Alexander C. Wiseman

Inferior kidney allograft outcomes in patients with de novo donor-specific antibodies are due to acute rejection episodes.

Background. Donor-specific antibodies (DSAs) after kidney transplantation have been associated with poor graft outcomes in multiple studies. However, these studies have generally used stored sera or a single cross sectional screening test to identify patients with DSA. We evaluated the effectiveness of a prospective DSA screening protocol in identifying kidney and kidney/pancreas recipients at risk for poor graft outcomes. Methods. From September 2007 through September 2009, 244 consecutively transplanted kidney and kidney/pancreas recipients without pretransplant DSA were screened for de novo DSA at 1, 6, 12, and 24 months and when clinically indicated. Results. DSA was detected in 27% of all patients by protocol or indication screening. Patients with DSA (DSA+) were significantly more likely to have experienced acute rejection (AR) compared with no DSA (DSA−) (29% vs. 9.5%, P<0.001), and lower estimated 2-year graft survival (83% vs. 98%, P<0.001). Only 3 of 19 DSA (+) patients with AR had DSA detected before the AR episode. When excluding patients with AR, 2-year graft survival was similar between DSA (+) and DSA (−) patients (100% vs. 99%) as was estimated glomerular filtration rate. Patients with DSA detected by protocol screening had similar outcomes compared with DSA (−), whereas those with DSA detected by indication experienced significantly worse outcomes. Conclusions. Patients with de novo DSA experience worse graft outcomes due to previous/concurrent episodes of AR. A prospective DSA screening protocol failed to identify patients at risk for AR or poor short-term graft outcomes.

Twelve-Month Pancreas Graft Function Significantly Influences Survival Following Simultaneous Pancreas-Kidney Transplantation

BACKGROUND AND OBJECTIVES Simultaneous pancreas-kidney transplantation (SPK) is regarded as the treatment of choice for type 1 diabetes (T1DM) and kidney dysfunction, despite the morbidity associated with pancreas transplantation. These morbidities often influence selection of SPK versus living-donor kidney alone (LD KA) transplant. This study quantifies the impact of pancreas graft function on outcomes following SPK. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using the SRTR database, SPK wait-listed patients transplanted from 1997 to 2005 were evaluated and segregated as: (1) SPK recipients with functioning pancreas graft 12 mo posttransplant (SPK, P+); (2) SPK recipients with loss of pancreas graft function within 12 mo posttransplant (SPK, P-); (3) recipients of deceased donor (DD) KA; (4) recipients of LD KA. The study compared patient and kidney graft survival to 84 mo posttransplant. RESULTS Patient survival for SPK, P+ was significantly better than the LD KA; SPK, P-; and DD KA cohorts (88.6% versus 80.0%, 73.9% and 64.8%, respectively [P < 0.001]), a finding confirmed by multivariate analysis and not influenced by pancreas-after-kidney transplantation (PAK) rates and outcomes. Unadjusted graft survival was also highest in the SPK, P+ cohort (72.0% versus 63.6%, 59.8%, 49.7%, P = 0.015 versus LD KA). CONCLUSIONS SPK recipients with functioning pancreas grafts have superior survival compared with LD KA and DD KA, including in the setting of PAK. Early pancreas graft failure results in kidney and patient survival rates similar to KA. These data help further clarify the decision-making of SPK versus KA transplant options for patients and providers.

Polyomavirus nephropathy: a current perspective and clinical considerations.

During the last decade, the human polyomaviruses (BK virus and, much less commonly, JC virus) have entered the realm of routine clinical decision making for providers caring for kidney transplant recipients. The emergence of polyomavirus-associated nephropathy (PVAN) as an important clinical entity coincided with the development and use of more potent immunosuppression agents, currently the only clear risk factor for reactivation of the virus. Ongoing efforts to define the pathogenesis, clinical presentation, and appropriate management of PVAN have led to a greater ability to prevent and control viral-induced interstitial nephritis despite continued deficiencies in our understanding of risk factors for disease and lack of published prospective polyomavirus-specific antiviral trials. The purpose of this review is to summarize advances made during the last decade and highlight emerging data that address common clinical considerations the clinician currently faces in the understanding and management of PVAN.

