The failing kidney allograft: A review and recommendations for the care and management of a complex group of patients.

The return to dialysis after allograft failure is associated with increased morbidity and mortality. This transition is made more complex by the rising numbers of patients who seek repeat transplantation and therefore may have indications for remaining on low levels of immunosuppression, despite the potential increased morbidity. Management strategies vary across providers, driven by limited data on how to transition off immunosuppression as the allograft fails and a paucity of randomized controlled trials to support one approach over another. In this review, we summarize the current data available for management and care of the failing allograft. Additionally, we discuss a suggested plan for immunosuppression weaning based upon the availability of re-transplantation and residual allograft function. We propose a shared-care model in which there is improved coordination between transplant providers and general nephrologists so that immunosuppression management and preparation for renal replacement therapy and/or repeat transplantation can be conducted with the goal of improved outcomes and decreased morbidity in this vulnerable patient group.

Quantifying infection risks in incompatible living donor kidney transplant recipients.

Desensitization has enabled incompatible living donor kidney transplantation (ILDKT) across HLA/ABO barriers, but added immunomodulation might put patients at increased risk of infections. We studied 475 recipients from our center from 2010 to 2015, categorized by desensitization intensity: none/compatible (n = 260), low (0-4 plasmaphereses, n = 47), moderate (5-9, n = 74), and high (≥10, n = 94). The 1-year cumulative incidence of infection was 50.1%, 49.8%, 66.0%, and 73.5% for recipients who received none, low, moderate, and high-intensity desensitization (P < .001). The most common infections were UTI (33.5% of ILDKT vs. 21.5% compatible), opportunistic (21.9% vs. 10.8%), and bloodstream (19.1% vs. 5.4%) (P < .001). In weighted models, a trend toward increased risk was seen in low (wIRR = 0.77 1.402.56 ,P = .3) and moderately (wIRR = 0.88 1.352.06 ,P = .2) desensitized recipients, with a statistically significant 2.22-fold (wIRR = 1.33 2.223.72 ,P = .002) increased risk in highly desensitized recipients. Recipients with ≥4 infections were at higher risk of prolonged hospitalization (wIRR = 2.62 3.574.88 , P < .001) and death-censored graft loss (wHR = 1.15 4.0113.95 ,P = .03). Post-KT infections are more common in desensitized ILDKT recipients. A subset of highly desensitized patients is at ultra-high risk for infections. Strategies should be designed to protect patients from the morbidity of recurrent infections, and to extend the survival benefit of ILDKT across the spectrum of recipients.

Kidney recipients with allograft failure, transition of kidney care (KRAFT): A survey of contemporary practices of transplant providers.

Kidney allograft failure and return to dialysis carry a high risk of morbidity. A practice survey was developed by the AST Kidney Pancreas Community of Practice workgroup and distributed electronically to the AST members. There were 104 respondents who represented 92 kidney transplant centers. Most survey respondents were transplant nephrologists at academic centers. The most common approach to immunosuppression management was to withdraw the antimetabolite first (73%), while only 12% responded they would withdraw calcineurin inhibitor (CNI) first. More than 60% reported that the availability of a living donor is the most important factor in their decision to taper immunosuppression, followed by risk of infection, risk of sensitization, frailty, and side effects of medications. More than half of respondents reported that embolization was either not available or offered to less than 10% as an option for surgical intervention. Majority reported that ≤50% of failed allograft patients were re-listed before dialysis, and less than a quarter of transplant nephrologists performed frequent visits with their patients with failed kidney allograft after they return to dialysis. This survey demonstrates heterogeneity in the care of patients with a failing allograft and the need for more evidence to guide improvements in clinical practice related to transition of care.

A 2020 Banff Antibody-mediatedInjury Working Group examination of international practices for diagnosing antibody-mediated rejection in kidney transplantation - a cohort study.

