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We report a 36-year-old female with mixed nephritic-nephrotic syndrome and recurrent pancreatitis. Kidney biopsy showed a crescentic membranoproliferative glomerulonephritis with dominant C3 staining on immunofluorescence (IF) but only scant deposits on electron microscopy (EM) and instead, evidence of severe acute and chronic microangiopathy - endothelial swelling, sub-endothelial fluff, and segmental basement membrane remodeling. Her serum C3 was normal, Factor Ba, and serum Membrane attack complex (sMAC) levels were elevated, and Properdin was low. Genetic testing revealed a heterozygous ultra rare C3 variant of unknown significance (c.4838GT, p.Gly1613Val) as well as a heterozygous deletion of CFHR3-CFHR1. She showed an initial response to terminal complement blockade with eculizumab, but her renal disease progressed in the next year. Notably, our patient never demonstrated microangiopathic hemolysis, yet pancreatitis of unclear etiology recurred periodically. Our case suggests the existence of a "C3G/aHUS overlap" clinicopathologic syndrome and highlights the challenges of treating complement-mediated kidney disease.

Donor-specific antibodies (DSA) against HLA are an important biomarker predicting graft injury, rejection (Rej), and failure in various solid-organ transplant recipients. However, the impact of DSA with or without histopathological evidence of rejection among pancreas transplant recipients (PTRs) is unknown.In this study, we included all PTRs at our center between 2005 and 2020, with pancreas allograft biopsy before March 31, 2021, and with DSA checked within 15 d of the biopsy. PTRs were divided into 4 groups based on the biopsy findings on the index biopsy and DSA status as Rej-/DSA-, Rej+/DSA-, Rej-/DSA+, and Rej+/DSA+.Two hundred two PTRs had a pancreas allograft biopsy during the study period. Thirty-nine were in Rej-/DSA-, 84 Rej+/DSA-, 24 Rej-/DSA+, and 55 Rej+/DSA+. The mean interval from transplant to index biopsy was not statistically different between the 4 groups. The most common type of rejection was T cell-mediated rejection; however, antibody-mediated rejection was more prevalent in the Rej+/DSA+ group. At 5 y postbiopsy, the rate of death-censored graft failure (DCGF) for Rej-/DSA- was 18%, 24% in Rej+/DSA-; 17% in Rej-/DSA+ and 36% in Rej+/DSA+ (P = 0.14). In univariate analysis, mixed rejection (hazard ratio [HR], 3.0; 95% confidence intervals [CI], 1.22-7.39; P = 0.02) along with solitary pancreas transplantation and Rej+/DSA+ were associated with DCGF. In multivariate analysis, compared with Rej-/DSA-, Rej+/DSA+ was significantly associated with DCGF (HR, 2.32; 95% CI, 1.03-5.20; P = 0.04); however, Rej+/DSA- was not (HR, 1.06; 95% CI, 0.32-3.56; P = 0.92).PTRs with pancreas allograft rejection and concomitant DSA have an increased risk of DCGF.

Chronic kidney disease involves disturbances in iron metabolism including anemia caused by insufficient erythropoietin (EPO) production. However, underlying mechanisms responsible for the dysregulation of cellular iron metabolism are incompletely defined. Using the unilateral ureteral obstruction (UUO) model in Irp1(+/+) and Irp1(−/−) mice, we asked if iron regulatory proteins (IRPs), the central regulators of cellular iron metabolism and suppressors of EPO production, contribute to the etiology of anemia in kidney failure. We identified a significant reduction in IRP protein level and RNA binding activity that associates with a loss of the iron uptake protein transferrin receptor 1 (TfR1), increased expression of the iron storage protein subunits H- and L-ferritin, and a low but overall variable level of stainable iron in the obstructed kidney. This reduction in IRP RNA binding activity and ferritin RNA levels suggests the concomitant rise in ferritin expression and iron content in kidney failure is IRP dependent. In contrast, the reduction in the Epo mRNA level in the obstructed kidney was not rescued by genetic ablation of IRP1, suggesting disruption of normal hypoxia-inducible factor (HIF)-2α regulation. Furthermore, reduced expression of some HIF-α target genes in UUO occurred in the face of increased expression of HIF-α proteins and prolyl hydroxylases 2 and 1, the latter of which is not known to be HIF-α mediated. Our results suggest that the IRP system drives changes in cellular iron metabolism that are associated with kidney failure in UUO but that the impact of IRPs on EPO production is overridden by disrupted hypoxia signaling. NEW & NOTEWORTHY This study demonstrates that iron metabolism and hypoxia signaling are dysregulated in unilateral obstructive nephropathy. Expression of iron regulatory proteins (IRPs), central regulators of cellular iron metabolism, and the iron uptake (transferrin receptor 1) and storage (ferritins) proteins they target is strongly altered. This suggests a role of IRPs in previously observed changes in iron metabolism in progressive renal disease. Hypoxia signaling is disrupted and appeared to dominate the action of IRP1 in controlling erythropoietin expression.

