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BACKGROUND: Kidney transplant recipients (KTRs) with COVID-19 have poor outcomes compared to non-KTRs. To provide insight into management of immunosuppression during acute illness, we studied immune signatures from the peripheral blood during and after COVID-19 infection from a multicenter KTR cohort.□ METHODS: Clinical data were collected by chart review. PAXgene blood RNA was poly-A selected and RNA sequencing was performed to evaluate transcriptome changes. RESULTS: A total of 64 cases of COVID-19 in KTRs were enrolled, including 31 acute cases (< 4 weeks from diagnosis) and 33 post-acute cases (>4 weeks). In the blood transcriptome of acute cases, we identified differentially expressed genes (DEGs) in positive or negative association COVID-19 severity scores. Functional enrichment analyses showed upregulation of neutrophil and innate immune pathways, but downregulation of T-cell and adaptive immune-activation pathways proportional to severity score. This finding was independent of lymphocyte count and despite reduction in immunosuppression (IS) in most KTRs. Comparison with post-acute cases showed “normalization” of these enriched pathways after >4 weeks, suggesting recovery of adaptive immune system activation despite reinstitution of IS. The latter analysis was adjusted for COVID-19 severity score and lymphocyte count. DEGs associated with worsening disease severity in a non-KTR cohort with COVID-19 (GSE152418) showed significant overlap with KTRs in these identified enriched pathways. CONCLUSION: Blood transcriptome of KTRs affected by COVID-19 shows decrease in T-cell and adaptive immune activation pathways during acute disease that associate with severity despite IS reduction and show recovery after acute illness. SIGNIFICANCE STATEMENT: Kidney transplant recipients (KTRs) are reported to have worse outcomes with COVID-19, and empiric reduction of maintenance immunosuppression is pursued. Surprisingly, reported rates of acute rejection have been low despite reduced immunosuppression. We evaluated the peripheral blood transcriptome of 64 KTRs either during or after acute COVID-19. We identified transcriptomic signatures consistent with suppression of adaptive T-cell responses which significantly associated with disease severity and showed evidence of recovery after acute disease, even after adjustment for lymphocyte number. Our transcriptomic findings of immune-insufficiency during acute COVID-19 provide an explanation for the low rates of acute rejection in KTRs despite reduced immunosuppression. Our data support the approach of temporarily reducing T –cell-directed immunosuppression in KTRs with acute COVID-19.

Characterization of anti-HLA versus anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) immune globulin isotypes in organ transplant recipients after coronavirus disease 2019 (COVID-19) infection has not been reported. We aimed to determine changes in anti-HLA antibodies in renal transplant patients with COVID-19 and compare the immunoglobulin and epitope-binding pattern versus anti-SARS-CoV-2 antibodies.This is a cross-sectional study of 46 kidney transplant recipients including 21 with longitudinal sampling. Using a semi-quantitative multiplex assay, we determined immunoglobulin (Ig) M, IgA, IgG, and IgG1-2-3-4 antibodies against Class I and Class II HLA, and 5 SARS-CoV-2 epitopes including the nucleocapsid protein and multiple regions of the spike protein.Fourteen of 46 (30%) patients had donor-specific anti-HLA antibodies (donor-specific antibody [DSA]), 12 (26%) had non-DSA anti-HLA antibodies and 45 (98%) had anti-SARS-CoV-2 antibodies. Most DSAs targeted HLA-DQ (71%), with a dominant IgG isotype and IgG1 subtype prevalence (93%), and/or IgG3 (64%), followed by IgG2 (36%). Comparatively, there was a higher prevalence of IgA (85% versus 14%, P = 0.0001) and IgM (87%, versus 36%, P = 0.001) in the anti-SARS-CoV-2 antibody profile, when compared to DSAs, respectively. Anti-SARS-CoV-2 antibody profile was characterized by increased prevalence of IgM and IgA, when compared to DSAs. The median calculated panel reactive antibody before COVID-19 diagnosis (24%) tended to decrease after COVID-19 diagnosis (10%) but it was not statistically significant ( P = 0.1).Anti-HLA antibody strength and calculated panel reactive antibody in kidney transplant recipients after COVID-19 do not significantly increase after infection. Although the IgG isotype was the dominant form in both HLA and SARS-CoV-2 antigens, the alloimmune response had a low IgA pattern, whereas anti-SARS-CoV-2 antibodies were high IgA/IgM.

