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The IgG-degrading enzyme derived from Streptococcus pyogenes (Imlifidase, Hansa Biopharma) is a novel agent that cleaves all four human subclasses of IgG and has therapeutic potential for HLA desensitization in kidney transplantation and antibody-mediated rejection. Data from clinical trials in kidney transplantation demonstrated rapid degradation of anti-HLA donor-specific antibodies facilitating HLA-incompatible transplantation, which led to conditional approval of imlifidase by the European Medicines Agency for desensitization in kidney transplant recipients of a deceased donor with a positive cross match. Important considerations arising from the early experiences with imilfidase on kinetics of donor-specific antibodies after administration, timing of complementary therapeutic monoclonal or polyclonal IgG antibodies, and interference with cross match assays should be recognized as imlifidase emerges as a therapeutic agent for clinical transplantation.

Because highly sensitized kidney transplant candidates must draw from a large donor pool to find a biologically compatible donor, living donor transplantation is uncommon among HLA-sensitized patients in need of kidney transplantations. We review current data on treatment options for highly sensitized kidney transplant candidates and provide recommendations based on the evidence and our clinical experience. As kidney paired donation becomes more common in the USA, recent studies have published outcomes from large, multi-center national exchange programs. Recent national studies have also provided data on experience with HLA-incompatible kidney transplantation options for the highly sensitized candidate including paired kidney exchange, desensitization with HLA-incompatible transplantation, or waiting for a deceased donor transplant. This review summarizes the pros and cons of these options and provides recommendations for the highly sensitized patient with an incompatible living donor. Considerations include the likelihood of finding a biologically compatible donor, the degree of HLA-incompatibility and their associated outcomes in comparison to compatible transplantation, the downside of remaining on dialysis while waiting for a more suitable donor, and patient preference. Given the challenges in finding biologically compatible donors, HLA-incompatible transplantation is an appropriate option for many highly sensitized kidney transplant candidates.

Objective: Elevated levels of pro-inflammatory cytokines are observed in severe COVID-19 infections, and cytokine storm is associated with disease severity. Tocilizumab, an interleukin-6 receptor antagonist, is used to treat chimeric antigen receptor T cell-induced cytokine release syndrome and may attenuate the dysregulated immune response in COVID-19. We compared outcomes among tocilizumab-treated and non-tocilizumab-treated critically ill COVID-19 patients. Design, setting, and participants: This was a retrospective observational study conducted at a tertiary referral center investigating all patients admitted to the intensive care unit for COVID-19 who had a disposition from the hospital because of death or hospital discharge between March 1 and May 18, 2020 (n = 96). The percentages of death and secondary infections were compared between patients treated with tocilizumab (n = 55) and those who were not (n = 41). Measurements and main results: More tocilizumab-treated patients required mechanical ventilation (44/55, 80%) compared to non-treated patients (15/41, 37%; P < 0.001). Of 55 patients treated with tocilizumab, 32 (58%) were on mechanical ventilation at the time of administration, and 12 (22%) progressed to mechanical ventilation after treatment. Of patients treated with tocilizumab requiring mechanical ventilation, 30/44 (68%) were intubated within 1 day of administration. Fewer deaths were observed among tocilizumab-treated patients, both in the overall population (15% vs 37%; P = 0.02) and among the subgroup of patients requiring mechanical ventilation (14% vs 60%; P = 0.001). Secondary infections were not different between the 2 groups (tocilizumab: 31%, non-tocilizumab: 17%; P = 0.16) and were predominantly related to invasive devices, such as urinary and central venous catheters. Conclusions: Tocilizumab treatment was associated with fewer deaths compared to non-treatment despite predominantly being used in patients with more advanced respiratory disease.

Antibody-mediated rejection (ABMR) is implicated as the leading cause of late kidney allograft failure. Current therapies inadequately control the antibody response and persistent donor-specific antibodies lead to chronic ABMR and allograft failure. Imlifidase is an IgG endopeptidase derived from Streptococcus pyogenes that cleaves human IgG into F(ab’)2 and Fc fragments, thereby protecting against complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Favorable outcomes with its use for desensitization in HLA-incompatible kidney transplantation have engendered interest in its use for ABMR. The experiences with imlifidase for a variety of antibody-mediated diseases, including anti-glomerular basement membrane disease, thrombotic thrombocytopenic purpura, and desensitization in HLA-incompatible kidney transplantation, are reviewed to provide a rationale for using imlifidase to treat ABMR in kidney transplantation. Imlifidase is currently being evaluated in comparison to plasmapheresis in a clinical trial and is a potential therapy for ABMR in kidney transplantation.

Background Preliminary data from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia patients indicate that a cytokine storm may increase morbidity and mortality. Tocilizumab (anti-IL-6R) is approved by the Food and Drug Administration for treatment of cytokine storm associated with chimeric antigen receptor T-cell therapy. Here we examined compassionate use of tocilizumab in patients with SARS-CoV-2 pneumonia. Methods We report on a single-center study of tocilizumab in hospitalized patients with SARS-CoV-2 pneumonia. All patients had confirmed SARS-CoV-2 pneumonia and oxygen saturations Results Twenty-seven SARS-CoV-2 pneumonia patients received one 400 mg dose of tocilizumab. Interleukin (IL)-6 was the predominant cytokine detected at tocilizumab treatment. Significant reductions in temperature and CRP were seen post-tocilizumab. However, 4 patients did not show rapid CRP declines, of whom 3 had poorer outcomes. Oxygen and vasopressor requirements diminished over the first week post-tocilizumab. Twenty-two patients required mechanical ventilation; at last follow-up, 16 were extubated. Adverse events and serious adverse events were minimal, but 2 deaths (7.4%) occurred that were felt unrelated to tocilizumab. Conclusions Compared to published reports on the morbidity and mortality associated with SARS-CoV-2, tocilizumab appears to offer benefits in reducing inflammation, oxygen requirements, vasopressor support, and mortality. The rationale for tocilizumab treatment is supported by detection of IL-6 in pathogenic levels in all patients. Additional doses of tocilizumab may be needed for those showing slow declines in CRP. Proof of efficacy awaits randomized, placebo-controlled clinical trials.