The Banff antibody-mediated rejection (ABMR) classification is vulnerable to misinterpretation, but the reasons are unclear. To better understand this vulnerability, we evaluated how ABMR is diagnosed in practice. To do this, the Banff Antibody-Mediated Injury Workgroup electronically surveyed an international cohort of nephrologists/surgeons (n = 133) and renal pathologists (n = 99). Most providers (97%) responded that they use the Banff ABMR classification at least sometimes, but DSA information is often not readily available. Only 41.1% (55/133) of nephrologists/surgeons and 19.2% (19/99) of pathologists reported that they always have DSA results when the biopsy is available. Additionally, only 19.6% (26/133) of nephrologists/surgeons responded that non-HLA antibody or molecular transcripts are obtained when ABMR histologic features are present but DSA is undetected. Several respondents agreed that histologic features concerning for ABMR in the absence of DSA and/or C4d are not well accounted for in the current classification [31.3% (31/99) pathologists and 37.6% (50/133) nephrologist/surgeons]. The Banff ABMR classification appears widely accepted, but efforts to improve the accessibility of DSA information for the multidisciplinary care team are needed. Further clarity is also needed in Banff ABMR nomenclature to account for the spectrum of ABMR and for histologic features suspicious for ABMR when DSA is absent.

Outcomes of cPRA 100% deceased donor kidney transplant recipients under the new Kidney Allocation System: A single-center cohort study.

In light of changes in donor/recipient case-mix and increased cold ischemia times under the Kidney Allocation System (KAS), there is some concern that cPRA 100% recipients might be doing poorly under KAS. We used granular, single-center data on 109 cPRA 100% deceased donor kidney transplant (DDKT) recipients to study post-KAS posttransplant outcomes not readily available in national registry data. We found that 3-year patient (96.4%) and death-censored graft survival (96.8%) was excellent. We also found that cPRA 100% recipients had a relatively low incidence of T cell-mediated rejection (9.2%) and antibody-mediated rejection (AMR) (13.8%). T cell-mediated rejection episodes tended to be relatively mild-50% (5 episodes) were grade 1, 50% (5 episodes) were grade 2, and none were grade 3. Only 1 episode was associated with graft loss, but this was in the context of a mixed rejection. Although only 15 recipients (13.8%) developed an AMR episode, 2 of these were associated with a graft loss. Despite the rejection episodes, the vast majority of recipients had excellent graft function 3 years posttransplant (median serum creatinine 1.5 mg/dL). In conclusion, cPRA 100% DDKT recipients are doing well under KAS, although every effort should be made to prevent AMR to ensure long-term outcomes remain excellent.

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.

Banff survey on antibody-mediated rejection clinical practices in kidney transplantation: Diagnostic misinterpretation has potential therapeutic implications.

The aim of this study was to determine how the Banff antibody-mediated rejection (ABMR) classification for kidney transplantation is interpreted in practice and affects therapy. The Banff Antibody-Mediated Injury Workgroup electronically surveyed clinicians and pathologists worldwide regarding diagnosis and treatment for 6 case-based scenarios. The participants' (95 clinicians and 72 renal pathologists) assigned diagnoses were compared to the Banff intended diagnoses (reference standard). The assigned diagnoses and reference standard differed by 26.1% (SD 28.1%) for pathologists and 34.5% (SD 23.3%) for clinicians. The greatest discordance between the reference standard and clinicians' diagnosis was when histologic features of ABMR were present but donor-specific antibody was undetected (49.4% [43/87]). For pathologists, the greatest discordance was in the case of acute/active ABMR C4d staining negative in a positive crossmatch transplant recipient (33.8% [23/68]). Treatment approaches were heterogeneous but linked to the assigned diagnosis. When acute/active ABMR was diagnosed by the clinician, treatment was recommended 95.3% (SD 18.4%) of the time vs only 77.7% (SD 39.2%) of the time when chronic active ABMR was diagnosed (P < .0001). In conclusion, the Banff ABMR classification is vulnerable to misinterpretation, which potentially has patient management implications. Continued efforts are needed to improve the understanding and standardized application of ABMR classification in the transplant community.