BACKGROUND: Kidney transplant recipients are at increased risk of severe outcomes during COVID-19. Antibodies against the virus are thought to offer protection, but a thorough characterization of anti–SARS-CoV-2 immune globulin isotypes in kidney transplant recipients following SARS-CoV-2 infection has not been reported. METHODS: We performed a cross-sectional study of 49 kidney transplant recipients and 42 immunocompetent controls at early (≤14 days) or late (>14 days) time points after documented SARS-CoV-2 infection. Using a validated semiquantitative Luminex-based multiplex assay, we determined the abundances of IgM, IgG, IgG1–4, and IgA antibodies against five distinct viral epitopes. RESULTS: Kidney transplant recipients showed lower levels of total IgG antitrimeric spike (S), S1, S2, and receptor binding domain (RBD) but not nucleocapsid (NC) at early versus late time points after SARS-CoV-2 infection. Early levels of IgG antispike protein epitopes were also lower than in immunocompetent controls. Anti–SARS-CoV-2 antibodies were predominantly IgG1 and IgG3, with modest class switching to IgG2 or IgG4 in either cohort. Later levels of IgG antispike, S1, S2, RBD, and NC did not significantly differ between cohorts. There was no significant difference in the kinetics of either IgM or IgA antispike, S1, RBD, or S2 on the basis of timing after diagnosis or transplant status. CONCLUSIONS: Kidney transplant recipients mount early anti–SARS-CoV-2 IgA and IgM responses, whereas IgG responses are delayed compared with immunocompetent individuals. These findings might explain the poor outcomes in transplant recipients with COVID-19. PODCAST: This article contains a podcast athttps://www.asn-online.org/media/podcast/JASN/2021_11_23_briggsgriffin112321.mp3

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.

Allograft biopsies with lesions of Antibody-Mediated Rejection (ABMR) with Microvascular Inflammation (MVI) have shown heterogeneous etiologies and outcomes.To examine factors associated with outcomes in biopsies that meet histologic ABMR criteria, we retrospectively evaluated for-cause biopsies at our center between 2011 and 2017. We included biopsies that met the diagnosis of ABMR by histology, along with simultaneous evaluation for anti-Human Leukocyte Antigen (HLA) donor-specific antibodies (DSA). We evaluated death-censored graft loss (DCGL) and used a principal component analysis (PCA) approach to identify key predictors of outcomes.Out of the histologic ABMR cohort (n = 118), 70 were DSA-positive ABMR, while 48 had no DSA. DSA(+)ABMR were younger and more often female recipients. DSA(+)ABMR occurred significantly later post-transplant than DSA(-)ABMR suggesting time-dependence. DSA(+)ABMR had higher inflammatory scores (i,t), chronicity scores (ci, ct) and tended to have higher MVI scores. Immunodominance of DQ-DSA in DSA(+)ABMR was associated with higher i+t scores. Clinical/histologic factors significantly associated with DCGL after biopsy were inputted into the PCA. Principal component-1 (PC-1), which contributed 34.8% of the variance, significantly correlated with time from transplantation to biopsy, ci/ct scores and DCGL. In the PCA analyses, i, t scores, DQ-DSA, and creatinine at biopsy retained significant correlations with GL-associated PCs.Time from transplantation to biopsy plays a major role in the prognosis of biopsies with histologic ABMR and MVI, likely due to ongoing chronic allograft injury over time.