Background and objectives Delayed graft function is related to ischemia-reperfusion injury and may be complement dependent. We previously reported from a randomized, placebo-controlled trial that treatment with C1 esterase inhibitor was associated with a shorter duration of delayed graft function and higher eGFR at 1 year. Here, we report longer-term outcomes from this trial. Design, setting, participants, & measurements This is a post hoc analysis of a phase 1/2, randomized, controlled trial enrolling 70 recipients of deceased donor kidney transplants at risk for delayed graft function (NCT02134314). Subjects were randomized to receive C1 esterase inhibitor 50 U/kg (n=35) or placebo (n=35) intraoperatively and at 24 hours. The cumulative incidence functions method was used to compare graft failure and death over 3.5 years. eGFR slopes were compared using a linear mixed effects model. Results Three deaths occurred among C1 esterase inhibitor–treated patients compared with none receiving placebo. Seven graft failures developed in the placebo group compared with one among C1 esterase inhibitor–treated recipients; the cumulative incidence of graft failure was lower over 3.5 years among C1 esterase inhibitor–treated recipients compared with placebo (P=0.03). Although no difference in eGFR slopes was observed between groups (P for group-time interaction =0.12), eGFR declined in placebo-treated recipients (−4 ml/min per 1.73 m2 per year; 95% confidence interval, −8 to −0.1) but was stable in C1 esterase inhibitor–treated patients (eGFR slope: 0.5 ml/min per 1.73 m2 per year; 95% confidence interval, −4 to 5). At 3.5 years, eGFR was 56 ml/min per 1.73 m2 (95% confidence interval, 42 to 70) in the C1 esterase inhibitor group versus 35 ml/min per 1.73 m2 (95% confidence interval, 21 to 48) in the placebo group, with an estimated mean eGFR difference of 21 ml/min per 1.73 m2 (95% confidence interval, 2 to 41 ml/min per 1.73 m2). Conclusions Treatment of patients at risk for ischemia-reperfusion injury and delayed graft function with C1 esterase inhibitor was associated with a lower incidence of graft failure.

Background Viral infections are controlled primarily by viral-specific T cells, raising concern for adequate T-cell response to clear CMV infection in transplant recipients receiving lymphocyte-depleting agents (LDA). We examined the rates of CMV viremia and clearance, seroconversion, and CMV-specific CD8+ T cell (CMV-Tc) activity with class of induction agent received. Methods Retrospective review of 45 pediatric renal transplant recipients who received induction with LDA (n = 31) or non-LDA (NLDA; n = 14) received valganciclovir prophylaxis for 6 months post-transplant and CMV-PCR monitoring. CMV-Tc was measured by intracellular IFNγ flow cytometry, when possible, at baseline, 1 month after CMV viremia (>5 copies/PCR) and serially until CMV-Tc was positive (≥0.2%). Results Viremia rates at 1, 2, and 4 years post-transplant were higher in LDA vs. NLDA (46.3% vs. 7.2%, 64.2% vs. 7.2%, and 64.2% vs. 7.2%, respectively; p = .002). Viremia rates at these time points in seronegative LDA (50.3%, 71.6%, 71.6%) were significantly or near significantly higher than seronegative NLDA (9.1%, 9.1%, 9.1%; p = .004), seropositive-LDA (22.3%, 22.3%, 22.3%; p = .07), or seropositive NLDA (0%, 0%, 0%; p = .07). Eleven of 17 (64.7%) viremic subjects required valganciclovir dose reduction during the prophylaxis period for leukopenia. All viremic LDA patients developed CMV-Tc. One viremic NLDA patient did not develop CMV-Tc. No patients developed CMV disease. Conclusion CMV seronegative pediatric renal transplant patients receiving LDA are more likely to have valganciclovir prophylaxis dose reduction and develop subclinical CMV viremia; however, all developed CMV-Tc. Larger prospective studies are needed to further understand the effects of induction agents on CMV-Tc and CMV-Tc's role post-transplant.

Background Tocilizumab is an interleukin-6 receptor antagonist recently described as a promising treatment for antibody-mediated rejection. We compared infectious complications among tocilizumab-treated kidney transplant patients with those receiving intravenous immunoglobulin (IVIG)/rituximab. Methods Infections occurring among 148 kidney recipients treated with tocilizumab 8 mg/kg IV monthly (n = 83) or IVIG/rituximab (n = 65) for donor-specific antibodies and antibody-mediated rejection through 1 year after treatment cessation were reviewed. Incidence rates of infections were compared using Poisson regression. Results There were 106 infections observed over 190.1 person-years, yielding an incidence rate of 558 infections/1000 patient-years. A lower incidence rate of infections was observed among tocilizumab-treated compared with IVIG/rituximab-treated patients (463 infections/1000 patient-years versus 730 infections/1000 patient-years; P = 0.02). Twenty-five of 49 infections (51%) in the IVIG/rituximab group required hospitalization compared with 31 of 57 (54%; P = 0.85) in the tocilizumab group. There were no infection-related deaths in either group. Urinary tract infections and pneumonia were the most common types of infections, whereas gastrointestinal, blood, skin/soft tissue, viral, and fungal infections were less common. On multivariable Poisson regression, there was a lower incidence rate of infections associated with tocilizumab compared with IVIG/rituximab (incidence rate ratio, 0.63; 95% confidence interval, 0.43-0.93). Conclusions Among kidney transplant patients treated with tocilizumab, there was no excess risk of infections compared with standard therapy with IVIG/rituximab.

International audience; Although the gold standard of monitoring kidney transplant function relies on glomerular filtration rate (GFR), little is known about GFR trajectories after transplantation, their determinants, and their association with outcomes. To evaluate these parameters we examined kidney transplant recipients receiving care at 15 academic centers. Patients underwent prospective monitoring of estimated GFR (eGFR) measurements, with assessment of clinical, functional, histological and immunological parameters. Additional validation took place in seven randomized controlled trials that included a total of 14,132 patients with 403,497 eGFR measurements. After a median follow-up of 6.5 years, 1,688 patients developed end-stage kidney disease. Using unsupervised latent class mixed models, we identified eight distinct eGFR trajectories. Multinomial regression models identified seven significant determinants of eGFR trajectories including donor age, eGFR, proteinuria, and several significant histological features: graft scarring, graft interstitial inflammation and tubulitis, microcirculation inflammation, and circulating anti-HLA donor specific antibodies. The eGFR trajectories were associated with progression to end stage kidney disease. These trajectories, their determinants and respective associations with end stage kidney disease were similar across cohorts, as well as in diverse clinical scenarios, therapeutic eras and in the seven randomized control trials. Thus, our results provide the basis for a trajectory-based assessment of kidney transplant patients for risk stratification and monitoring.

Background Many kidneys donated for transplant in the United States are discarded because of abnormal histology. Whether histology adds incremental value beyond usual donor attributes in assessing allograft quality is unknown. Methods This population-based study included patients who received a deceased donor kidney that had been biopsied before implantation according to a prespecified protocol in France and Belgium, where preimplantation biopsy findings are generally not used for decision making in the allocation process. We also studied kidneys that had been acquired from deceased United States donors for transplantation that were biopsied during allocation and discarded because of low organ quality. Using donor and recipient characteristics, we fit multivariable Cox models for death-censored graft failure and examined whether predictive accuracy (C index) improved after adding donor histology. We matched the discarded United States kidneys to similar kidneys transplanted in Europe and calculated predicted allograft survival. Results In the development cohort of 1629 kidney recipients at two French centers, adding donor histology to the model did not significantly improve prediction of long-term allograft failure. Analyses using an external validation cohort from two Belgian centers confirmed the lack of improved accuracy from adding histology. About 45% of 1103 United States kidneys discarded because of histologic findings could be accurately matched to very similar kidneys that had been transplanted in France; these discarded kidneys would be expected to have allograft survival of 93.1% at 1 year, 80.7% at 5 years, and 68.9% at 10 years. Conclusions In this multicenter study, donor kidney histology assessment during allocation did not provide substantial incremental value in ascertaining organ quality. Many kidneys discarded on the basis of biopsy findings would likely benefit United States patients who are wait listed.

