Increasing use of marginal kidneys has become common practice to expand the donor pool to meet the growing demand and will lead to increased recognition of kidney disease in cadaver donors with an unknown effect on graft outcome. This is a case report of a recipient of a cadaver kidney with marked siderosis monitored by surveillance biopsies and evaluated by clinico-pathological correlation. The recipient continued to have transplant kidney function, and a surveillance biopsy shows the natural course of the pathologic resolution of renal siderosis

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

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

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

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. METHODS: A randomized-controlled SA trial (early discontinuation, days 2-7) was conducted in a population (n = 77) including African-Americans and cadaveric kidney recipients. Patients received basiliximab, cyclosporine (CsA), and mycophenolate mofetil (MMF). In controls, steroids were tapered to 5 mg prednisone/d by day 30. Protocol biopsies were performed (1, 6, 12 and 24 months) to evaluate subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). RESULTS: The SA did not result in significantly higher incidences of graft loss, AR, SCAR, CAN, or renal fibrosis. SA patients experienced similar renal function, comparable serum lipid levels, and a trend toward fewer cases of new-onset diabetes. Clinical outcomes of African-American and non-African-American patients did not significantly differ. CONCLUSIONS: The SA is safe in the context of basiliximab induction and CsA-based immunosuppression. This protocol could minimize steroid-related side effects in susceptible groups, including African-Americans, without increasing the risk of AR or graft failure

Safety and success of kidney transplantation and concomitant immunosuppression in HIV-positive patients.

BACKGROUND: Human immunodeficiency virus-associated nephropathy (HIVAN) has become the third leading cause of end-stage renal disease (ESRD) in African Americans, and is expected to grow exponentially. Highly active antiretroviral therapy (HAART) has significantly prolonged the survival of patients with HIV infection. Despite the growing number of HIV-positive dialysis patients with prolonged life expectancy, kidney transplantation with immunosuppression has been declined because it is considered a waste of scarce donor kidneys due to potential increases in morbidity and mortality. METHODS: The institutional review board of Drexel University College of Medicine and Hahnemann University Hospital approved this prospective study. The aim was to find out safety and success of kidney transplantation, and the effect of immunosuppression on HIV infection. Forty HIV-positive dialysis patients received kidney transplantation between February 2001 and January 2004. Patient inclusion criteria were maintenance of HAART, plasma HIV-1 RNA of/mL, absolute CD4 counts of 200 cells/muL or more. Immunosuppression was basiliximab induction and maintenance with cyclosporine, sirolimus, and steroids. HAART was continued post-transplant. Acute rejections were diagnosed by biopsy and treated with methylprednisolone. Surveillance biopsies were completed at 1, 6, 12, and 24 months, and evaluated for subclinical acute rejection, chronic allograft nephropathy, and HIVAN. RESULTS: One- and 2-year actuarial patient survival was 85% and 82%, respectively, and graft survival was 75% and 71%, respectively. Plasma HIV-1 RNA remained undetectable, and CD4 counts remained in excess of 400 cells per muL with no evidence of AIDS for up to 2 years. CONCLUSION: One- and 2-year graft survival is comparable to other high-risk populations receiving kidney transplantation. One- and 2-year patient survival is higher than HIV patients maintained on dialysis. Immunosuppression does not adversely affect HIV recipients maintained on HAART in the short term

Safety and success of kidney transplantation and concomitant immunosuppression in HIV-positive patients

Safety and success of kidney transplantation and concomitant immunosuppression in HIV-positive patients.BackgroundHuman immunodeficiency virus–associated nephropathy (HIVAN) has become the third leading cause of end-stage renal disease (ESRD) in African Americans, and is expected to grow exponentially. Highly active antiretroviral therapy (HAART) has significantly prolonged the survival of patients with HIV infection. Despite the growing number of HIV-positive dialysis patients with prolonged life expectancy, kidney transplantation with immunosuppression has been declined because it is considered a waste of scarce donor kidneys due to potential increases in morbidity and mortality.MethodsThe institutional review board of Drexel University College of Medicine and Hahnemann University Hospital approved this prospective study. The aim was to find out safety and success of kidney transplantation, and the effect of immunosuppression on HIV infection. Forty HIV-positive dialysis patients received kidney transplantation between February 2001 and January 2004. Patient inclusion criteria were maintenance of HAART, plasma HIV-1 RNA of <400 copies/mL, absolute CD4 counts of 200 cells/μL or more. Immunosuppression was basiliximab induction and maintenance with cyclosporine, sirolimus, and steroids. HAART was continued post-transplant. Acute rejections were diagnosed by biopsy and treated with methylprednisolone. Surveillance biopsies were completed at 1, 6, 12, and 24 months, and evaluated for subclinical acute rejection, chronic allograft nephropathy, and HIVAN.ResultsOne- and 2-year actuarial patient survival was 85% and 82%, respectively, and graft survival was 75% and 71%, respectively. Plasma HIV-1 RNA remained undetectable, and CD4 counts remained in excess of 400 cells per μL with no evidence of AIDS for up to 2 years.ConclusionOne- and 2-year graft survival is comparable to other high-risk populations receiving kidney transplantation. One- and 2-year patient survival is higher than HIV patients maintained on dialysis. Immunosuppression does not adversely affect HIV recipients maintained on HAART in the short term