(1) Determine inter-observer reproducibility and test-retest repeatability of 4D flow parameters in renal allograft vessels; (2) determine if 4D flow measurements in the renal artery (RA) and renal vein (RV) can distinguish between functional and dysfunctional allografts; (3) correlate haemodynamic parameters with estimated glomerular filtration rate (eGFR), perfusion measured with dynamic contrast-enhanced MRI (DCE-MRI) and histopathology. Twenty-five prospectively recruited renal transplant patients (stable function/chronic renal allograft dysfunction, 12/13) underwent 4D flow MRI at 1.5 T. 4D flow coronal oblique acquisitions were performed in the transplant renal artery (RA) (velocity encoding parameter, VENC = 120 cm/s) and renal vein (RV) (VENC = 45 cm/s). Test-retest repeatability (n = 3) and inter-observer reproducibility (n = 10) were assessed by Cohen’s kappa, coefficient of variation (CoV) and Bland-Altman statistics. Haemodynamic parameters were compared between patients and correlated to the estimated glomerular filtration rate, DCE-MRI parameters (n = 10) and histopathology from allograft biopsies (n = 15). For inter-observer reproducibility, kappa was > 0.99 and 0.62 and CoV of flow was 12.6% and 7.8% for RA and RV, respectively. For test-retest repeatability, kappa was > 0.99 and 0.5 and CoV of flow was 27.3% and 59.4%, for RA and RV, respectively. RA (p = 0.039) and RV (p = 0.019) flow were both significantly reduced in dysfunctional allografts. Both identified chronic allograft dysfunction with good diagnostic performance (RA: AUC = 0.76, p = 0.036; RV: AUC = 0.8, p = 0.018). RA flow correlated negatively with histopathologic interstitial fibrosis score ci (ρ = − 0.6, p = 0.03). 4D flow parameters had better repeatability in the RA than in the RV. RA and RV flow can identify chronic renal allograft dysfunction, with RA flow correlating with histopathologic interstitial fibrosis score. • Inter-observer reproducibility of 4D flow measurements was acceptable in both the transplant renal artery and vein, but test-retest repeatability was better in the renal artery than in the renal vein. • Blood flow measurements obtained with 4D flow MRI in the renal artery and renal vein are significantly reduced in dysfunctional renal transplants. • Renal transplant artery flow correlated negatively with histopathologic interstitial fibrosis score.

Morphometric estimates of mean glomerular volume (MGV) have clinical implications, over and above histologic data. However, MGV estimation is time-consuming, could waste tissue sections and requires expertise limiting its utility in retrospective clinical studies.MethodsWe evaluated MGV using both plastic and paraffin-embedded tissue from control and FSGS mice (n=10 each) using the gold-standard Disector/Cavalieri technique (Vglom-Cav) and other reported techniques [2- or 3-profile technique, Weibel-Gomez method (W-G)]. Within Vglom-Cav we examined the precision of MGV estimation while using MGVs obtained from 5- or 10-individual glomeruli measurements vs the true mean (20 glomeruli).ResultsIn both FSGS and controls, we identified an acceptable precision of 10-glomerular sampling vs true MGV within Vglom-Cav technique [88 (79-94) % of MGV obtained were within 10% of the true MGV]. The 5-glomerular sampling was less precise [70 (56, 81) % of MGV obtained were within 10% of true MGV]. In plastic based techniques, 2- or 3-profile MGVs showed greater concordance with Vglom-Cav, than W-G MGV. The new 3-profile technique offered incremental benefit to the existing 2-profile method (improved Lin’s concordance in control and FSGS animals). We observed a consistent reduction of Vglom values within control animals (52+/-0.06%) in paraffin-embedded tissue (vs corresponding methods in plastic) demonstrating a clear shrinkage artefact due to tissue processing. FSGS glomeruli showed significantly less and more variable shrinkage artefact likely due to glomerular fibrosis.ConclusionWe report the precision of 5- or 10-glomerular sampling for MGV estimation using controls and FSGS animals. We demonstrate and quantify the shrinkage bias in MGV during tissue processing for paraffin-embedding that also differentiated control animals and FSGS. Our findings have implications for experimental studies using glomerular morphometry.