We studied the variation in molecular T cell-mediated rejection (TCMR) activity in kidney transplant indication biopsies and its relationship with histologic lesions (particularly tubulitis and atrophy-fibrosis) and time posttransplant.We examined 175 kidney transplant biopsies with molecular TCMR as defined by archetypal analysis in the INTERCOMEX study (ClinicalTrials.gov #NCT01299168). TCMR activity was defined by a molecular classifier.Archetypal analysis identified 2 TCMR classes, TCMR1 and TCMR2: TCMR1 had higher TCMR activity and more antibody-mediated rejection ("mixed") activity and arteritis but little hyalinosis, whereas TCMR2 had less TCMR activity but more atrophy-fibrosis. TCMR1 and TCMR2 had similar levels of molecular injury and tubulitis. Both TCMR1 and TCMR2 biopsies were uncommon after 2 y posttransplant and were rare after 10 y, particularly TCMR1. Within late TCMR biopsies, TCMR classifier activity and activity molecules such as IFNG fell progressively with time, but tubulitis and molecular injury were sustained. Atrophy-fibrosis was increased in TCMR biopsies, even in the first year posttransplant, and rose with time posttransplant. TCMR1 and TCMR2 both reduced graft survival, but in random forests, the strongest determinant of survival after biopsies with TCMR was molecular injury, not TCMR activity.TCMR varies in intensity but is always strongly related to molecular injury and atrophy-fibrosis, which ultimately explains its effect on survival. We hypothesize, based on the reciprocal relationship with hyalinosis, that the TCMR1-TCMR2 gradient reflects calcineurin inhibitor drug underexposure, whereas the time-dependent decline in TCMR activity and frequency after the first year reflects T-cell exhaustion.

Background Chronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials. Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR. Methods IMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) 2, or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia. Discussion IMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR. Trial registration ClinicalTrials.govNCT03744910. Registered on November 19, 2018.

BackgroundLong-term kidney allograft survival remains suboptimal. Emerging evidence indicates donor-recipient (D-R) mismatches outside of human leukocyte antigens (HLA) contribute to graft survival but mechanisms remain unclear, specifically for those mismatches within intronic regions.MethodsWe analyzed genome-wide SNP data of D-R pairs from two well-phenotyped kidney transplant cohorts (median follow-up ~1800 days), Genomics of Chronic Allograft Rejection (GoCAR; n=385) and Clinical Trials in Organ Transplantation 1/17 (CTOT1/17; n=146), quantifying genetic mismatches outside of HLA for every D-R pair at variant, gene, and genome-wide scales.ResultsUnbiased genome-wide screen of GoCAR D-R pairs uncovered the LIMS1 locus as the topranked candidate where D-R mismatches associated with death censored graft loss (DCGL). Independent of HLA, a previously unreported relationship between mismatches at a highly linked, intronic haplotype of 30 SNPs was seen as associated with DCGL, with confirmatory association in intra-ancestry D-Rs. Validation testing within the CTOT-01/17 showed similar associations with DCGL. Haplotype D-R mismatches showed a dosage effect, and the introduction of minor alleles in the donor to major allele-carrying recipients showed a greater risk of DCGL. Both the new LIMS1 haplotype and the previously reported LIMS1 SNP rs893403 are expression quantitative trait loci (eQTL) for the gene GCC2 in recipient immune cells, without alterations in GCC2 or LIMS1 coding sequences. Transcriptome enrichment analyses performed on whole blood and within multiple T cell subsets demonstrated significant associations of GCC2 gene, and of either allelic locus, with regulation of TGF-beta-SMAD signaling, implying a role in Treg function and association with rejection.ConclusionsOur analysis unravels intronic non-HLA SNP mismatches within LIMS1 that do not induce protein sequence variation but associate with DCGL. By acting as cis-eQTLs for GCC2 expression, these SNPs modulates TGF-beta signaling and T cell function, associating with immune events and graft outcomes. The findings have clinical implications for risk assessment and individualized therapy in kidney transplant recipients.