COVID-19 is a severe infectious disease that has claimed >150,000 lives and infected millions in the United States thus far, especially the elderly population. Emerging evidence has shown the virus to cause hemorrhagic and immunologic responses, which impact all organs, including lungs, kidneys, and the brain, as well as extremities. SARS-CoV-2 also affects patients’, families’, and society’s mental health at large. There is growing evidence of re-infection in some patients. The goal of this paper is to provide a comprehensive review of SARS-CoV-2-induced disease, its mechanism of infection, diagnostics, therapeutics, and treatment strategies, while also focusing on less attended aspects by previous studies, including nutritional support, psychological, and rehabilitation of the pandemic and its management. We performed a systematic review of >1,000 articles and included 425 references from online databases, including, PubMed, Google Scholar, and California Baptist University’s library. COVID-19 patients go through acute respiratory distress syndrome, cytokine storm, acute hypercoagulable state, and autonomic dysfunction, which must be managed by a multidisciplinary team including nursing, nutrition, and rehabilitation. The elderly population and those who are suffering from Alzheimer’s disease and dementia related illnesses seem to be at the higher risk. There are 28 vaccines under development, and new treatment strategies/protocols are being investigated. The future management for COVID-19 should include B-cell and T-cell immunotherapy in combination with emerging prophylaxis. The mental health and illness aspect of COVID-19 are among the most important side effects of this pandemic which requires a national plan for prevention, diagnosis and treatment.

Background Severe Acute Respiratory Syndrome caused by coronavirus 2 (SARS-CoV-2) is characterized by an overwhelming cytokine response. Various treatment strategies have been attempted. Methods and Results A 61-year-old male with heart transplantation in 2017 presented with fever, cough, and dyspnea, and confirmed positive for the SARS-CoV-2 disease (COVID-19). Laboratory tests showed significant elevations in C-reactive protein and interleukin-6 (IL-6). Echocardiogram showed LVEF 58% (with EF 57% 6 months prior). Given the lack of clear management guidelines, the patient was initially managed symptomatically. However, the patient subsequently had a rapid respiratory deterioration with worsening inflammatory markers on day 5 of admission. Tocilizumab (anti-IL-6R) was in low supply in the hospital. The patient was offered clazakizumab (anti-IL-6) for compassionate use. Patient received 25 mg intravenously x1 dose. Within 24 hours, he noted significant improvement in symptoms, oxygen requirements, radiological findings and inflammatory markers. There was a transient leukopenia which improved in 4 days. He was discharged home on day 11, with negative nasopharyngeal SARS-CoV-2 PCR as an outpatient on day 35, development of positive serum COVID-19 IgG antibody, and he continued to do well on day 60, with no heart-related symptoms. Conclusion Clazakizumab is a monoclonal antibody against human IL-6, which may be helpful in inhibiting the cytokine response to SARS-CoV-2 in COVID-19. Although not yet FDA approved, it is being investigated for treatment of renal antibody-mediated rejection. Clinical trials of clazakizumab for treatment of COVID-19 are underway worldwide., Highlights • Severe Acute Respiratory Syndrome caused by coronavirus 2 (SARS-CoV-2) is characterized by an overwhelming cytokine response. • A 61-year-old male with heart transplantation in 2017 presented with fever, cough, and dyspnea, and confirmed positive for the SARS-CoV-2 disease (COVID-19). Laboratory tests showed significant elevations in C-reactive protein, interleukin-6 (IL-6), and other inflammatory markers. Echocardiogram showed normal LV function. • The patient received clazakizumab (anti-IL-6 monoclonal antibody) 25 mg as a single dose, with significant improvement in symptoms, oxygen requirements, radiological findings and inflammatory markers within 24 hours, and discharge to home on day 11. He had a negative nasopharyngeal SARS-CoV-2 PCR as an outpatient on day 35, developed a positive serum COVID-19 IgG antibody, and was continuing to do well clinically on day 60. • Clazakizumab is a monoclonal antibody against human IL-6, which may be helpful in inhibiting the cytokine response to SARS-CoV-2 in COVID-19.

Interleukin 6 (IL-6) is a cytokine with critical innate and adaptive immunity functions. It's diverse immunologic and physiologic actions include direction of immune cell differentiation, initial response to invading pathogens and ischemic injury, sustained plasma cell growth, and immunoglobulin production. IL-6 transcriptional dysregulation is commonly seen in patients with autoimmune or inflammatory disorders. Emerging information suggests IL-6 transcription is upregulated in patients with kidney and heart transplant rejection and may account for perpetuation of inflammatory responses in the allograft, leading to allograft rejection and vasculopathy. IL-6 directed therapeutics include monoclonal antibodies directed at IL-6, the IL-6 receptor (IL-6R) and Janus Kinase (JAK) inhibitors. IL-6 mediated signaling to cell targets is unique, involving classic signaling (IL-6->IL-6R) cell membrane receptors, trans signaling (IL-6->soluble IL-6R->gp130) which activates any cell, and the recently discovered IL-6/IL-6R transpresentation where antigen presenting cells (APC) synthesize and express IL-6/IL-6R complexes which are transported through the cell membrane subsequently interacting with gp130 to costimulate T-cells. Currently, there are new trials in autoimmunity and heart and kidney transplantation to determine effectiveness of inhibiting IL-6/IL-6R to ameliorate chronic allograft rejection and coronary allograft vasculopathy. Therapeutic trials aimed at prevention of ischemia/reperfusion injury (IRI) to allografts based on animal data should be considered.

JC virus-associated nephropathy is rare in kidney transplant recipients, and even rarer in recipients of other solid organ transplants. We present a case of JC virus-associated nephropathy in a heart-kidney transplant recipient, which to our knowledge is the first case reported in the literature. We discuss the findings on renal biopsy for JC virus nephropathy and our management approach to this rare complication.

BackgroundBK virus infection remains an important cause of loss of allograft function after kidney transplantation. We sought to determine whether polyfunctional T cells secreting multiple cytokines simultaneously, which have been shown to be associated with viral control, could be detected early after start of BK viremia, which would provide insight into the mechanism of successful antiviral control.MethodsPeripheral blood mononuclear cells collected during episodes of BK viral replication were evaluated by multiparameter flow cytometry after stimulation by overlapping peptide pools of BK virus antigen to determine frequency of CD8+ and CD4+ T cells expressing 1 or more cytokines simultaneously, as well as markers of T-cell activation, exhaustion, and maturation.ResultsBK virus controllers, defined as those with episodes of BK viremia of 3 months or less, had an 11-fold increase in frequency of CD8+ polyfunctional T cells expressing multiple cytokines, as compared with patients with prolonged episodes of BK viremia. Patients with only low level BK viremia expressed low frequencies of polyfunctional T cells. Polyfunctional T cells were predominantly of the effector memory maturation subtype and expressed the cytotoxicity marker CD107a.ConclusionsNoninvasive techniques for immune assessment of peripheral blood can provide insight into the mechanism of control of BK virus replication and may allow for future patient risk stratification and customization of immune suppression at the onset of BK viremia.