Aggressive Immunosuppression Minimization Reduces Graft Loss Following Diagnosis of BK Virus-Associated Nephropathy: A Comparison of Two Reduction Strategies

BACKGROUND AND OBJECTIVES BK virus-associated nephropathy (BKVAN) has emerged as a leading cause of kidney graft loss, with no known predictors for graft loss and no consensus regarding treatment other than reduction of immunosuppression. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS A single-center retrospective analysis was performed of all cases of BKVAN from 1999 to 2005 for clinical predictors of graft loss, with evaluation of the impact of immunosuppression withdrawal (3-drug to 2-drug immunosuppression) within the first month versus reduction of immunosuppression. RESULTS Of 910 kidney transplants, 35 (3.8%) cases of BKVAN were diagnosed at a median of 15 months after transplant (range, 5.5 to 90 months after transplant), 16 (46%) of which progressed to graft failure at a median of 11 months (range, 2 to 36 months) after diagnosis. Depleting antibody induction was a significant risk factor for graft loss on univariate analysis, whereas early drug withdrawal (<1 mo following diagnosis) protected against graft loss. On multivariate analysis, these findings were independent predictors of graft outcomes. Additionally, when patients were comanaged by referring nephrologists and the transplant center before the diagnosis of BKVAN, the risk of graft loss was 11-fold higher (P = 0.03) than if patients were managed solely by the transplant center. CONCLUSIONS Increased awareness and early diagnosis of BKVAN, with aggressive tapering of immunosuppression once established, is critical to preserve kidney graft function. Early drug withdrawal to low-dose two-drug therapy maintenance may be preferable to a general reduction of agents.

Induction of Indoleamine 2,3-Dioxygenase by Interferon-γ in Human Islets

Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial, rate-limiting step of tryptophan (Trp) catabolism along the kynurenine (KYN) pathway, and its induction in cells of the immune system in response to cytokines has been implicated in the regulation of antigen presentation and responses to cell-mediated immune attack. Microarray and quantitative PCR analyses of isolated human islets incubated with interferon (IFN)-γ for 24 h revealed increased expression of IDO mRNA (>139-fold) and Trp-tRNA synthase (WARS) (>17-fold) along with 975 other transcripts more than threefold, notably the downstream effectors janus kinase (JAK)2, signal transducer and activator of transcription (STAT)1, IFN-γ regulatory factor-1, and several chemokines (CXCL9/MIG, CXCL10/IP10, CXCL11/1-TAC, CCL2, and CCL5/RANTES) and their receptors. IDO protein expression was upregulated in IFN-γ–treated islets and accompanied by increased intracellular IDO enzyme activity and the release of KYN into the media. The response to IFN-γ was countered by interleukin-4 and 1α-methyl Trp. Immunohistochemical localization showed IDO to be induced in cells of both endocrine, including pancreatic duodenal homeobox 1–positive β-cells, and nonendocrine origin. We postulate that in the short term, IDO activation may protect islets from cytotoxic damage, although chronic exposure to various Trp metabolites could equally lead to β-cell attrition.

Kidney Transplantation for Systemic Sclerosis Improves Survival and may Modulate Disease Activity

Systemic sclerosis (SS) may lead to sclerodema renal crisis, an unusual cause of end‐stage renal disease (ESRD) with historically poor hemodialysis outcomes. Little information is available on outcomes after kidney transplantation. Information from the UNOS registry was obtained on SS patients in the United States, listed for kidney transplants between 1985–2002. We compared survival at 1 and 3 years in patients who received cadaveric transplants with patients who remained on the waiting list. Graft survival, cause of graft loss, frequency of early graft loss and pre‐ and post‐transplant skin scores were analyzed. Two hundred and fifty‐eight patients with SS were listed for transplantation. Survival was significantly prolonged in patients receiving transplants (p = 0.005). Graft survival at 1 and 3 years was 68% and 60%. Early graft loss was common. Skin scores improved in all four subjects at our center, with an average decline of 60.7% (p = 0.024). Kidney transplantation confers a survival benefit in ESRD due to SS. Transplantation may be associated with an improvement in systemic manifestations of disease. Despite suboptimal graft survival, kidney transplant should be considered the treatment of choice in ESRD due to SS.

The impact of human leukocyte antigen mismatching on sensitization rates and subsequent retransplantation after first graft failure in pediatric renal transplant recipients.

Background U.S. allocation policies currently place less emphasis on human leukocyte antigen (HLA) matching in pediatric kidney transplant candidates to minimize dialysis time. The impact this may have on pediatric recipients after graft failure has not been extensively examined. Methods Using the Scientific Registry of Transplant Recipients database, we examined HLA sensitization after graft loss and regraft survival of all pediatric primary kidney transplant recipients younger than 18 years transplanted between 1990 and 2008, stratified by HLA-DR mismatch (MM) of first and second kidney transplant. Results Of 11,916 pediatric primary kidney transplant recipients, 2704 were relisted after first graft failure. 1847 received a retransplants, and 857 remained on the waiting list. Mean % panel reactive antibody increased from 6% to 45% for retransplant and from 8% to 76% for those on the waiting list. The degree of sensitization and waiting time to retransplantation increased with DR MM at first kidney transplantation. Two DR MM statuses at first transplant were associated with a 20% reduction in the hazard of receiving a retransplant (hazard ratio, 0.80 for 2 vs. 0–1 DR MM; P<0.001). Five-year retransplant graft survival was associated with the number of HLA MM at first and second kidney transplant. Retransplant graft survival was similar in the circumstance of a 0–1 DR MM living donor following a deceased donor, and the converse. Conclusion In pediatric recipients, increasing number of initial HLA-DR MMs is associated with HLA sensitization, longer waiting time, decreased rate of retransplant, and decreased regraft survival. Consideration of DR matching at first transplant may mitigate these risks.