Initial skin cancer screening for solid organ transplant recipients in the United States: Delphi method development of expert consensus guidelines.

Skin cancer is the most common malignancy affecting solid organ transplant recipients (SOTR), and SOTR experience increased skin cancer-associated morbidity and mortality. There are no formal multidisciplinary guidelines for skin cancer screening after transplant, and current practices are widely variable. We conducted three rounds of Delphi method surveys with a panel of 84 U.S. dermatologists and transplant physicians to establish skin cancer screening recommendations for SOTR. The transplant team should risk stratify SOTR for screening, and dermatologists should perform skin cancer screening by full-body skin examination. SOTR with a history of skin cancer should continue regular follow-up with dermatology for skin cancer surveillance. High-risk transplant patients include thoracic organ recipients, SOTR age 50 and above, and male SOTR. High-risk Caucasian patients should be screened within 2 years after transplant, all Caucasian, Asian, Hispanic, and high-risk African American patients should be screened within 5 years after transplant. No consensus was reached regarding screening for low-risk African American SOTR. We propose a standardized approach to skin cancer screening in SOTR based on multidisciplinary expert consensus. These guidelines prioritize and emphasize the need for screening for SOTR at greatest risk for skin cancer.

The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials.

The kidney sessions of the 2017 Banff Conference focused on 2 areas: clinical implications of inflammation in areas of interstitial fibrosis and tubular atrophy (i-IFTA) and its relationship to T cell-mediated rejection (TCMR), and the continued evolution of molecular diagnostics, particularly in the diagnosis of antibody-mediated rejection (ABMR). In confirmation of previous studies, it was independently demonstrated by 2 groups that i-IFTA is associated with reduced graft survival. Furthermore, these groups presented that i-IFTA, particularly when involving >25% of sclerotic cortex in association with tubulitis, is often a sequela of acute TCMR in association with underimmunosuppression. The classification was thus revised to include moderate i-IFTA plus moderate or severe tubulitis as diagnostic of chronic active TCMR. Other studies demonstrated that certain molecular classifiers improve diagnosis of ABMR beyond what is possible with histology, C4d, and detection of donor-specific antibodies (DSAs) and that both C4d and validated molecular assays can serve as potential alternatives and/or complements to DSAs in the diagnosis of ABMR. The Banff ABMR criteria are thus updated to include these alternatives. Finally, the present report paves the way for the Banff scheme to be part of an integrative approach for defining surrogate endpoints in next-generation clinical trials.

The prognostic value of the furosemide stress test in predicting delayed graft function following deceased donor kidney transplantation.

OBJECTIVES AND METHODS: The Furosemide Stress Test (FST) is a novel dynamic assessment of tubular function that has been shown in preliminary studies to predict patients who will progress to advanced stage acute kidney injury, including those who receive renal replacement therapy (RRT). The aim of this study is to investigate if the urinary response to a single intraoperative dose of intravenous furosemide predicts delayed graft function (DGF) in patients undergoing deceased donor kidney transplant. RESULTS: On an adjusted multiple logistic regression, a single 100 mg dose of intraoperative furosemide after the anastomosis of the renal vessels (FST) predicted the need for RRT at 2 and 6 h post kidney transplantation (KT). Recipient urinary output was measured at 2 and 6 h post furosemide administration. In receiver-operating characteristic (ROC) analysis, the FST predicted DGF with an area-under-the curve of 0.85 at an optimal urinary output cut-off of <600 mls at 6 h with a sensitivity of and a specificity of 83% and 74%, respectively. CONCLUSIONS: The FST is a predictor of DGF post kidney transplant and has the potential to identify patients requiring RRT early after KT.

Outcomes and risk stratification for late antibody-mediated rejection in recipients of ABO-incompatible kidney transplants: a retrospective study.