The effects of HLA mismatching on pancreas outcomes among pancreas after kidney (PAK) recipients are undefined. Outcomes might potentially differ depending on whether there is a mismatch between pancreas donor and recipient (PD-R) or pancreas donor and kidney donor(PD-KD). All primary PAK at our centre were included in this study. Patients were divided into two groups based on the degree of HLA mismatching: low (L-MM) as 0-4 and high (H-MM) as 5-6. We analysed all (N = 73) PAK for PD-R mismatch and the subset of PAK for PD-KD mismatch (N = 71). Comparing PD-R L-MM (n = 39) and H-MM (n = 34) PAKs, we observed no difference in the rate of pancreas graft failure. There was also no difference in the rate of rejection (L-MM 33% vs. H-MM 41%) or the severity of rejection. However, we observed a significantly (P

Introduction Peritoneal dialysis (PD) has been used increasingly in past decade. Many of these patients undergo transplantation and may require dialysis for delayed graft function (DGF). The outcomes of DGF based on the post-transplantation dialysis modality are not well known. Methods We retrospectively reviewed all adult kidney transplant recipients (KTRs) from the University of Wisconsin School of Medicine and Public Health who developed DGF between November 2015 and April 2019. Patients were divided into those who received hemodialysis (HD) or PD during the DGF period. Immediate graft explant, DGF among living donor KTRs, or those requiring just a single dialysis treatment were excluded. Results Of 224 KTRs with DGF during the study period, 167 fulfilled our selection criteria. There were 16 patients in the PD and 151 in the HD group. Baseline characteristics were similar between the two groups, except diabetes was more prevalent in the HD group. Five of 16 PD patients had to be transitioned to HD. There was no difference in DGF duration, hospital length of stay, infectious or surgical complications, rejection at various time periods, graft function at last follow-up, or graft failure. In multivariate analysis, only rejection within the first year of transplantation (hazard ratio [HR]: 4.26; 95% confidence interval [CI]: 1.20–15.08; P = 0.02) and post-surgical complications (HR: 3.79; 95% CI: 1.03– 13.91; P = 0.04) were associated with death-censored graft failure (DCGF). The use of PD for treatment of DGF was not associated with DCGF. Conclusions In carefully selected patients, PD can be continued safely for DGF without any effect on short-term or long-term transplant outcomes., Graphical abstract