BackgroundKidney transplant recipients (KTRs) with COVID-19 have poor outcomes compared to non-KTRs. To provide insight into management of immunosuppression during acute illness, we studied immune signatures from the peripheral blood during and after COVID-19 infection from a multicenter KTR cohort.□MethodsClinical data were collected by chart review. PAXgene blood RNA was poly-A selected and RNA sequencing was performed to evaluate transcriptome changes.ResultsA total of 64 cases of COVID-19 in KTRs were enrolled, including 31 acute cases (< 4 weeks from diagnosis) and 33 post-acute cases (>4 weeks). In the blood transcriptome of acute cases, we identified differentially expressed genes (DEGs) in positive or negative association COVID-19 severity scores. Functional enrichment analyses showed upregulation of neutrophil and innate immune pathways, but downregulation of T-cell and adaptive immune-activation pathways proportional to severity score. This finding was independent of lymphocyte count and despite reduction in immunosuppression (IS) in most KTRs. Comparison with post-acute cases showed “normalization” of these enriched pathways after >4 weeks, suggesting recovery of adaptive immune system activation despite reinstitution of IS. The latter analysis was adjusted for COVID-19 severity score and lymphocyte count. DEGs associated with worsening disease severity in a non-KTR cohort with COVID-19 (GSE152418) showed significant overlap with KTRs in these identified enriched pathways.ConclusionBlood transcriptome of KTRs affected by COVID-19 shows decrease in T-cell and adaptive immune activation pathways during acute disease that associate with severity despite IS reduction and show recovery after acute illness.Significance statementKidney transplant recipients (KTRs) are reported to have worse outcomes with COVID-19, and empiric reduction of maintenance immunosuppression is pursued. Surprisingly, reported rates of acute rejection have been low despite reduced immunosuppression. We evaluated the peripheral blood transcriptome of 64 KTRs either during or after acute COVID-19. We identified transcriptomic signatures consistent with suppression of adaptive T-cell responses which significantly associated with disease severity and showed evidence of recovery after acute disease, even after adjustment for lymphocyte number. Our transcriptomic findings of immune-insufficiency during acute COVID-19 provide an explanation for the low rates of acute rejection in KTRs despite reduced immunosuppression. Our data support the approach of temporarily reducing T –cell-directed immunosuppression in KTRs with acute COVID-19.

Despite significant improvement in the rates of acute allograft rejection, proportionate improvements in kidney allograft longevity have not been realized, and are a source of intense research efforts. Emerging translational data and natural history studies suggest a role for anti-donor immune mechanisms in a majority of cases of allograft loss without patient death, even when overt evidence of acute rejection is not identified. At the level of the donor and recipient genome, differences in highly polymorphic HLA genes are routinely evaluated between donor and recipient pairs as part of organ allocation process, and utilized for patient-tailored induction and maintenance immunosuppression. However, a growing body of data have characterized specific variants in donor and recipient genes, outside of HLA loci, that induce phenotypic changes in donor organs or the recipient immune system, impacting transplant outcomes. Newer mechanisms for “mismatches” in these non-HLA loci have also been proposed during donor–recipient genome interactions with transplantation. Here, we review important recent data evaluating the role of non-HLA genetic loci and genome-wide donor-recipient mismatches in kidney allograft outcomes.

Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss, but whether recipient risk allele expression affects transplant outcomes is unclear. To test whether recipient APOL1 risk alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data on donors and recipients from 2 kidney transplant cohorts: Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 01/17 (CTOT-01/17). We estimated genetic ancestry (quantified as the proportion of African ancestry, or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we noted that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with an increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), as well as within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with an increased risk of any T cell–mediated rejection (TCMR) event. These associations were validated in CTOT-01/17. Ex vivo studies of PMBCs revealed, unexpectedly, high expression levels of APOL1 in activated CD4(+)/CD8(+) T cells and NK cells. We detected enriched immune response gene pathways in risk allele carriers compared with noncarriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk alleles associated with TCMR and DCAL. We believe this finding has broader implications for immune-mediated injury to native kidneys.

Herein, we report that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without focal segmental glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease (MCD), where podocyte Fyn inactivation was reported, also showed lower glomerular volumes than FSGS. We hypothesized that lower glomerular volume prevented the progression to podocytopenia. To test this hypothesis, we utilized unilateral and 5/6th nephrectomy models in Shroom3-KD mice. Knockdown mice exhibited less glomerular and podocyte hypertrophy after nephrectomy. FYN-knockdown podocytes had similar reductions in podocyte volume, implying that Fyn was downstream of Shroom3. Using SHROOM3 or FYN knockdown, we confirmed reduced podocyte protein content, along with significantly increased phosphorylated AMPK, a negative regulator of anabolism. AMPK activation resulted from increased cytoplasmic redistribution of LKB1 in podocytes. Inhibition of AMPK abolished the reduction in glomerular volume and induced podocytopenia in mice with FPE, suggesting a protective role for AMPK activation. In agreement with this, treatment of glomerular injury models with AMPK activators restricted glomerular volume, podocytopenia, and progression to FSGS. Glomerular transcriptomes from MCD biopsies also showed significant enrichment of Fyn inactivation and Ampk activation versus FSGS glomeruli. In summary, we demonstrated the important role of AMPK in glomerular volume regulation and podocyte survival. Our data suggest that AMPK activation adaptively regulates glomerular volume to prevent podocytopenia in the context of podocyte injury.

