Aparna Padiyar

Independent of nephrectomy, weaning immunosuppression leads to late sensitization after kidney transplant failure

Background Patients returning to dialysis therapy after renal transplant failure have a high rate of human leukocyte antigen antibody sensitization, and sensitization has been linked to allograft nephrectomy. We hypothesized that nephrectomy for cause is a consequence of weaning immunosuppression and that weaning leads to sensitization even in the absence of nephrectomy. Methods We examined outcomes in 300 consecutive patients with kidney allograft failure and survival of more than 30 days after failure. We analyzed a subset of 119 patients with a low panel reactive antibody (PRA) before transplantation and follow-up PRA testing at 6 to 24 months after failure (late PRA). Results By late PRA testing, 56% of patients were highly sensitized (class I or II PRA ≥80%). On multivariate analysis controlling for human leukocyte antigen matching, allograft nephrectomy, and other variables, weaning of immunosuppression predicted high sensitization (odds ratio, 14.34; P=0.004). In a subset of patients, the percentage of those who were highly sensitized increased from 21% at the time of failure on immunosuppressive therapy to 68% by late PRA after weaning (P<0.001). Conversely, patients who maintained immunosuppression showed minimal sensitization after failure. Transplant nephrectomy was required in 41% of patients who weaned immunosuppression versus 0% of the 24 patients who maintained immunosuppression with calcineurin inhibitor therapy after failure (P<0.001). Conclusions Weaning immunosuppression was a triggering event leading to late rejection and allograft nephrectomy and was an independent predictor of alloantibody sensitization after kidney allograft failure.

Induction Antibody Therapy in Kidney Transplantation

Antilymphocyte antibodies have been used for the prevention or treatment of acute rejection in kidney transplant recipients since the 1960s. Both monoclonal and polyclonal agents now are available and generally are classified as either lymphocyte-depleting or nondepleting agents. Use of such antibodies for induction therapy in the immediate postoperative period has varied over the years. Currently, induction antibodies are administered to more than 70% of kidney transplant recipients in the United States. However, the choice of specific agents and the patients for whom they are used vary substantially between and within transplant centers. Many centers use antibody induction therapy only in patients perceived to be at high risk of acute rejection or delayed graft function. Recently, induction antibody therapy also has become the standard of practice in protocols designed to facilitate minimization of such maintenance immunosuppressive drugs as corticosteroids or calcineurin inhibitors. The benefits of induction therapy, including a decreased incidence and delayed onset of acute rejection, must be balanced against the considerable cost and side effects of the individual agents, including risk of infection. Some, but not all, antibodies are associated with increased risk of posttransplantation lymphoproliferative disease and other malignancies.

Influence of African-American Ethnicity on Acute Rejection after Early Steroid Withdrawal in Primary Kidney Transplant Recipients

BACKGROUND AND PURPOSE The influence of African-American ethnicity on outcomes of kidney transplant recipients subjected to early steroid withdrawal remains controversial. Recent studies that suggest no higher risk among African Americans may be biased by recruitment of relatively small number of African Americans or by patient selection. We compared outcomes of African Americans to non-African Americans in a center in which early steroid withdrawal has become the standard of practice. METHODS This was a single-center prospective study of 133 consecutive patients receiving primary kidney transplants between January 2006 and December 2008, followed for >or=3 months, and managed with a similar immunosuppression regimen that included induction antibody therapy, tacrolimus, mycophenolate mofetil, and withdrawal of steroids on postoperative day 5. Acute rejection and other outcomes were compared in African-American patients (n = 55) and compared with those of non-African-American patients (n = 78). RESULTS During the first 12 months after early steroid withdrawal, African-American patients experienced a significantly higher cumulative incidence of acute rejection than non-African Americans (23.6% vs 7.7%; P = .020). Using multivariate logistic regression, ethnicity (odds ratio 3.33; P = .047) and HLA mismatch (odds ratio 1.44; P = .041) were significantly correlated with acute rejection independent of recipient age, gender, historical peak panel reactive antibody level (PRA) or PRA at time of transplant, time on dialysis, or donor source. CONCLUSIONS African Americans are at increased risk of acute rejection after early steroid withdrawal, particularly when they receive kidneys from poorly matched donors.

Fever, Infection, and Rejection After Kidney Transplant Failure.