Introduction It is critical to identify kidney transplant recipients (KTRs) at higher risk for adverse outcomes, to focus on monitoring and interventions to improve outcomes. We examined the associations between graft function variability and long-term outcomes in KTRs in an observational study. Methods We identified 2919 KTRs in the Wisconsin Allograft Recipient Database (WisARD) who had a functioning allograft 2 years posttransplantation and at least 3 outpatient measurements of estimated glomerular filtration rate (eGFR) from 1 to 2 years posttransplantation. Graft function slope was calculated from a linear regression of eGFR, and variability was defined as the coefficient of variation around this regression line. Associations of eGFR variability and slope with death, graft failure, cardiovascular events, and acute rejection were estimated. Results Compared to the lowest quartile, the highest quartile of eGFR variability was associated with a higher risk of death (adjusted hazard ratio [HR] = 1.85; 95% CI = 1.23−2.76), but not with a higher risk of graft failure (subhazard ratio = 1.16; 95% CI = 0.85−1.58), independent of eGFR and slope of eGFR. Greater eGFR variability was associated with higher risk of cardiovascular- and infection-related death and cardiovascular events but not malignancy-related death or allograft rejection. Including variability of eGFR significantly improved prediction of mortality but not prediction of graft failure. Conclusion Variability of eGFR is independently associated with risk of death, especially cardiovascular disease−related death and cardiovascular events, but not graft failure. Variability of eGFR may help identify KTRs at higher risk for death and cardiovascular events., Graphical abstract

Delayed graft function (DGF) is a common complication among deceased donor kidney transplant recipients (DDKTs) and is associated with worse outcomes. The effect on outcomes of concordance versus discordance in DGF between two different recipients of kidneys from the same donor is largely unknown.We reviewed all adult DDKTs for which both kidneys were transplanted to two different recipients at our center between 2014-2019. DDKTs were divided into four groups based on the DGF status: concordance no DGF (cc-no-DGF); discordance no DGF(dd-no-DGF); discordance DGF (dd-DGF) and concordance in DGF (cc-DGF). Acute rejection (AR) and death censored graft failure (DCGF) were outcomes of interest.A total of 578 DDKTs fulfilled our selection criteria, 280were in cc-no-DGF, 83 in dd-no-DGF, 83 in dd-DGF, and 132 in cc-DGF. Compared to cc-no-DGF, in univariate analysis, dd-DGF was associated with an increased risk of AR (HR: 1.60; 95% CI: 1.0-2.56) but cc-DGF was not (HR: 1.01; 95% CI: 0.63-1.62). dd-DGF was not associated with an increased risk of AR in multivariate analysis. In multivariate analysis, dd-DGF was associated with an increased risk of DCGF (HR: 2.70; 95% CI: 1.05-6.93) but cc-DGFwas not (HR: 2.36; 95% CI: 0.97-5.70).Discordance in DGF is associated with worse outcomes and may need closefollow-up and monitoring to improve the outcomes.

Cytomegalovirus (CMV) and BK virus (BKV) are common viral infections after kidney transplant. Their negative effects on patient and graft outcomes have been well described. However, despite improvement in screening and prophylaxis strategies, CMV and BKV continue to negatively affect both short- and long-term graft survival. Adequate cell-mediated immunity is essential for the control and prevention of opportunistic viral infections, such as CMV and BKV. Therefore, immune reconstitution, in particular T cell recovery, is a key factor in antiviral control after kidney transplantation. Cell-based immunotherapy offers an attractive alternative approach to traditional interventions. Adoptive T cell transfer, via infusions of allogeneic virus-specific T lymphocytes is capable of restoring virus-specific T cell immunity, and are safe and effective in the treatment of viral infections after hematopoietic stem cell transplantation. In this article, we review the emerging role of virus-specific T cell therapy in the management of CMV and BKV after kidney transplantation. On the basis of the available data, virus-specific T cell therapy may be a promising addition to the antiviral treatment armamentarium after kidney transplantation. Future studies are needed to more clearly define the efficacy and risks of virus-specific T cell therapy in the kidney transplant population.