The required intensity of monitoring for antibody-mediated rejection (AMR) after of ABO-incompatible (ABOi) kidney transplantation is not clearly formulized. We retrospectively evaluated a single-center cohort of 115 ABO-incompatible (ABOi) kidney transplant recipients, of which 32% were also HLA incompatible (ABOi/HLAi) with their donors. We used an adjusted negative binomial model to evaluate risk factors for late AMR. Using this model, we risk-stratified patients into high- and low-risk groups for the development of late AMR; 26% of patients had at least one AMR episode; 49% of AMR episodes occurred within 30-days after transplant and were considered early AMR. Patients with an early AMR episode had a 5.5-fold greater incidence of developing late AMR [IRR = 5.5, (95% CI: 1.5-19.3), P = 0.01]. ABOi/HLAi recipients trended toward increased late AMR risk [IRR = 1.9, (95% CI: 0.5-6.6), P = 0.3]. High-risk recipients (those with an early AMR or those who were ABOi/HLAi) had a sixfold increased incidence of late AMR [IRR = 6.3, (95% CI: 1.6-24.6), P = 0.008] versus low-risk recipients. The overall incidence of late AMR was 20.8% vs. 1.5% in low-risk recipients. Changes in anti-A/B titer did not correlate with late AMR (IRR = 0.9 per log titer increase, P = 0.7). This risk-stratification scheme uses information available within 30 days of ABOi transplantation to determine risk for late AMR and can help direct longitudinal follow-up for individual patients.

Severe chronic norovirus diarrheal disease in transplant recipients: Clinical features of an under-recognized syndrome.

BACKGROUND: Norovirus (NV) infection has been reported as a cause of severe chronic diarrhea in transplant recipients, but this entity remains under-recognized in clinical practice, leading to diagnostic delays. Transplant clinicians should become familiar with this syndrome in order to facilitate early detection and management. METHODS: Demographic, clinical, and outcomes variables were summarized from a series of transplant recipients with positive stool NV reverse transcription polymerase chain reaction (RT-PCR) assays at Johns Hopkins in 2013-2014. Factors associated with longer duration of symptoms were compared using random forest analysis. RESULTS: Thirty-one of 193 (16%) transplant recipients who were tested for NV had positive stool RT-PCRs. Symptoms included diarrhea (100%), nausea/vomiting (58%), abdominal pain (52%), and wasting (35%). Acute kidney injury occurred in 23%, and persisted in 21% after 6 months. Median duration of diarrheal symptoms was 4 months (range, <1-20) and 11/31 (35.4%) patients had relapses after improvement. Wasting, incompatible kidney transplant status, and plasmapheresis were associated with longer diarrhea durations. Treatments included nitazoxanide (in 74%), reduction of immunosuppression (58%), and intravenous immunoglobulin (32%). Six patients died, but no deaths were attributed to NV. CONCLUSIONS: It is important for clinicians to recognize that NV can cause severe chronic diarrhea in transplant recipients. In this series, receipt of a human leukocyte antigen- and/or blood type-incompatible kidney transplant, and plasmapheresis were associated with longer symptom duration.

Abnormalities in biomarkers of mineral and bone metabolism in kidney donors.