Background Patients returning to dialysis therapy after renal transplant failure have high morbidity and retransplant rates. After observing frequent hospitalizations with fever after failure, it was hypothesized that maintaining immunosuppression for the failed allograft increases the risk of infection, while weaning immunosuppression can lead to symptomatic rejection mimicking infection. Methods One hundred eighty-six patients with failed kidney transplants were analyzed for rates of hospitalization with fever within 6 months of allograft failure. Patients were stratified by the presence of full immunosuppression versus minimal (low-dose prednisone) or no immunosuppression, before hospital admission. Subsequent rates of documented infection and nephrectomy, as well as patient survival, were ascertained. Results Hospitalization with fever within 6 months of allograft failure was common, occurring in 44% of patients overall. However, among febrile hospitalized patients who had been weaned off of immunosuppression before admission, only 38% had documented infection. In contrast, 88% of patients maintained on immunosuppression had documented infection (P<0.001). In both groups, dialysis catheter–related infections were the most common infection source. Allograft nephrectomy was performed in 81% of hospitalized patients with no infection, compared to 30% of patients with documented infection (P<0.001). Mortality risk was significantly higher in patients with concurrent pancreas transplants or who were hospitalized with documented infection. Conclusions Maintenance immunosuppression after kidney allograft failure was associated with a greater incidence of infection, while weaning of immunosuppression commonly resulted in symptomatic rejection with fever mimicking infection on presentation. Management of the failed allograft should include planning to avoid both infection and sensitizing events.BACKGROUND Patients returning to dialysis therapy after renal transplant failure have high morbidity and retransplant rates. After observing frequent hospitalizations with fever after failure, it was hypothesized that maintaining immunosuppression for the failed allograft increases the risk of infection, while weaning immunosuppression can lead to symptomatic rejection mimicking infection. METHODS One hundred eighty-six patients with failed kidney transplants were analyzed for rates of hospitalization with fever within 6 months of allograft failure. Patients were stratified by the presence of full immunosuppression versus minimal (low-dose prednisone) or no immunosuppression, before hospital admission. Subsequent rates of documented infection and nephrectomy, as well as patient survival, were ascertained. RESULTS Hospitalization with fever within 6 months of allograft failure was common, occurring in 44% of patients overall. However, among febrile hospitalized patients who had been weaned off of immunosuppression before admission, only 38% had documented infection. In contrast, 88% of patients maintained on immunosuppression had documented infection (P<0.001). In both groups, dialysis catheter-related infections were the most common infection source. Allograft nephrectomy was performed in 81% of hospitalized patients with no infection, compared to 30% of patients with documented infection (P<0.001). Mortality risk was significantly higher in patients with concurrent pancreas transplants or who were hospitalized with documented infection. CONCLUSIONS Maintenance immunosuppression after kidney allograft failure was associated with a greater incidence of infection, while weaning of immunosuppression commonly resulted in symptomatic rejection with fever mimicking infection on presentation. Management of the failed allograft should include planning to avoid both infection and sensitizing events.

Immune factors influencing ethnic disparities in kidney transplantation outcomes

An influence of ethnicity on the outcomes of kidney transplant recipients has been recognized for several decades. Both immune and nonimmune factors have been explored as potential explanations. Most studies have focused on the inferior outcomes of African–Americans. As a group, African–Americans differ from Caucasians with respect to a number of measurable components of the alloimmune response, including the T-cell repertoire and the expression and function of costimulatory molecules and various cytokines and chemokines. In general, these differences suggest that African–Americans may be high immune responders. However, no single difference in any of these components of alloimmunity satisfactorily explains the disparities in outcomes. It seems probable that some combination of immune factors interacts with nonimmune factors, such as socioeconomic resources, to influence transplant outcomes in a complex manner.

Reduction in erythropoietin resistance after conversion from sirolimus to enteric coated mycophenolate sodium

Background. Anemia is a known adverse effect of sirolimus (SRL) therapy. Sirolimus may contribute to anemia by a direct antiproliferative effect or by increasing inflammation, worsening kidney function, or decreasing iron utilization. After observing the need for high dose exogenous erythropoietin dosage in some patients on SRL, we hypothesized that SRL therapy may influence anemia by inducing a state of erythropoietin resistance. Methods. Twenty-five stable renal transplant patients on maintenance tacrolimus and SRL therapy were enrolled in a prospective trial with conversion from SRL to enteric coated mycophenolate sodium. Measurement of plasma erythropoietin and red cell indices were performed pre- and postconversion. Results. Renal function remained unchanged after conversion. Serum hemoglobin (Hb) increased in 18/21 (86%) of patients after conversion. Endogenous erythropoietin level decreased from a median of 28.3 (11.5–374) to 16.6 (3.1–78.8) mIU/mL, (P<0.001); and the erythropoietin:Hb ratio dropped from 2.7 (0.7–34.3) to 1.2 (0.2–6.7), (P<0.001); indicating less erythropoietin resistance after conversion. Mean corpuscular volume increased after conversion, but transferrin saturation and ferritin did not change. Conversion was complicated by posttransplant erythrocytosis in two patients. Discussion. Conversion from SRL to enteric coated mycophenolate sodium led to an increase in Hb and a decrease in erythropoietin resistance in stable kidney transplant recipients. Increase in Hb seemed to be independent of renal functional changes or changes in iron sequestration.