Incompatible living donor kidney transplant recipients (ILDKTr) have pre-existing donor-specific antibody (DSA) that, despite desensitization, may persist or reappear with resulting consequences, including delayed graft function (DGF) and acute rejection (AR). To quantify the risk of DGF and AR in ILDKT and downstream effects, we compared 1406 ILDKTr to 17 542 compatible LDKT recipients (CLDKTr) using a 25-center cohort with novel SRTR linkage. We characterized DSA strength as positive Luminex, negative flow crossmatch (PLNF); positive flow, negative cytotoxic crossmatch (PFNC); or positive cytotoxic crossmatch (PCC). DGF occurred in 3.1% of CLDKT, 3.5% of PLNF, 5.7% of PFNC, and 7.6% of PCC recipients, which translated to higher DGF for PCC recipients (aOR = 1.03 1.682.72 ). However, the impact of DGF on mortality and DCGF risk was no higher for ILDKT than CLDKT (p interaction > .1). AR developed in 8.4% of CLDKT, 18.2% of PLNF, 21.3% of PFNC, and 21.7% of PCC recipients, which translated to higher AR (aOR PLNF = 1.45 2.093.02 ; PFNC = 1.67 2.403.46 ; PCC = 1.48 2.243.37 ). Although the impact of AR on mortality was no higher for ILDKT than CLDKT (p interaction = .1), its impact on DCGF risk was less consequential for ILDKT (aHR = 1.34 1.621.95 ) than CLDKT (aHR = 1.96 2.292.67 ) (p interaction = .004). Providers should consider these risks during preoperative counseling, and strategies to mitigate them should be considered.

Kidney is one of the most common organs affected by coronavirus disease 2019 (COVID-19) after the respiratory and immune systems. Among the renal parenchymal components, the tubulointerstitial compartment is presumed to be the prime target of injury in COVID-19. The main mechanism of renal tubular damage by COVID-19 is considered to be indirect, i.e., cytokine-mediated injury. A proportion of infected individuals mount a strong inflammatory response to the virus by an exaggerated immune response of the body, namely cytokine storm. Sudden and massive release of cytokines may lead to serious systemic hyper-inflammation and renal tubular injury and inflammation resulting in acute renal failure. In addition, a number of cases of glomerulopathies, particularly collapsing glomerulopathy (CG) have been reported, predominantly in people of African ancestry, as a rare form of kidney involvement by SARS-CoV-2 that may originate from the background genetic susceptibility in this population complicated by the second hit of SARS-CoV-2 infection, either directly or indirectly. It is noteworthy that renal injury in COVID-19 could be severe in individuals of African origin due to the aforementioned genetic susceptibility, especially the presence of high-risk apolipoprotein L1 (APOL1) genotypes. Although the exact mechanism of kidney injury by SARS-CoV-2 is as yet unknown, multiple mechanisms are likely involved in renal damage caused by this virus. This review was aimed to summarize the salient points of pathogenesis of kidney injury, particularly glomerular injury in COVID-19 disease in the light of published data. A clear understanding of these is imperative for the proper management of these cases. For this review, a search was made of Google Scholar, Web of Science, Scopus, EBSCO and PubMed for finding English language articles related to COVID-19, kidney injury and glomerulopathy. From the information given in finally selected papers, the key aspects regarding glomerular involvement in COVID-19 were drawn out and are presented in this descriptive review.

Malaltia renal en fase terminal; Trasplantament de ronyó Enfermedad renal en etapa terminal; Transplante de riñón End-stage renal disease; Kidney Transplant Background. There are challenges in designing adequate, well-controlled studies of patients with active antibody-mediated rejection (AMR) after kidney transplantation (KTx). Methods. We assessed the functional relationship between change in estimated glomerular filtration rate (eGFR) following the diagnosis of AMR and the risk of subsequent death-censored graft failure using the joint modeling framework. We included recipients of solitary KTx between 1995 and 2013 at 4 transplant centers diagnosed with biopsy-proven active AMR at least 1 year post-KTx, who had a minimum of 3-year follow-up. Results. A total of 91 patients across participating centers were included in the analysis. Of the 91 patients, n = 54 patients (59%) met the death-censored graft failure endpoint and n = 62 patients (68%) met the all-cause graft failure composite endpoint. Kaplan-Meier death-censored graft survival rates at 12, 36, and 60 months postdiagnosis of AMR pooled across centers were 88.9%, 58.9%, and 36.4%, respectively. Spaghetti plots indicated a linear trend in the change in eGFR, especially in the first 12 months postdiagnosis of active AMR. A significant change in eGFR was observed within the first 12 months postdiagnosis of active AMR, getting worse by a factor of −0.757 mL/min/1.73 m2 per month during the 12-month analysis period (a delta of −9.084 mL/min/1.73 m2 at 1 y). Notably, an extrapolated 30% improvement in the slope of eGFR in the first 12 months was associated with a 10% improvement in death-censored graft failure at 5 years. Conclusions. If prospectively validated, this study may inform the design of pivotal clinical trials for therapies for late AMR.