Patients who develop malignancy after kidney transplantation typically undergo a reduction in immunosuppression and referral to an oncologist for chemotherapeutic considerations for the management of their malignancy. Traditional cytotoxic chemotherapy agents can result in kidney transplant injury, but the decision about which agents to be used has largely been determined by oncologists without the involvement of nephrologists. More recently, several classes of drugs with immunomodulatory actions have been approved for the treatment of cancer, including multiple myeloma. Activation of the immune system against malignant cells may have unintended consequences in solid-organ transplant recipients, who require suppression of the immune system to avoid transplant rejection. In this report, we present a case of acute kidney transplant rejection in a 65-year-old woman following administration of the newer immunomodulatory agent lenalidomide for the treatment of multiple myeloma. A greater awareness of the mechanisms of newly introduced chemotherapy agents and discussion with the treating oncologist and patient are paramount in caring for patients who develop malignancy following transplantation.

© 2017 by the American Society of Nephrology. Background and objectives Waitlist inactivity is a barrier to transplantation, because inactive candidates cannot receive deceased donor organ offers. We hypothesized that temporarily inactive kidney transplant candidates living in linguistically isolated communities would be less likely to achieve active waitlist status. Design, setting, participants, & measurements We merged Organ Procurement and Transplantation Network/ United Network for Organ Sharing data with five-digit zip code socioeconomic data from the 2000 US Census. The cumulative incidence of conversion to active waitlist status, death, and delisting before conversion among 84,783 temporarily inactive adult kidney candidates from 2004 to 2012 was determined using competing risks methods. Competing risks regression was performed to characterize the association between linguistic isolation, incomplete transplantation evaluation, and conversion to active status. A household was determined to be linguistically isolated if all members ≥14 years old speak a non-English language and also, speak English less than very well. ResultsA total of 59,147 candidates (70% of the studypopulation) achieved active status over the studyperiod of 9.8 years. Median follow-up was 110 days (interquartile range, 42–276 days) for activated patients and 815 days (interquartile range, 361–1244 days) for candidates not activated. The cumulative incidence of activation over the studyperiod was 74%, the cumulative incidence of death before conversion was 10%, and the cumulative incidence of delisting was 13%. After adjusting for other relevant covariates, living in a zip code with higher percentages of linguistically isolated households was associated with progressively lower subhazards of activation both in the overall population (reference

The prognostic value of preformed donor-specific HLA antibodies (DSA), which are only detectable by sensitive methods, remains controversial for kidney transplantation.The outcome of 4233 consecutive kidney transplants performed between 2012 and 2015 in 18 German transplant centers was evaluated. Most centers used a stepwise pretransplant antibody screening with bead array tests and differentiation of positive samples by single antigen assays. Using these screening results, DSA against HLA-A, -B, -C, -DRB1 and -DQB1 were determined. Data on clinical outcome and possible covariates were collected retrospectively.Pretransplant DSA were associated with lower overall graft survival, with a hazard ratio of 2.53 for living donation (95% confidence interval [95% CI], 1.49 to 4.29;Preformed DSA were associated with an increased risk for graft loss in kidney transplantation, which was greater in living than in deceased donation. Even weak DSA3000 MFI were associated with worse graft survival. This association was stronger in living than deceased donation.

Highly HLA-sensitized (HS) patients have an increased risk for the development of donor-specific antibodies (DSA) and antibody-mediated rejection (AMR) posttransplant. Here, we examined the risk for AMR in HS patients transplanted after desensitization (DES) who were DSA+ versus DSA- at transplant. We also examined the incidence and clinical impact of de novo DSAs (dnDSAs) and compared with dnDSA- patients.From January 2013 to October 2016, 90 HS patients (PRA80%, DSA+ = 50 versus DSA- = 40) received kidney transplantation after DES with IVIG + rituximab ± PLEX (plasma exchange) ± tocilizumab. DSAs were monitored at transplant and at 1, 3, 6, 12, 24, 36, and 48 months posttransplant.Patients were divided into 4 groups: DSA+/+ (n = 31), DSA+/- (n=19), DSA-/+ (n=10), and DSA-/- (n = 30). Median follow-up time was 2.9 years. DSA-negative patients who developed dnDSA had the highest incidence of AMR (70%) compared with the DSA+/+ (45%), DSA+/- (11%), and DSA-/- (10%) patients (P0.0001). Among patients who developed AMR, Banff 2013 AMR scores did not differ among the 4 groups. Graft survival and estimated glomerular filtration rate determinations at 4 years were similar.Persistence of preexisting DSAs or development of dnDSA after transplant is associated with an increased risk for AMR. Despite this, we did not observe a difference in Banff biopsy scores, graft survival, or patient survival compared with those without DSAs after transplant. Thus, for HS patients undergoing HLA-incompatible kidney transplant, DES therapy and frequent monitoring for dnDSAs appears critical for good long-term survival in at-risk groups.

Background Although individuals classified as nonresident aliens, including undocumented immigrants, are entitled to receive emergency dialysis in the United States regardless of their ability to pay, most states do not provide them with subsidized care for maintenance dialysis or kidney transplantation. We explored whether nonresident aliens have similar outcomes to US citizens after receiving kidney transplants covered by Medicaid, a joint federal and state health insurance program. Study Design Retrospective observational cohort study. Setting & Participants All adult Medicaid patients in the US Renal Data System who received their first kidney transplant from 1990 to 2011. Predictor Citizenship status, categorized as US citizen, nonresident alien, or permanent resident. Outcome All-cause transplant loss. Measurements HRs and 95% CIs estimated by applying Cox proportional hazards frailty models with transplantation center as a random effect. Results Of 10,495 patients, 8,660 (82%) were US citizens, 1,489 (14%) were permanent residents, and 346 (3%) were nonresident aliens, whom we assumed were undocumented immigrants. Nonresident aliens were younger, healthier, receiving dialysis longer, and more likely to have had a living donor. 71% underwent transplantation in California, and 61% underwent transplantation after 2005. Nonresident aliens had a lower unadjusted risk for transplant loss compared with US citizens (HR, 0.48; 95% CI, 0.35-0.65). Results were attenuated but still significant when adjusted for demographics, comorbid conditions, dialysis, and transplant-related factors (HR, 0.67; 95% CI, 0.46-0.94). Limitations Citizenship status was self-reported, possible residual confounding. Conclusions Our study suggests that the select group of insured nonresident aliens who undergo transplantation with Medicaid do just as well as US citizens with Medicaid. Policymakers should consider expanding coverage for kidney transplantation in nonresident aliens, including undocumented immigrants, given the associated high-quality outcomes in these patients.