Effects of cellular sensitization and donor age on acute rejection and graft function after deceased-donor kidney transplantation.

Background Allografts from older donors may be more immunogenic than those from younger donors. Pretransplantation cellular sensitization may interact with advanced donor age to increase the risk of immune injury after deceased-donor kidney transplantation. Methods The outcomes of 118 consecutive deceased-donor kidney transplant recipients with available pretransplantation donor-stimulated enzyme-linked immunosorbent spot (ELISPOT) assays for interferon gamma were analyzed retrospectively to determine the impact of cellular sensitization and other clinical variables, including donor age, on the incidence of acute rejection (AR) in the first year after deceased-donor transplantation and on estimated glomerular filtration rate 12 months after transplantation. Results The incidence of AR was higher in patients with positive pretransplantation ELISPOT assays versus those with negative assays (36% vs. 14%, P=0.009). Logistic regression indicated that the combination of donor age 50 years or older and a positive pretransplantation ELISPOT assay was more strongly associated with AR (odds ratio, 12.1; confidence interval, 1.1–133) than either variable alone. Estimated glomerular filtration 12 months after transplantation was highest in ELISPOT-negative patients receiving kidneys from donors younger than 50 years and lowest in ELISPOT-positive recipients with donors 50 years or older. Conclusion The combination of advanced donor age and pretransplantation cellular sensitization increases the risk of AR and poor graft function after deceased-donor kidney transplantation beyond the risk associated with each factor alone.

Genetic and genomic approaches to glomerulosclerosis

Chronic kidney disease (CKD) is common, progressive and expensive to manage. Although modifiable risk factors can be treated and outcomes improved, CKD remains a chronic disease with excessive morbidity and mortality. The completion of the human genome sequence and the advent of methodologies to define gene function provide new opportunities to manage and treat patients with CKD and other chronic diseases. Despite the lack of clear correspondence between genotype and phenotype and an obvious Mendelian inheritance pattern, CKD susceptibility has a genetic basis. In this review, we focus on recent studies of familial focal segmental glomerulosclerosis and the discoveries that have resulted from both genetic and genomic approaches used to understand its pathogenesis. Key slit diaphragm proteins were discovered using linkage analyses of these rare causes of glomerulosclerosis and subsequent work has characterized slit diaphragm function in health and disease. Podocyte dysfunction is now recognized as a key contributor to the functional and histologic derangements that characterize glomerular dysfunction in many common causes of CKD. In aggregate, these studies provide a paradigm for approaches to better define mechanisms of CKD and to identify novel therapeutic targets.

Clinical Predictors of Proteinuria after Conversion to Sirolimus in Kidney Transplant Recipients

Proteinuria is an increasingly recognized effect of sirolimus (SRL) therapy in kidney transplant recipients. Predictors of proteinuria after conversion to SRL are not well described, and in particular the risk in African‐American (AA) kidney recipients is unknown. We sought to analyze risk factors for proteinuria with SRL therapy in a cohort of 39 patients (44% AA) converted from tacrolimus to SRL at a mean time of 4 months posttransplantation. Patients were maintained on therapy with mycophenolate mofetil while most patients underwent early steroid withdrawal. Urinary protein to creatinine ratio (Up/cr) at a mean of 14 months postconversion increased to ≥500 mg/g in 65% of AAs versus 14% of non‐AAs (p = 0.001). Mean arterial blood pressure at the time of conversion and pretransplant proteinuric kidney disease were also predictors of proteinuria after SRL conversion. In conclusion, AAs appear to be at high risk for proteinuria and should be monitored closely after conversion to SRL in calcineurin inhibitor sparing protocols.

Management of the kidney transplant recipient.

The short-term outcomes of kidney transplant recipients have improved dramatically in the past 20 years, in large part resulting from the availability of more potent immunosuppressive drugs capable of preventing or treating acute allograft rejection. Ironically, side effects from these same immunosuppressants play a role in the long-term morbidity and mortality of this patient population. As kidney transplant recipients survive for longer periods of time with functioning allografts, primary care physicians will likely become more involved in their management, mandating at least a basic understanding of immunosuppression and its complications.