After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death

Progressive focal segmental glomerulosclerosis, characterized by podocyte loss, is often refractory to treatment and leads to progressive proteinuric chronic kidney disease. Interleukin-9 (IL-9) is reported to play important roles in innate and adaptive immunity in extrarenal inflammatory diseases. By using an IL-9 knockout mouse model, Xiong et al. demonstrate IL-9 as a novel pro-podocyte survival cytokine in the adriamycin nephropathy model of focal segmental glomerulosclerosis. Sequential in vitro and in vivo data corroborate a direct protective role, rather than an immunologic role, for IL-9 on podocyte survival. This commentary highlights these novel data and discusses the necessary steps for developing IL-9 as a potential novel therapeutic for focal segmental glomerulosclerosis.

Introduction Much of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (APOL1). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)–sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes. Methods APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys. Results The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses. Conclusion This article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of APOL1 genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation., Graphical abstract

The essential role of membrane associated guanylate kinase 2 (MAGI2) in podocytes is indicated by the phenotypes of severe glomerulosclerosis of both MAGI2 knockout mice and in patients with congenital nephrotic syndrome (CNS) caused by mutations in MAGI2. Here, we show that MAGI2 forms a complex with the Rap1 guanine nucleotide exchange factor, RapGEF2, and that this complex is lost when expressing MAGI2 CNS variants. Co-expression of RapGEF2 with wild-type MAGI2, but not MAGI2 CNS variants, enhanced activation of the small GTPase Rap1, a central signaling node in podocytes. In mice, podocyte-specific RapGEF2 deletion resulted in spontaneous glomerulosclerosis, with qualitative glomerular features comparable to MAGI2 knockout mice. Knockdown of RapGEF2 or MAGI2 in human podocytes caused similar reductions in levels of Rap1 activation and Rap1-mediated downstream signaling. Furthermore, human podocytes expressing MAGI2 CNS variants show severe abnormalities of cellular morphology and dramatic loss of actin cytoskeletal organization, features completely rescued by pharmacological activation of Rap1 via a non-MAGI2 dependent upstream pathway. Finally, immunostaining of kidney sections from patients with congenital nephrotic syndrome and MAGI2 mutations showed reduced podocyte Rap1-mediated signaling. Thus, MAGI2-RapGEF2-Rap1 signaling is essential for normal podocyte function. Hence, disruption of this pathway is an important cause of the renal phenotype induced by MAGI2 CNS mutations.

Recommendations regarding the appropriateness of renal transplantation in patients with prior hematologic malignancies are limited. Given the lack of available data, studies are needed to assess which of these patients will maximally benefit from renal transplantation. This study was undertaken to describe the incidence of new or recurrent malignancy as well as patient and allograft survival, acute rejection, and serious infections in patients with prior hematologic malignancies receiving renal transplantation. This was a single center retrospective review of all adult patients with a previous hematologic malignancy who received a living or deceased renal transplantation between January 2009 and January 2016. Eight renal transplantation recipients with prior hematologic malignancies were identified and followed for a minimum of 3 years. Six patients received prior chemotherapy and five had a prior hematopoietic stem cell transplant. Median time from remission to transplant was 2.6 years. Three-year patient and allograft survival were 87% and 75%, respectively. Three patients were diagnosed with new cancers within 3 years post-renal transplantation; one of which died from cancer-related complications with a functioning allograft. There was concern for recurrent hematologic malignancies in two patients based on serologic studies, but, both of these patients were alive with functioning allografts at 3-year follow-up. Our experience suggests that renal transplantation can be successfully performed in select patients with prior hematologic malignancy but with a significant risk for de novo malignancy post-transplant, which may be associated with an overall poor prognosis. Decisions regarding renal transplantation candidacy should be made based on risk stratification and multidisciplinary discussions with patients, hematologists, and transplant providers.