Previous studies have suggested that kidney donors may have abnormalities of mineral and bone metabolism typically seen in chronic kidney disease. This may have important implications for the skeletal health of living kidney donors and for our understanding of the pathogenesis of long-term mineral and bone disorders in chronic kidney disease. In this prospective study, 182 of 203 kidney donors and 173 of 201 paired normal controls had markers of mineral and bone metabolism measured before and at 6 and 36 months after donation (ALTOLD Study). Donors had significantly higher serum concentrations of intact parathyroid hormone (24.6% and 19.5%) and fibroblast growth factor-23 (9.5% and 8.4%) at 6 and 36 months, respectively, as compared to healthy controls, and significantly reduced tubular phosphate reabsorption (-7.0% and -5.0%) and serum phosphate concentrations (-6.4% and -2.3%). Serum 1,25-dihydroxyvitamin D3 concentrations were significantly lower (-17.1% and -12.6%), while 25-hydroxyvitamin D (21.4% and 19.4%) concentrations were significantly higher in donors compared to controls. Moreover, significantly higher concentrations of the bone resorption markers, carboxyterminal cross-linking telopeptide of bone collagen (30.1% and 13.8%) and aminoterminal cross-linking telopeptide of bone collagen (14.2% and 13.0%), and the bone formation markers, osteocalcin (26.3% and 2.7%) and procollagen type I N-terminal propeptide (24.3% and 8.9%), were observed in donors. Thus, kidney donation alters serum markers of bone metabolism that could reflect impaired bone health. Additional long-term studies that include assessment of skeletal architecture and integrity are warranted in kidney donors.

Isolated endarteritis and kidney transplant survival: a multicenter collaborative study.

Isolated endarteritis of kidney transplants is increasingly recognized. Notably, microarray studies revealed absence of immunologic signatures of rejection in most isolated endarteritis biopsy samples. We investigated if isolated endarteritis responds to rejection treatment and affects kidney transplant survival. We retrospectively enrolled recipients of kidney transplant who underwent biopsies between 1999 and 2011 at seven American and Canadian centers. Exclusion criteria were recipients were blood group-incompatible or crossmatch-positive or had C4d-positive biopsy samples. After biopsy confirmation, patients were divided into three groups: isolated endarteritis (n=103), positive controls (type I acute T cell-mediated rejection with endarteritis; n=101), and negative controls (no diagnostic rejection; n=103). Primary end points were improved kidney function after rejection treatment and transplant failure. Mean decrease in serum creatinine from biopsy to 1 month after rejection treatment was 132.6 µmol/L (95% confidence interval [95% CI], 78.7 to 186.5) in patients with isolated endarteritis, 96.4 µmol/L (95% CI, 48.6 to 143.2) in positive controls (P=0.32), and 18.6 µmol/L (95% CI, 1.8 to 35.4) in untreated negative controls (P<0.001). Functional improvement after rejection treatment occurred in 80% of patients with isolated endarteritis and 81% of positive controls (P=0.72). Over the median 3.2-year follow-up period, kidney transplant survival rates were 79% in patients with isolated endarteritis, 79% in positive controls, and 91% in negative controls (P=0.01). In multivariate analysis, isolated endarteritis was associated with an adjusted 3.51-fold (95% CI, 1.16 to 10.67; P=0.03) risk for transplant failure. These data indicate that isolated endarteritis is an independent risk factor for kidney transplant failure.

A closer look at rituximab induction on HLA antibody rebound following HLA-incompatible kidney transplantation.

Rituximab has been used to increase the efficacy of desensitization protocols for human leukocyte antigen (HLA)-incompatible kidney transplantation; however, controlled comparisons have not been reported. Here we examined 256 post-transplant HLA antibody levels in 25 recipients desensitized with and 25 without rituximab induction, to determine the impact of B-cell depletion. We found significantly less HLA antibody rebound in the rituximab-treated patients (7% of donor-specific antibodies (DSAs) and 33% of non-DSAs) compared with a control cohort desensitized and transplanted without rituximab (32% DSAs and 55% non-DSAs). The magnitude of the increase was significantly larger among patients who did not receive rituximab. Interestingly, in rituximab-treated patients, of the 39 HLA antibodies that increased post transplant, 34 were specific for HLA mismatches present in previous allografts or pregnancies, implying limited efficacy in memory B-cell depletion. Compared with controls, rituximab-treated patients had a significantly greater mean reduction in DSA (-2505 vs. -292 mean fluorescence intensity), but a similar rate of DSA persistence (52% in rituximab treated-and 40% in non-treated recipients). Thus, rituximab induction in HLA-incompatible recipients reduced the incidence and magnitude of HLA antibody rebound, but did not affect DSA elimination, antibody-mediated rejection, or 5-year allograft survival when compared with recipients desensitized and transplanted without rituximab.