Background/Aims: We examined post-transplant survival among obese kidney candidates who were temporarily designated waitlist inactive (status 7) due to their weight. Methods: Using OPTN/United Network for Organ Sharing data, patient and graft survival of adult status 7 recipients with a registration body mass index (BMI) ≥30 kg/m2 (n = 328) were compared to all others (controls; n = 74,066). Status 7 recipients were then matched to controls to assess whether pre-transplant weight loss was associated with a survival benefit. Results: Median BMI at registration (38 vs. 27 kg/m2, p < 0.001) and transplant (36 vs. 27 kg/m2, p < 0.001) and reduction in BMI while waitlisted (-5.0 vs. 0.0%, p < 0.001) were higher among status 7 than controls. Patient (status 7: 87.3%; control: 89.3%; p = 0.90) and graft survival (status 7: 82.9%; control: 81.6%; p = 0.75) were similar over 4 years. There was no association between status 7 and mortality (HR 0.96, 95% CI 0.59-1.57) or graft loss (HR 0.95, 95% CI 0.66-1.38) in the overall population nor between matched status 7 recipients and controls (patient survival: 86.0 vs. 87.5%, p = 0.20; graft survival: 82.6 vs. 77.2%, p = 0.61). Conclusion: Among obese status 7 kidney candidates previously considered too obese for transplant, patient and graft survival were comparable to the general transplant population. No difference in survival was observed with pre-transplant weight loss.

Author(s): Huang, Edmund | Advisor(s): Elashoff, Robert M; Elashoff, David | Abstract: Background: Candidates may be active or temporarily inactive (status 7) on the kidney transplant waiting list. One reason candidates may be inactive is for a “weight currently inappropriate for transplantation”. We hypothesized that many of these candidates would not achieve active status. Methods: Using OPTN/UNOS data from 2006-2012, we used competing risks methods to determine the cumulative incidence of conversion to active status (activation), death, and delisting before conversion among 1679 obese adult kidney candidates designated as status 7 due to a weight inappropriate for transplantation. Fine and Gray competing risks regression was performed to characterize factors associated with conversion to active status in the overall study population and of eventual transplantation among a subgroup of activated candidates. Results: At six years, the cumulative incidence of activation was 49%, of death before conversion was 15%, and of delisting was 21%. Higher body mass index (BMI) was strongly associated with a decreased subhazard of activation (BMI ≥45 vs. 30-34.9, sHR: 0.22; 95% CI: 0.16-0.33). Female gender, diabetic end-stage renal disease, history of a previous transplant, panel reactive antibodies l80%, dialysis-dependence at listing, and UNOS region 5 were negatively associated with activation. Among activated candidates, the cumulative incidence of transplantation at six years after initial waitlisting was 61%. Conclusions: Our findings indicate that half of obese status 7 candidates with a weight inappropriate for transplantation will not achieve active waitlist status. BMI at listing had a strong association with conversion to active status; however, co-morbid factors and regional variation also impact activation.

Background/Aims: Gastrointestinal (GI) symptoms in renal transplant recipients may be caused due to mycophenolic acid (MPA) toxicity. Using small bowel capsule endoscopy (SBCE) we examined the impact of conversion from Mycophenolate Mofetil (MMF) to enteric-coated formulation of Mycophenolate Sodium (EC-MPS) given to treat GI mucosal lesions. Methods: Adult kidney-only recipients at least 30 days after transplant, presenting with GI symptoms while receiving MMF completed a Gastrointestinal Symptom Rating Scale (GSRS) questionnaire, underwent SBCE, and had MMF substituted by EC-MPS. After 30 days, GSRS and SBCE were repeated and findings were compared to baseline values. Patients who were still on EC-MPS 6-24 months post-conversion were contacted for completing a follow-up GSRS questionnaire and SBCE. Results: Eighteen out of 23 subjects completed the first part of the study. Subjects' median ages and post-transplant time were 47.5 years old and 4.5 months, respectively. Tacrolimus, MMF and prednisone was the main regimen (94%), with a median MMF dose of 750 mg BID. The average baseline GSRS was 2.99 ± 0.81; it significantly decreased to 2.19 ± 0.8 at 30 days post-conversion. At baseline, 50 had gastric and 89% had small bowel lesions. At 30 days, 29 and 62% of the SBCE were still showing gastric and small bowel lesions, respectively. Of 5 patients in the study extension, 4 had abnormal SBCE findings but have been reporting improvement in their symptoms. Conclusion: Stomach and small bowel mucosal lesions are common in kidney recipients with GI symptoms when treated with MMF. Conversion to EC-MPS for 30 days significantly alleviated the GI symptoms; however, no evident correlation with SBCE findings was found.

Pre-transplant dialysis is known to affect kidney graft survival. Here, we report the impact of pre-transplant dialysis on patient and graft survival of type 1 diabetic recipients of either a simultaneous pancreas-kidney (SPK) or living donor kidney (LDK) transplant.Using the Organ Procurement Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database, 6822 adult type 1 diabetic recipients transplanted through 2000-2011 were identified. Patients were categorized based on pre-transplant dialysis time (DT): preemptive recipients (P-LDK, n = 498; P-SPK, n = 1529), recipients with1 year of DT (0-1 year DT; LDK n = 582, SPK n = 1700), and those with 1-2 years DT (1-2 year DT; LDK n = 301, SPK n = 2212). Seven-year patient and kidney survival were examined.Compared with the P-SPK group, both 0-1 year DT and 1-2 year DT SPK recipients had lower 7-year patient survival (89, 8484% respectively; log-rank P-value versus P-SPK = 0.010.001). For LDK groups, DT1 year was associated with inferior patient survival (7-year survival 76% versus 87% for P-LDK, P-value versus P-LDK = 0.009). Comparing P-LDK to all other SPK groups, there was no significant difference in 7-year patient or kidney survival.Preemptive transplantation is associated with the highest patient survival in both LDK and SPK. Compared with the P-LDK group, DT1 year is associated with lower patient survival among LDK recipients, but there is no difference in survival with dialysis up to 2 years with SPK. These results highlight the differential impact of DT on LDK and SPK transplantation.

Posttransplant malignancy (PTM) is one of the leading causes of late death in kidney recipients. Those with a cancer history may be more prone to develop a recurrent or a new cancer. We studied the association between pretransplant skin cancer, PTM, death, and graft failure.Primary adult kidney recipients transplanted between 2005 and 2013 were included. Malignancy information was obtained from Organ Procurement Kidney Transplant Network/United Network for Organ Sharing registration and follow-up forms. Posttransplant malignancy was classified into skin cancer, solid tumor, and posttransplant lymphoproliferative disorder (PTLD). Competing risk and survival analysis with adjustment for confounders were used to calculate risk for PTM, death and graft failure in recipients with pretransplant skin cancer compared with those without cancer. Risk was reported in hazard ratios (HR) with 95% confidence interval (CI).The cohort included 1671 recipients with and 102 961 without pretransplant skin malignancy. The 5-year cumulative incidence of PTM in patients with and without a pretransplant skin cancer history was 31.6% and 7.4%, respectively (P0.001). Recipients with pretransplant skin cancer had increased risk of PTM (sub-HR [SHR], 2.60; 95% CI, 2.27-2.98), and posttransplant skin cancer (SHR, 2.92; 95% CI, 2.52-3.39), PTLD (SHR, 1.93; 95% CI, 1.01-3.66), solid tumor (SHR, 1.44; 95% CI, 1.04-1.99), death (HR, 1.20; 95% CI, 1.07-1.34), and graft failure (HR, 1.17; 95% CI, 1.05-1.30) when compared with those without pretransplant malignancy.Pretransplant skin cancer was associated with an increased risk of posttransplant skin cancer, PTLD, solid organ cancer, death and graft failure.