Immune checkpoint inhibitors (ICIs) are widely used for various malignancies. However, their safety and efficacy in patients with a kidney transplant have not been defined. To delineate this, we conducted a multicenter retrospective study of 69 patients with a kidney transplant receiving ICIs between January 2010 and May 2020. For safety, we assessed the incidence, timing, and risk factors of acute graft rejection. For efficacy, objective response rate and overall survival were assessed in cutaneous squamous cell carcinoma and melanoma, the most common cancers in our cohort, and compared with stage-matched 23 patients with squamous cell carcinoma and 14 with melanoma with a kidney transplant not receiving ICIs. Following ICI treatment, 29 out of 69 (42%) patients developed acute rejection, 19 of whom lost their allograft, compared with an acute rejection rate of 5.4% in the non-ICI cohort. Median time from ICI initiation to rejection was 24 days. Factors associated with a lower risk of rejection were mTOR inhibitor use (odds ratio 0.26; 95% confidence interval, 0.09-0.72) and triple-agent immunosuppression (0.67, 0.48-0.92). The objective response ratio was 36.4% and 40% in the squamous cell carcinoma and melanoma subgroups, respectively. In the squamous cell carcinoma subgroup, overall survival was significantly longer in patients treated with ICIs (median overall survival 19.8 months vs. 10.6 months), whereas in the melanoma subgroup, overall survival did not differ between groups. Thus, ICIs were associated with a high risk of rejection in patients with kidney transplants but may lead to improved cancer outcomes. Prospective studies are needed to determine optimal immunosuppression strategies to improve patient outcomes. ispartof: KIDNEY INTERNATIONAL vol:100 issue:1 pages:196-205 ispartof: location:United States status: published

BackgroundInterstitial fibrosis, tubular atrophy, and inflammation are major contributors to renal allograft failure. Here we seek an objective, quantitative pathological assessment of these lesions to improve predictive utility.MethodsWe constructed a deep-learning-based pipeline recognizing normal vs. abnormal kidney tissue compartments and mononuclear leukocyte (MNL) infiltrates from Periodic acid-Schiff (PAS) stained slides of transplant biopsies (training: n=60, testing: n=33) that quantified pathological lesions specific for interstitium, tubules and MNL infiltration. The pipeline was applied to 789 whole slide images (WSI) from baseline (n=478, pre-implantation) and 12-month post-transplant (n=311) protocol biopsies in two independent cohorts (GoCAR: 404 patients, AUSCAD: 212 patients) of transplant recipients to correlate composite lesion features with graft loss.ResultsOur model accurately recognized kidney tissue compartments and MNLs. The digital features significantly correlated with Banff scores, but were more sensitive to subtle pathological changes below the thresholds in Banff scores. The Interstitial and Tubular Abnormality Score (ITAS) in baseline samples was highly predictive of 1-year graft loss (p=2.8e-05), while a Composite Damage Score (CDS) in 12-month post-transplant protocol biopsies predicted later graft loss (p=7.3e-05). ITAS and CDS outperformed Banff scores or clinical predictors with superior graft loss prediction accuracy. High/intermediate risk groups stratified by ITAS or CDS also demonstrated significantly higher incidence of eGFR decline and subsequent graft damage.ConclusionsThis deep-learning approach accurately detected and quantified pathological lesions from baseline or post-transplant biopsies, and demonstrated superior ability for prediction of posttransplant graft loss with potential application as a prevention, risk stratification or monitoring tool.

We reported that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease, where podocyte Fyn inactivation was reported, also showed lower glomerular volumes than FSGS. We hypothesized that lower glomerular volume prevented the progression to podocytopenia. To test this hypothesis, we utilized unilateral- and 5/6th nephrectomy models in Shroom3 knockdown mice. Knockdown mice exhibited lower glomerular volume, and less glomerular and podocyte hypertrophy after nephrectomy. FYN-knockdown podocytes had similar reductions in podocyte volume, implying Fyn was downstream of Shroom3. Using SHROOM3- or FYN-knockdown, we confirmed reduced podocyte protein content, along with significantly increased phosphorylated AMP-kinase, a negative regulator of anabolism. AMP-Kinase activation resulted from increased cytoplasmic redistribution of LKB1 in podocytes. Inhibition of AMP-Kinase abolished the reduction in glomerular volume and induced podocytopenia in mice with FPE, suggesting a protective role for AMP-Kinase activation. In agreement with this, treatment of glomerular injury models with AMP-Kinase activators restricted glomerular volume, podocytopenia and progression to FSGS. In summary, we demonstrate the important role of AMP-Kinase in glomerular volume regulation and podocyte survival. Our data suggest that AMP-Kinase activation adaptively regulates glomerular volume to prevent podocytopenia in the context of podocyte injury.