A prospective controlled study of living kidney donors: three-year follow-up.

BACKGROUND: There have been few prospective controlled studies of kidney donors. Understanding the pathophysiologic effects of kidney donation is important for judging donor safety and improving our understanding of the consequences of reduced kidney function in chronic kidney disease. STUDY DESIGN: Prospective, controlled, observational cohort study. SETTING & PARTICIPANTS: 3-year follow-up of kidney donors and paired controls suitable for donation at their donor's center. PREDICTOR: Kidney donation. OUTCOMES: Medical history, vital signs, glomerular filtration rate, and other measurements at 6, 12, 24, and 36 months after donation. RESULTS: At 36 months, 182 of 203 (89.7%) original donors and 173 of 201 (86.1%) original controls continue to participate in follow-up visits. The linear slope of the glomerular filtration rate measured by plasma iohexol clearance declined 0.36±7.55mL/min per year in 194 controls, but increased 1.47±5.02mL/min per year in 198 donors (P=0.005) between 6 and 36 months. Blood pressure was not different between donors and controls at any visit, and at 36 months, all 24-hour ambulatory blood pressure parameters were similar in 126 controls and 135 donors (mean systolic blood pressure, 120.0±11.2 [SD] vs 120.7±9.7mmHg [P=0.6]; mean diastolic blood pressure, 73.4±7.0 vs 74.5±6.5mmHg [P=0.2]). Mean arterial pressure nocturnal dipping was manifest in 11.2% ± 6.6% of controls and 11.3% ± 6.1% of donors (P=0.9). Urinary protein-creatinine and albumin-creatinine ratios were not increased in donors compared with controls. From 6 to 36 months postdonation, serum parathyroid hormone, uric acid, homocysteine, and potassium levels were higher, whereas hemoglobin levels were lower, in donors compared with controls. LIMITATIONS: Possible bias resulting from an inability to select controls screened to be as healthy as donors, short follow-up duration, and dropouts. CONCLUSIONS: Kidney donors manifest several of the findings of mild chronic kidney disease. However, at 36 months after donation, kidney function continues to improve in donors, whereas controls have expected age-related declines in function.

Clinical excellence in nephrology: Examples from the published literature.

BACKGROUND: Provision of exceptional medical care is a goal for the medical profession because this is what the public needs and deserves. Academic medical centers that value excellent clinicians may have the best chance to recruit and retain these faculty members. When our institution hoped to launch the Miller Coulson Academy of Clinical Excellence to measure and reward master clinicians, a critical first step was to use rigorous methods to develop a definition of clinical excellence. Published papers have illustrated that this general definition of clinical excellence is applicable to fields of psychiatry, cardiology, and pediatrics. In this manuscript, we apply the definition of clinical excellence to nephrology. Using the same framework, we reviewed the literature to find clinical cases and exemplary nephrologists that highlight the specific domains. This collection of reports in nephrology illustrates that the definition of clinical excellence set forth by the Miller Coulson Academy is highly applicable to physicians caring for individuals with kidney disease. Relating the definition of clinical excellence to renal medicine is worthwhile in that it can help to exemplify the model to which physicians and trainees may seek to aspire. KEY MESSAGE: Many examples of clinical excellence in renal medicine can be found in the published medical literature. The domains of clinical excellence, described by the Miller-Coulson Academy of Clinical Excellence, apply very well to the field of nephrology.

Intimal arteritis in renal allografts: new takes on an old lesion.