BACKGROUND: Polycystic kidney disease (PKD) accounts for approximately 15% of kidney transplants, but long-term outcomes in patients with PKD who have received a kidney transplant are not well understood. METHODS: In primary recipients of kidney transplants at our center (1994–2014), we compared outcomes of underlying PKD (N=619) with other native diseases (non-PKD, N=4312). Potential factors influencing outcomes in PKD were evaluated using Cox proportional-hazards regression and a rigorous multivariable model. RESULTS: Patients with PKD were older and were less likely to be sensitized or to experience delayed graft function (DGF). Over a median follow-up of 5.6 years, 1256 of all recipients experienced death-censored graft failure (DCGF; 115 patients with PKD) and 1617 died (154 patients with PKD). After adjustment for demographic, dialysis, comorbid disease, surgical, and immunologic variables, patients with PKD had a lower risk of DCGF (adjusted hazard ratio [aHR], 0.73; 95% CI, 0.57 to 0.93; P=0.01) and death (aHR, 0.62; 95% CI, 0.51 to 0.75; P

Third-party vascular allografts (VAs) are an invaluable resource in kidney and pancreas transplantation when vascular reconstruction is needed and additional vessels from the organ donor are not available. We report the largest single-center experience to date on VA use, at a high-volume U.S. transplant center. Over a 7-year period, VAs were used for vascular reconstruction of 65 kidneys and 5 pancreases, in 69 recipients. The renal vein required reconstruction more often with right kidney transplantation (72.5% vs 27.5%, P < .001), and the renal artery required reconstruction more often with left kidney transplantation (67.6% vs 32.4%, P = .003). Eleven patients (15.9%) developed anti-VA de novo HLA donor-specific antibodies (dnDSAs) at a median time after transplantation of 19.0 months. Higher number of HLA mismatches between the VA donor and the recipient, and development of anti-organ allograft dnDSAs were significant predictors of anti-VA dnDSA development. Those with anti-VA dnDSAs had a higher rate of organ allograft rejection (45.4% vs 13.8%, P = .03) compared to those without, but there was no significant difference in incidence of vascular complications or graft outcomes. VAs can help circumvent challenging surgical situations. Anti-VA dnDSAs do not adversely affect organ allograft outcomes; however, they can contribute to HLA sensitization in the recipients.

BACKGROUND: Optimal induction for patients without pretransplant donor-specific antibodies (DSAs) is poorly defined. The goal of this study was to compare the incidence of de novo DSA (dnDSA) and graft outcomes between induction therapies in patients with a negative virtual crossmatch (VXM). METHODS: A retrospective chart review was performed, identifying 782 patients with a negative VXM who underwent kidney transplantation at a single, high-volume institution between January 2013 and May 2017. Kaplan–Meier analysis was used to assess the incidence of dnDSA and allograft survival between induction therapies in this group. dnDSA is defined as the development of new post-transplant DSA, at any MFI level. RESULTS: Induction therapy included alemtuzumab (N=87, 11%), basiliximab (N=522, 67%), and anti-thymocyte globulin (ATG; N=173, 22%). One-year graft survival was similar between groups (alemtuzumab, 100%; basiliximab, 98%; ATG, 99%). Incidence of acute rejection at 1 year was