Dachshund homolog 1 (DACH1), a key cell-fate determinant, regulates transcription by DNA sequence-specific binding. We identified diminished Dach1 expression in a large-scale screen for mutations that convert injury-resistant podocytes into injury-susceptible podocytes. In diabetic kidney disease (DKD) patients, podocyte DACH1 expression levels are diminished, a condition that strongly correlates with poor clinical outcomes. Global Dach1 KO mice manifest renal hypoplasia and die perinatally. Podocyte-specific Dach1 KO mice, however, maintain normal glomerular architecture at baseline, but rapidly exhibit podocyte injury after diabetes onset. Furthermore, podocyte-specific augmentation of DACH1 expression in mice protects from DKD. Combined RNA sequencing and in silico promoter analysis reveal conversely overlapping glomerular transcriptomic signatures between podocyte-specific Dach1 and Pax transactivation-domain interacting protein (Ptip) KO mice, with upregulated genes possessing higher-than-expected numbers of promoter Dach1-binding sites. PTIP, an essential component of the activating histone H3 lysine 4 trimethylation (H3K4Me3) complex, interacts with DACH1 and is recruited by DACH1 to its promoter-binding sites. DACH1-PTIP recruitment represses transcription and reduces promoter H3K4Me3 levels. DACH1 knockdown in podocytes combined with hyperglycemia triggers target gene upregulation and increases promoter H3K4Me3. These findings reveal that in DKD, diminished DACH1 expression enhances podocyte injury vulnerability via epigenetic derepression of its target genes.

Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss but whether recipient risk allele expression impacts kidney transplant outcomes is unclear. To test whether recipient APOL1 allelic variants independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data of donors and recipients from two kidney transplant cohorts, Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 1/17 (CTOT1/17). We estimated genetic ancestry (quantified as proportion of African ancestry or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we observed that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with increased risk of death-censored allograft loss (DCAL), independent of genetic ancestry (HR = 2.14; P = 0.006), and within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with increased risk of any T cell-mediated rejection (TCMR) event. Analysis of the CTOT cohort validated these associations. Ex vivo studies of peripheral blood mononuclear cells revealed unanticipated high APOL1 expression in activated CD4+/CD8+ T cells and natural killer cells. We detected enriched immune response gene pathways in G1/G2 allele carriers vs. non-carriers among patients on the kidney waitlist and healthy controls. Together our findings highlight a previously unrecognized contribution of recipient APOL1 risk alleles to renal allograft outcomes. This immunomodulatory role has broader implications for immune mediated injury to native kidneys.

There have been recent significant advances in short-term outcomes in renal transplantation, however, long-term allograft survival remains a challenge. With reported incidences as high of 74.5% of chronic graft loss in patients with biopsies showing transplant glomerulopathy (TG), this syndrome represents an important factor for chronic allograft complications. In this review we show an overview of the novel mechanistic insights into pathogenesis of TG, as well as a brief description of the pathology, diagnosis and newer prognostic indices within TG diagnosis. These data raise intriguing roles for cell-mediated immunity and podocyte stress in TG as well as reinforce previous associations of TG with ABMR. We also delve into management strategies for TG and report the paucity of existing clinical trial data for this prevalent condition in renal transplants.

The influence of patient characteristics and immunosuppression management on COVID‐19 outcomes in kidney transplant recipients (KTRs) remains uncertain. We performed a single‐center, retrospective review of all adult KTRs admitted to the hospital with confirmed COVID‐19 between 03/15/2020 and 05/15/2020. Patients were followed from the date of admission up to 1 month following hospital discharge or study conclusion (06/15/2020). Baseline characteristics, laboratory parameters, and immunosuppression were compared between survivors and patients who died to identify predictors of mortality. 38 KTRs with a mean baseline eGFR of 52.5 ml/min/1.73 m2 were hospitalized during the review period. Maintenance immunosuppression included tacrolimus (84.2%), mycophenolate (89.5%), and corticosteroids (81.6%) in the majority of patients. Eleven patients (28.9%) died during the hospitalization. Older age (OR = 2.05; 1.04‐4.04), peak D‐dimer (OR = 1.20; 1.04‐1.39), and peak white blood cell count (OR = 1.11; 1.02‐1.21) were all associated with mortality among KTRs hospitalized for COVID‐19. Increased mortality was also observed among KTRs with concomitant HIV infection (87.5% vs. 36.1%; p