Author(s): Molnar, Miklos Z; Bunnapradist, Suphamai; Huang, Edmund; Krishnan, Mahesh; Nissenson, Allen R; Kovesdy, Csaba P; Kalantar-Zadeh, Kamyar | Abstract: BackgroundThe role of pre-transplant erythropoiesis-stimulating agent (ESA) responsiveness in affecting post-transplant outcomes is not clear.MethodsLinking the 5-year patient data of a large dialysis organization to the 'Scientific Registry of Transplant Recipients', we identified 8795 hemodialyzed patients who underwent first kidney transplantation. Mortality or graft failure, delayed graft function (DGF) and acute rejection risks were estimated by Cox regression [hazard ratio (HR)] and logistic regression, respectively.ResultsPatients were 48 ± 14 years old and included 38% women and 36% diabetics. Compared to renal allograft recipients who were in the first quartile of pre-transplant ESA responsiveness index (ERI), i.e. ESA dose divided by hemoglobin and weight, recipients in second, third and fourth quartiles had higher adjusted graft-censored death HR (and 95% confidence intervals) of 1.7 (1.0-2.7), 1.8 (1.1-2.9) and 2.3 (1.4-3.9) and higher death-censored graft failure HR of 1.6 (1.0-2.5), 2.0 (1.2-3.1) and 1.6 (0.9-2.6), respectively. No significant association between pre-transplant ERI and post-transplant DGF or acute rejection was detected.ConclusionsHigher pre-transplant ERI during the hemodialysis treatment period was associated with worse post-transplant long-term outcomes including increased all-cause death and higher risk of graft failure.

The majority of kidney transplant recipients in the United States receive antibody induction, but its impact on outcomes in living donor transplant is not well-described. We used Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) data as of November 2009 to compare acute rejection (AR) and graft survival among all primary adult living donor kidney recipients of no antibody induction, antithymocyte globulin (ATG) and interleukin-2 receptor antagonists (IL-2RA) in an earlier era (1998-2002; n=21,919) and a later era (2003-2008, n=26,837). The incidence of AR in the overall cohort decreased from 18.5% in 1998 to 8% in 2008. From 1998 to 2002, antibody induction was associated with a decreased risk of acute rejection at six months (RR 0.67, 95% CI 0.62-0.72) and one yr (RR 0.71, 0.65-0.76), while in the recent era, induction was not associated with acute rejection at six months (RR 0.97, 0.88-1.07) or one yr (RR 1.01, 0.91-1.10). There was no difference in graft survival over five yr with antibody induction in either era. Although antibody induction was associated with a decreased risk of AR from 1998 to 2002, it was not associated with a decreased risk of acute rejection from 2003 to 2008, nor was it associated with a difference in graft survival in either era.

Introduction. Delayed graft function (DGF) and slow graft function (SGF) due to ischemic and reperfusion injury (IRI) are common complications of deceased donor kidney transplantation. We tested whether a panel of serum and urine cytokines represent early biomarkers for DGF and SGF. Methods. We collected serum and urine samples from 61 patients 48 hours posttransplantation and used a multiplex enzyme-linked immunosorbent assay (ELISA) technique to measure levels of 23 cytokines. Fourteen patients developed poor graft function (PGF), with 6 having DGF and 8 with SGF. Results. Area under receiver operation characteristics curve (AUC) demonstrated the following: serum levels of SCF (0.88) and interleukin (IL) 16 (0.74). Conclusions. This study showed that a select panel of cytokines measured early post kidney transplantation may predict poor graft function.

There is an increase in the older incident end-stage renal disease population that is associated with an increasing prevalence of end-stage renal disease in the United States. This trend is paralleled by an increasing rate of kidney transplantation in the elderly. Although patient survival is lower in older versus younger kidney recipients, the elderly benefit from a reduction in mortality rate and improved quality of life with transplantation compared with dialysis. Immunologic, physiologic, and psychosocial factors influence transplant outcomes and should be recognized in the care of the elderly transplant patient. In this review, we discuss transplantation in the elderly patient, particularly the topics of access to transplantation, patient and graft survival, the impact of donor quality on transplant outcomes, immunology and immunosuppression of aging, and ethical considerations in the development of an equitable organ allocation scheme.

BK virus nephropathy is an important cause of kidney allograft failure. Retransplantation has been successfully performed for patients with previous allograft loss due to BK virus nephropathy; however, whether allograft nephrectomy and viral clearance are required prior to retransplantation is controversial. Some recent studies have suggested that retransplantion can be successfully achieved without allograft nephrectomy if viremia is cleared prior to retransplant. The only published experience of successful retransplantation in the presence of active viremia occurred in the presence of concomitant allograft nephrectomy of the failing kidney. In this report, we describe a case of successful repeat kidney transplant in a patient with high-grade BK viremia and fulminant hepatic failure without concomitant allograft nephrectomy performed under the setting of a simultaneous liver-kidney transplant.

Posttransplant malignancy is a major cause of death in orthotopic heart transplant recipients. Our study objective is to identify whether pretransplant malignancy increases the risk for posttransplant malignancy.Using the Organ Procurement and Transplantation Network/United Network for Organ Sharing database, adult (≥18 years old) recipients of a primary orthotopic heart transplant performed between 2000 and 2012 were included. The cohort was stratified according to the presence and type of pretransplant malignancy. Outcomes were posttransplant overall, skin, solid malignancies, and posttransplant lymphoproliferative disorder. Incidence of and time to first posttransplant malignancy, accounting for death as a competing event, were calculated. Fine and Gray competing risks regression was performed to examine risk factors associated with posttransplant malignancy.Of 23,171 recipients, overall posttransplant malignancy was diagnosed in 2673 recipients (11.5%).The median time to overall, skin, solid posttransplant malignancies, and posttransplant lymphoproliferative disorder were 3.2 (1.6-5.7), 3.2 (1.7-5.6), 3.5 (1.7-5.9), and 2.5 years(0.8-5.2), respectively. Pretransplant malignancy increased the risk of posttransplant overall (subhazard ratio [SHR], 1.51; 95% confidence interval [95% CI], 1.27-1.81), skin (SHR, 1.55, 95% CI, 1.23-1.93), and solid organ malignancies (SHR, 1.54; 95% CI, 1.13-2.11). Pretransplant skin malignancy increased the risk of posttransplant skin malignancy (SHR, 2.79; 95% CI, 1.82-4.28). Pretransplant solid malignancy also increased the risk of posttransplant skin malignancy (SHR, 1.55; 95% CI, 1.07-2.25) but not of posttransplant solid tumors (SHR, 1.23; 95% CI, 0.69-2.19). Older, male, and white were also risk factors for posttransplant malignancy.A history of any pretransplant malignancy was associated with increased risks of skin and solid malignancies after transplantation. The specific type of posttransplant malignancy risk differed according to the type of pretransplant malignancy.