Acute kidney injury in kidney transplantation.

Purpose of reviewAcute kidney injury (AKI) in transplant recipients is a prevalent condition with a broad list of potential inciting causes. This review highlights recent data describing the epidemiology and long-term consequences of transplant AKI, novel interventions in the management of delayed graft function (DGF), and noninvasive diagnostic strategies. Recent findingsThe incidence and outcomes of nontransplant AKI are well documented, and similar data are emerging in the transplant setting with recent reports suggesting a high incidence rate and significant impact on long-term graft outcomes. DGF represents a ‘pure’ form of transplant AKI, and many interventional trials aiming to limit ischemia–reperfusion-induced injury have recently been reported or are currently ongoing. The search for accurate noninvasive predictors of DGF and acute rejection is ongoing and recent literature describes novel plasma and urine-based biomarkers as well as transcriptional profiling methods with high potential for clinical applicability. SummaryAKI in transplant recipients is a frequent occurrence with significant potential for poor long-term graft outcomes. Recent efforts to limit ischemia–reperfusion injury and diagnose transplant AKI via noninvasive methods may help to minimize the impact of AKI on future graft function.

Dominant negative mutant forms of the cAMP response element binding protein induce apoptosis and decrease the anti-apoptotic action of growth factors in human islets

Aims/hypothesisTransplantation of islets is a viable option for the treatment of diabetes. A significant proportion of islets is lost during isolation, storage and after transplantation as a result of apoptosis. cAMP response element binding protein (CREB) is an important cell survival factor. The aim of the present study was to determine whether preservation of CREB function is needed for survival of human islets.Materials and methodsTo determine the effects of downregulation of CREB activity on beta cell apoptosis in a transplantation setting, adenoviral vectors were used to express two dominant negative mutant forms of CREB in human islets isolated from cadaveric donors. Markers of apoptosis were determined in these transduced islets under basal conditions and following treatment with growth factor.ResultsExpression of CREB mutants in human islets resulted in significant (p < 0.001) activation of caspase-9, a key regulatory enzyme in the mitochondrial pathway of apoptosis, when compared with islets transduced with adenoviral beta galactosidase. Immunocytochemical analysis showed the activation of caspase-9 to be predominantly in beta cells. Other definitive markers of apoptosis such as parallel activation of caspase-3, accumulation of cleaved poly-(ADP-ribose) polymerase and nuclear condensation were also observed. Furthermore, the anti-apoptotic action of growth factors exendin-4 and betacellulin in human islets exposed to cytokines was partially lost when CREB function was impaired.Conclusions/interpretationOur findings suggest that impairment of CREB-mediated transcription could lead to loss of islets by apoptosis with potential implications in islet transplantation as well as in the mechanism of beta cell loss leading to diabetes.

Simultaneous Pancreas Kidney Transplant versus Other Kidney Transplant Options in Patients with Type 2 Diabetes

BACKGROUND AND OBJECTIVES Current organ allocation policy prioritizes placement of kidneys (with pancreas) to patients listed for simultaneous pancreas-kidney transplantation (SPK). Patients with type 2 diabetes mellitus (T2DM) may undergo SPK, but it is unknown whether these patients enjoy a survival advantage with SPK versus deceased-donor kidney transplantation alone (DDKA) or living-donor kidney transplantation alone (LDKA). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using the Scientific Registry of Transplant Recipients database, patients with T2DM, age 18-59 years, body mass index 18-30 kg/m(2), who underwent SPK, DDKA, or LDKA from 2000 through 2008 were identified. Five-year patient and kidney graft survival rates were compared, and multivariable analysis was performed to determine donor, recipient, and transplant factors influencing these outcomes. RESULTS Of 6416 patients identified, 4005, 1987, and 424 underwent DDKA, LDKA, and SPK, respectively. On unadjusted analysis, patient and kidney graft survival rates were superior for LDKA versus SPK, whereas patient but not graft survival was higher for SPK versus DDKA. On multivariable analysis, survival advantage for SPK versus DDKA was related not to pancreas transplantation but younger donor and recipient ages in the SPK cohort. CONCLUSIONS Good outcomes can occur with SPK in selected patients with T2DM, but no patient or graft survival advantage is provided by added pancreas transplantation compared with DDKA; outcomes were superior with LDKA. These results support cautious use of SPK in T2DM when LDKA is not an option, with close oversight of the effect of kidney (with pancreas) allocation priority over other transplant candidates.