PURPOSE OF REVIEW: Inflammation of the arterial wall has been recognized as a key element of rejection since the early studies of pathologic changes in transplanted organs. Better elucidation of the mechanisms involved in endothelial injury has brought increasing complexity to the diagnostic classification of this lesion in the context of transplantation, and has affected the clinical management of patients with allograft rejection. Here, we examine how our understanding of the significance of intimal arteritis in renal graft biopsies has evolved in the past decades. RECENT FINDINGS: Recognition that antidonor antibody may cause intimal arteritis has prompted revision of histologic classifications of transplant rejection. Although molecular signatures/biomarkers are being developed and proposed as new tools for aiding in the identification of cell-mediated and antibody-mediated types of rejection, histological examination is still needed to identify intimal arteritis in allograft biopsies. Outcome studies are contributing to clarify the prognostic significance of intimal arteritis in transplant rejection. SUMMARY: Intimal arteritis remains an important histologic feature of allograft rejection, which comes in different nuances requiring tailored therapeutic approaches.

Desensitization in HLA-incompatible kidney recipients and survival.

BACKGROUND: More than 20,000 candidates for kidney transplantation in the United States are sensitized to HLA and may have a prolonged wait for a transplant, with a reduced transplantation rate and an increased rate of death. One solution is to perform live-donor renal transplantation after the depletion of donor-specific anti-HLA antibodies. Whether such antibody depletion results in a survival benefit as compared with waiting for an HLA-compatible kidney is unknown. METHODS: We used a protocol that included plasmapheresis and the administration of low-dose intravenous immune globulin to desensitize 211 HLA-sensitized patients who subsequently underwent renal transplantation (treatment group). We compared rates of death between the group undergoing desensitization treatment and two carefully matched control groups of patients on a waiting list for kidney transplantation who continued to undergo dialysis (dialysis-only group) or who underwent either dialysis or HLA-compatible transplantation (dialysis-or-transplantation group). RESULTS: In the treatment group, Kaplan-Meier estimates of patient survival were 90.6% at 1 year, 85.7% at 3 years, 80.6% at 5 years, and 80.6% at 8 years, as compared with rates of 91.1%, 67.2%, 51.5%, and 30.5%, respectively, for patients in the dialysis-only group and rates of 93.1%, 77.0%, 65.6%, and 49.1%, respectively, for patients in the dialysis-or-transplantation group (P<0.001 for both comparisons). CONCLUSIONS: Live-donor transplantation after desensitization provided a significant survival benefit for patients with HLA sensitization, as compared with waiting for a compatible organ. By 8 years, this survival advantage more than doubled. These data provide evidence that desensitization protocols may help overcome incompatibility barriers in live-donor renal transplantation. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Charles T. Bauer Foundation.).

Blood dendritic cell levels associated with impaired IL-12 production and T-cell deficiency in patients with kidney disease: implications for post-transplant viral infections.

Reduced pretransplant blood myeloid dendritic cell (mDC) levels are associated with post-transplant BK viremia and cytomegalovirus (CMV) disease after kidney transplantation. To elucidate potential mechanisms by which mDC levels might influence these outcomes, we studied the association of mDC levels with mDC IL-12 production and T-cell level/function. Peripheral blood (PB) was studied in three groups: (i) end stage renal disease patients on hemodialysis (HD; n = 81); (ii) chronic kidney disease stage IV-V patients presenting for kidney transplant evaluation or the day of transplantation (Eval/Tx; n = 323); and (iii) healthy controls (HC; n = 22). Along with a statistically significant reduction in mDC levels, reduced CD8(+) T-cell levels were also demonstrated in the kidney disease groups compared with HC. Reduced PB mDC and monocyte-derived DC (MoDC) IL-12 production was observed after in vitro LPS stimulation in the HD versus HC groups. Finally, ELISpot assays demonstrated less robust CD3(+) INF-γ responses by MoDCs pulsed with CMV pp65 peptide from HD patients compared with HC. PB mDC level deficiency in patients with kidney disease is associated with deficient IL-12 production and T-cell level/function, which may explain the known correlation of CD8(+) T-cell lymphopenia with deficient post-transplant antiviral responses.