Background Advanced fibrosis or cirrhosis is still regarded as a contraindication for kidney transplantation alone by most centers. The value of aminotransferase to platelet ratio index (APRI) and other non-invasive markers has been less studied in hepatitis C virus (HCV)-positive patients with concurrent end-stage renal disease to predict hepatic fibrosis. Can these be used to effectively decrease the number of biopsies done in these patients being evaluated for transplantation? Methods Our study population included 255 patients with liver biopsy data. All patient information was collected and reviewed from medical records. The diagnostic accuracy of the predictive models was analyzed by calculating sensitivity, specificity, positive predictive value and negative predictive value. Results The variables associated with F3-F4 were aspartate aminotransferase (P = 0.007), bilirubin (P ≤ 0.001), platelet count (P = 0.01) and APRI (P ≤ 0.001). The use of any one laboratory abnormality to predict liver biopsy scores did not show high positive predictive values (22.6-72.7%). Having abnormal liver findings or cirrhosis on imaging was associated with high specificities (92.0-97.8%) but low sensitivities (31.4-42.9%). Using APRI levels of ≥0.40 and ≤0.95 as an indication for liver biopsy, 50% of patients with F3-F4 would have correctly avoided having a biopsy. However, 33% of patients with F3-F4 would have been mislabeled and not be indicated for biopsy. Conclusions Our data suggest that there may not currently be a simple and sufficiently accurate non-invasive test to replace liver biopsy in renal transplant workup for HCV-positive patients. The risks outweigh the benefits when it comes to using non-invasive markers like the APRI.

BACKGROUND: Studies from older cohorts of kidney recipients have observed that recipients with sickle cell disease (SCD) have lower patient survival compared with age- and race-matched controls. We examined whether survival has improved among SCD recipients in the current era. METHODS: Using Organ Procurement and Transplantation Network/United Network for Organ Sharing data, all black/African-American kidney recipients were stratified according to transplant year into an early (1988-99) and recent era (2000-11). Patient and allograft survival among SCD recipients and those with other diagnoses were compared (early era: SCD n = 67, others n = 20 694; recent era: SCD n = 106, others n = 34 428). A secondary-matched cohort analysis compared patient and allograft survival between SCD recipients matched to recipients with other diagnoses based on recipient and donor age, gender and donor type (deceased versus living). RESULTS: Patient survival at 6 years was lower among SCD recipients in the early era compared with other diagnoses (55.7 versus 78.0%; P < 0.001). Six-year patient survival among sickle cell recipients improved in the recent era (69.8%; P versus early era = 0.04), although still trended toward lower survival compared with other diagnoses (80.0%; P = 0.07). Multivariate Cox proportional hazard models revealed an increased mortality risk with SCD in both eras [early: hazard ratio (HR) = 3.12; 95% confidence interval (CI): 2.15-4.54; recent: HR: 2.03; 95% CI: 1.31-3.16]. Patient survival among matched SCD recipients in the recent era was comparable to diabetic recipients (SCD: 73.1%, diabetes: 74.1%; P = 0.44). CONCLUSIONS: Patient survival has improved among contemporary sickle cell recipients compared with an earlier cohort and is comparable to a matched cohort of diabetic kidney recipients. Appropriately selected SCD patients may receive kidney transplants with reasonable survival outcome.

Recent studies show a survival advantage with kidney transplant in elderly patients compared with those on dialysis therapy.In our present study, we examined and compared the association of expanded criteria donor (ECD) kidney and living kidney donation with the outcome of kidney transplant across different ages, including elderly recipients.Using the Scientific Registry of Transplant Recipients, we identified 145,470 adult kidney transplant patients. Mortality and death-censored transplant failure risks were estimated by Cox proportional regression analyses during follow-up with a median of 3.9 years.ECD kidney and living kidney donation and age compared with others.Mortality and death-censored transplant failure risk.Patients were aged 45 ± 16 years and included 40% women and 19% patients with diabetes. Compared with transplant recipients 55 to younger than 65 years, the fully adjusted death-censored transplant failure risk was higher in patients 75 years and older (HR, 1.30; 95% CI, 1.09-1.56), 35 to younger than 55 years (HR, 1.13; 95% CI, 1.08-1.17), and 18 to younger than 35 years (HR, 1.64; 95% CI, 1.57-1.71). Compared with non-ECD kidneys, ECD kidneys were significant predictors of mortality in nonelderly patients (18-35 years: HR, 1.46 [95% CI, 1.19-1.77]; 35-55 years: HR, 1.23 [95% CI, 1.14-1.32]; and 55-65 years: HR, 1.26 [95% CI, 1.15-1.38]) and patients 65 to younger than 70 years (HR, 1.20; 95% CI, 1.05-1.36), but not in other groups of elderly patients (HRs of 1.12 [95% CI, 0.93-1.36] for 70-75 years and 1.04 [95% CI, 0.74-1.47] for ≥75 years). Similar results were found for risk of transplant loss. Compared with deceased donor kidneys, a living donor kidney was associated with better survival in all age groups and lower transplant loss risk in patients younger than 70 years.Unmeasured confounders cannot be adjusted for.For deceased donors, ECD kidneys are not associated with increased mortality or transplant failure in recipients older than 70 years. For all types of donors, the persistent association between living donor kidneys and lower all-cause mortality across all ages suggests that, if possible, elderly patients gain longevity from living donor kidney transplant.

OBJECTIVE Observational studies have yielded inconsistent findings regarding the association of hemoglobin A1c (HbA1c) with survival in diabetic patients on dialysis. The association between pretransplant glycemic control and short- and long-term posttransplant outcomes in kidney transplant recipients is not clear. RESEARCH DESIGN AND METHODS Linking the 5-year patient data of a large dialysis organization (DaVita) to the Scientific Registry of Transplant Recipients, we identified 2,872 diabetic dialysis patients who underwent first kidney transplantation. Mortality or graft failure and delayed graft function (DGF) risks were estimated by Cox regression (hazard ratio [HR]) and logistic regression (odds ratio), respectively. RESULTS Patients were 53 ± 11 years old and included 36% women and 24% African Americans. In our fully adjusted model, allograft failure–censored, all-cause death HR and 95% CI for time-averaged pretransplant HbA1c categories of 7 to CONCLUSIONS Poor pretransplant glycemic control appears associated with decreased posttransplant survival in kidney transplant recipients, whereas allograft outcomes may not be affected.