There is conflicting data regarding the association of pre-transplant AT1R antibody levels and long-term outcomes following kidney transplantation.We examined the association between pre-transplant antibodies and long-term graft outcome by assaying pre-transplant sera from 125 kidney transplant recipients from 1999 to 2009.The mean age at transplant was 55.7 ± 13 years; 67.2% were male, 87.2% were Caucasian, and 67.2% received a deceased donor transplant. Induction therapy included 44.8% thymoglobulin. Human leukocyte antigen (HLA) donor-specific antibodies (DSA) were present in 22 (17.6%) patients, while AT1R antibodies 17 U/mL were present in 24 (19.2%). The mean AT1R antibodies level was 13 ± 7.2 U/mL. Patients were followed-up for 7.1 ± 1.9 years after transplant. Pre-transplant AT1R antibodies were associated with rejection (p 0.0001), antibody-mediated rejection (ABMR) (p 0.0001), and death-censored graft failure (DCGF) (p = 0.01). This was confirmed by univariate Cox regression analyses for AT1R antibodies 10 U/mL (HR 2.64, 95% Cl 1.35 - 5.17, p = 0.04) and AT1R antibodies 17 U/mL (HR = 1.74, 95% Cl 1.061 - 2.98, p = 0.04). Multivariable analyses did not retain AT1R antibodies as independent predictors of DCGF; however, pre-transplant HLA, DSA, and acute rejection during the first year were associated with DCGF (HR 2.07, 95% Cl 1.13 - 3.78, p = 0.02 and HR 3.03, 95% Cl 1.13 - 3.78, p = 0.0002, respectively).Our study indicates that in patients with a functioning kidney allograft 5 years, pre-transplant AT1R antibodies may be associated with a greater risk of rejection and late graft failure.

Kidney transplant recipients (KTR) present unique characteristics, including disease vintage, immunosuppression, and single functioning kidneys. We conducted preliminary analyses to assess the impact of coronavirus disease 2019 (COVID-19) on outcomes in KTR compared to nontransplant patients.We evaluated published information in peer-reviewed journals between January 1, 2020, and April 24, 2020, with available data on acute kidney injury (AKI), renal replacement therapy (RRT), intensive care unit (ICU) stay, and death and compared clinical outcomes in KTR vs nontransplant recipients with COVID-19.A total of 19 published articles were identified, including a total of 88 KTR and 5342 nontransplant patients. The sample size varied between 2 and 2634. Mean age was 58.6 years vs 58.9 years in KTR vs nontransplant patients. Patient-level incidence of AKI (27.5% vs 13.3%, P .001), RRT (15.4% vs 3.3%, P .001), ICU stay (34.1% vs 15.1%, P .001), and death (22.7% vs 16.2%, P = .10) was higher in KTR, representing relative risks of 2.06 (1.44, 2.96), 4.72 (2.62, 8.51), 2.25 (1.67, 3.03), and 1.41 (0.95, 2.08), respectively.Early results suggest that the KTR are at significantly higher risk of AKI, RRT, and ICU stay from SARS-CoV-19 infection compared to the general population. The risk of death may not be significantly different.

Background Kidney allograft biopsy is the gold standard for diagnosis of rejection. Under the current extraordinary circumstances of the coronavirus disease 2019 (COVID-19), where social distancing is key to limiting the spread of the virus, the model used to provide care to transplant recipients has undergone a very rapid transformation. In the spirit of medical distancing, we have been using the donor-derived cell-free DNA test for screening for rejection. Methods This manuscript describes our experience with this approach between March 15th and May 20th, 2020. Results This test was obtained for-cause in 23 patients and for monitoring in 9 patients. Normal results aided in foregoing biopsy in 63% of the patients where the test was obtained in the outpatient setting. The test is neither 100% sensitive nor specific for rejection; however, when used in combination with the available clinical information, can be used for determining whether bringing in a transplant recipient into a medical facility is necessary. Conclusions In the event the COVID-19 becomes a long-term challenge for our community, non-invasive biomarkers such as the donor-derived cell-free DNA may become more relevant than ever in enhancing our ability to care for our transplant patients while maximizing the distancing measures.

Purpose of review Antibody-mediated rejection (ABMR) is the leading cause of allograft failure in kidney transplant recipients. This article provides a summary of the clinical research relating to donor-specific antibodies (DSA) and ABMR in kidney transplant recipients at the University of Wisconsin-Madison Transplant Center. Recent findings Over 40% of the kidney transplant candidates on the UNOS waitlist are sensitized, and both preformed and de novo DSA are associated with increased risk of rejection and graft loss. We have developed graded induction-desensitization treatment and monitoring protocols based on the degree of immunologic risk. We have also implemented standard treatment and surveillance strategies for patients with ABMR. Additional important observations from our studies include high rates of ABMR in patients with positive C4d staining in postreperfusion biopsies and rise in DSA at 1 week after transplant, and increased risk of kidney allograft failure in patients with de novo DSA and ABMR, as well as in patients with HLA-DSA undetectable ABMR. We also found worse outcomes with de novo DSA following simultaneous pancreas--kidney and liver--kidney transplantation. Notably, favorable long-term graft outcomes were observed in patients with DSA who do not present the classic histopathological findings of ABMR. Summary In order to improve long-term outcomes for kidney transplant recipients, further research focusing on the pathogenic mechanisms elicited by HLA and non-HLA DSA, and novel therapies targeting these pathways is needed.

Delayed graft function (DGF) is a common complication associated with significant untoward effects in kidney-alone transplantation. The incidence and outcomes following kidney delayed graft function (K-DGF) among patients undergoing simultaneous pancreas-kidney (SPK) transplantation are less certain. We analyzed SPK recipients transplanted at our center between January 1994 and December 2017. A total of 632 recipients fulfilled the selection criteria, including 69 (11%) with K-DGF and 563 without. The incidence of K-DGF was significantly higher in recipients of organs from older donors and donation after circulatory death (DCD). The presence of K-DGF was significantly associated with an increased risk of pancreas graft failure during the first 90 days (n = 9, incidence rate [IR] 2.45/100 person-months), but not with late pancreas failure (n = 32, IR 0.84/100 person-months), kidney graft failure, or patient death. Although DCD was associated with K-DGF, it was not associated with either pancreas (hazard ratio [HR] 0.91, 95% CI 0.58-1.44, P = .69) or kidney (HR 1.09, 95% CI 0.66-1.82, P = .74) graft failure after adjustment for potential confounders. We found K-DGF to be a significant risk factor for pancreas graft failure but not kidney graft failure, with the major risk period being early (

Clinical application of biomarkers is an integral component of transplant care. Clinicians and scientists alike are in search of better biomarkers than the current serologic (serum creatinine, donor-specific antibodies), urine-derived (urinalysis, urine protein), and histologic ones we now use. The science behind recent biomarker discovery spans across multiple molecular biologic disciplines, including transcriptomics, proteomics, and metabolomics. Innovative methodology and integration of basic and clinical approaches have allowed researchers to unearth molecular phenomena preceding clinical disease. Biomarkers can be classified in several ways. In this review, we have classified them via their origin and outcome: Primarily immunologic, i.e., representative of immune regulation and dysfunction and non-immunologic, pertaining to delayed graft function, cardiovascular events/mortality, infection, malignancy, post-transplant diabetes, graft, and patient survival. Novel biomarker uses to guide the diagnosis and management of transplant-related outcomes is a promising area of research. However, the use of biomarkers to predict outcomes after kidney transplantation is not well studied. In this review, we summarize the recent studies illustrating biomarker use and transplant outcomes.

Background: The effects of delayed graft function on long-term kidney allograft outcomes are poorly defined among simultaneous liver and kidney transplant recipients. Methods: We analyzed data of all simultaneous liver and kidney recipients transplanted at the University of Wisconsin between 2010 and 2017. Risk factors for the development of delayed graft function, kidney graft failure, and patient mortality were outcomes of interest. Results: There were a total of 60 simultaneous liver and kidney recipients; 28 (47%) had delayed graft function. After adjustment for multiple variables, we found that pretransplant dialysis >6 weeks (hazard ratio [HR] = 5.6, 95% CI: 1.23-25.59, P = .02), pretransplant albumin Conclusion: The incidence of delayed graft function was high in simultaneous liver and kidney recipients. However, with appropriate management, delayed graft function may not have a negative impact on patient or kidney allograft survival.