Background Prior studies have indicated that type 1 diabetic (T1DM) recipients of a simultaneous pancreas-kidney (SPK) transplant have greater short-term mortality compared with living donor kidney (LDK) transplantation. Whether this association remains and how outcomes compare to deceased donor kidney (DDK) transplantation in the preemptive setting are unknown. Methods Using data on recipients transplanted between 2000 and 2010 from the Organ Procurement and Transplantation Network/United Network of Organ Sharing, patient and graft survival (calculated from the time of kidney transplant) of pancreas after preemptive LDK (PALK, n=389), preemptive LDK not receiving a pancreas transplant (LDK/noP, n=289), preemptive DDK (n=112), and preemptive SPK transplantations (n=1402) were compared. Results At 6 years, patient survival was excellent (PALK=89.4%, LDK/noP=84.9%, DDK=81.2%, and SPK=91.1%) and not different between PALK, LDK/noP, and SPK (P value vs. PALK: LDK/noP=0.08; SPK=0.85) but was lower with preemptive DDK versus preemptive PALK (P=0.03). When both LDK groups were considered together, there was higher mortality in the first 180 days after transplant with preemptive DDK (3.7% vs. 1.1%; P=0.03) and similar mortality with preemptive SPK (2.3%; P=0.07). After multivariate adjustment, there was a trend toward increased risk of death with preemptive DDK compared with preemptive PALK (hazard ratio: 1.91; 95% confidence interval: 0.95-3.84). Conclusions Patient survival associated with preemptive transplantation among T1DM recipients was excellent at 6 years, with the greatest survival favoring PALK, LDK/noP, and SPK rather than DDK. In contrast with prior studies reporting greater short-term mortality with SPK among the general T1DM population, short-term mortality after preemptive transplant is similar between LDK and SPK.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by age-dependent growth of kidney cysts with end-stage renal disease developing in approximately 50% of affected individuals. Living donors from ADPKD families are at risk for developing ADPKD and may be excluded from renal donation if the diagnosis cannot be conclusively ruled out. Radiographic imaging may be adequate to screen for kidney cysts in most at-risk donors but may fail to identify affected individuals younger than 40 years or older individuals from families with mild disease. In this article, we report a strategy that incorporates genetic testing in the evaluation of live kidney donors at risk for ADPKD whose disease status cannot be established with certainty on the basis of imaging studies alone. We show that DNA diagnostics can be used to enhance safe donation for certain living donor candidates at risk for ADPKD.

Background. The use of alemtuzumab for induction therapy in kidney transplantation has been increasing. Herein is a report of graft outcomes associated with alemtuzumab induction from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database. Methods. A total of 14,362 deceased donor kidney transplants from 2003 to 2004 received no induction (n=4,364), antithymocyte globulin (ATG; n=4,930), interleukin-2 receptor antagonists (IL-2RA; n=4,378), or alemtuzumab (n=690). Acute rejection within the initial hospitalization, 6 months, and 1 year; graft survival; and rejection-free survival were examined. Graft and rejection-free survival of alemtuzumab recipients maintained with tacrolimus (FK) or cyclosporine (CSA), mycophenolate mofetil (MMF), and steroids versus no calcineurin inhibitors (CNI), MMF, and steroids were compared. Results. Alemtuzumab recipients had less acute rejection during the initial hospitalization (2.3%) than no induction, ATG, and IL-2RA (7.6%, 3.4%, and 4.8%, respectively; P

BACKGROUND: New-onset diabetes mellitus after kidney transplantation (NODM) is an important co morbid condition that is associated with inferior graft and patient survival. The objective of this study was to identify donor, recipient and transplant factors, and choices of immunosuppression associated with development of NODM using Organ Procurement Transplant Network/United Network of Organ Sharing database (OPTN/UNOS). METHODS: From January 2004 to December 2005, 15,309 adult kidney transplants alone with at least one follow-up report as of March 2006 were identified in the OPTN/UNOS database. Among these, 1,581 patients developed NODM during the follow-up period. We examined the risk factors of NODM using multivariate Cox regression analysis using the time to diagnosis of NODM as a time-varying end point. Other events such as graft loss, patient death, and lost to follow-up were censored. RESULTS: NODM was reported in 10% in our study population with mean follow-up time of 306 days. After adjusting for other known factors, independent factors associated with the development of NODM included recipient age (29% increase of relative risk [RR] for every 10-year age increment), obesity (RR = 1.39 for body mass index [BMI] 25-30 and RR = 1.85 for BMI > 30 vs. BMI < 25), tacrolimus use (RR = 1.50), hepatitis C virus (HCV) positivity (RR = 1.42), and African-American recipients (RR = 1.32). Alemtuzumab was associated with a lower risk of NODM (RR = 0.52). DISCUSSION: Using OPTN/UNOS database, we identified risk factors for development of NODM. Some of these factors are potentially modifiable, including obesity, HCV infection, and the use of tacrolimus. Clinical trials are needed to assess whether modifying these "modifiable risk factors" will indeed prevent NODM.

The epithelial tight junction (TJ) has three major functions. As a “gate,” it serves as a regulatory barrier separating and maintaining biological fluid compartments of different composition. As a “fence,” it generates and maintains the apicobasal polarity of cells that form the confluent epithelium. Finally, the TJ proteins form a trafficking and signaling platform that regulates cell growth, proliferation, differentiation, and dedifferentiation. Six examples are selected that illustrate the emerging link between TJ dysfunction and kidney disease. First, the glomerular slit diaphragm (GSD) is evolved, in part, from the TJ and, on maturation, exhibits all three functions of the TJ. GSD dysfunction leads to proteinuria and, in some instances, podocyte dedifferentiation and proliferation. Second, accumulating evidence supports epithelial-mesenchymal transformation (EMT) as a major player in renal fibrosis, the final common pathway that leads to end-stage renal failure. EMT is characterized by a loss of cell-cell contact and apicobasal polarity, which are hallmarks of TJ dysfunction. Third, in autosomal dominant polycystic kidney disease, mutations of the polycystins may disrupt their known interactions with the apical junction complex, of which the TJ is a major component. This can lead to disturbances in epithelial polarity regulation with consequent abnormal tubulogenesis and cyst formation. Fourth, evidence for epithelial barrier and polarity dysregulation in the pathogenesis of ischemic acute renal failure will be summarized. Fifth, the association between mutations of paracellin-1, the first TJ channel identified, and clinical disorders of magnesium and calcium wasting and bovine renal fibrosis will be used to highlight an integral TJ protein that can serve multiple TJ functions. Finally, the role of WNK4 protein kinase in shunting chloride across the TJ of the distal nephron will be addressed.

Establishing and maintaining adequate vascular access is essential to providing an appropriate dialysis dose in patients with end-stage renal disease. Complications related to vascular access have a significant role in dialysis-related morbidity and mortality. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) clinical practice guideline for dialysis access was last updated in 2000 and provides a framework for the optimal establishment and maintenance of dialysis access, and treatment of complications related to dialysis access. This paper reviews the 2000 K/DOQI dialysis access guideline as well as updated information published subsequently.