Acute rejection (AR) in renal transplantation is an established risk factor for reduced allograft survival. Molecules with regulatory control among immune pathways of AR that are inadequately suppressed, despite standard-of-care immunosuppression, could serve as important targets for therapeutic manipulation to prevent rejection. Here, an integrative, network-based computational strategy incorporating gene expression and genotype data of human renal allograft biopsy tissue was applied, to identify the master regulators — the key driver genes (KDGs) — within dysregulated AR pathways. A 982–meta-gene signature with differential expression in AR versus non-AR was identified from a meta-analysis of microarray data from 735 human kidney allograft biopsy samples across 7 data sets. Fourteen KDGs were derived from this signature. Interrogation of 2 publicly available databases identified compounds with predicted efficacy against individual KDGs or a key driver–based gene set, respectively, which could be repurposed for AR prevention. Minocycline, a tetracycline antibiotic, was chosen for experimental validation in a murine cardiac allograft model of AR. Minocycline attenuated the inflammatory profile of AR compared with controls and when coadministered with immunosuppression prolonged graft survival. This study demonstrates that a network-based strategy, using expression and genotype data to predict KDGs, assists target prioritization for therapeutics in renal allograft rejection.

Donor-recipient (D-R) differences at human leukocyte antigen (HLA) loci are currently incorporated into organ sharing, allocation and immunosuppression decisions. However, while acute rejection episodes have substantially diminished, progressive histologic damage occurs in allografts and improved long-term survival remains an unrealized goal among kidney recipients. Here we tested the hypothesis that non-HLA dependent, genome-wide D-R genetic differences could contribute to unchecked alloimmunity with histologic and functional consequences, culminating in long-term allograft failure. Genome-wide single nucleotide polymorphism (SNP) array data, excluding the HLA region, was utilized from 385 transplants to study the role of D-R differences upon serial histology and allograft survival. ADMIXTURE analysis was performed to quantitatively estimate ancestry in each D-R pair and PLINK was used to estimate the proportion of genome-shared identity-by-descent (pIBD) between D-R pairs. Subsequently, quantitative measures of recipient ancestry based on non-HLA SNPs was associated with death-censored allograft survival in adjusted Cox models. In D-R pairs of similar ancestry, pIBD was significantly associated with allograft survival independent of HLA mismatches in 224 transplants. Surprisingly, pIBD and recipient ancestry were not associated with clinical or subclinical rejection at any time post-transplant. Significantly, in multivariable analysis, pIBD inversely correlated with vascular intimal fibrosis in 160 biopsies obtained less than one year which in turn was significantly associated with allograft survival. Thus, our novel data show that non-HLA D-R differences associate with early vascular intimal fibrosis and allograft survival.

ImportancePreliminary reports indicate that acute kidney injury (AKI) is common in coronavirus disease (COVID)-19 patients and is associated with worse outcomes. AKI in hospitalized COVID-19 patients in the United States is not well-described.ObjectiveTo provide information about frequency, outcomes and recovery associated with AKI and dialysis in hospitalized COVID-19 patients.DesignObservational, retrospective study.SettingAdmitted to hospital between February 27 and April 15, 2020.ParticipantsPatients aged ≥18 years with laboratory confirmed COVID-19ExposuresAKI (peak serum creatinine increase of 0.3 mg/dL or 50% above baseline).Main Outcomes and MeasuresFrequency of AKI and dialysis requirement, AKI recovery, and adjusted odds ratios (aOR) with mortality. We also trained and tested a machine learning model for predicting dialysis requirement with independent validation.ResultsA total of 3,235 hospitalized patients were diagnosed with COVID-19. AKI occurred in 1406 (46%) patients overall and 280 (20%) with AKI required renal replacement therapy. The incidence of AKI (admission plus new cases) in patients admitted to the intensive care unit was 68% (553 of 815). In the entire cohort, the proportion with stages 1, 2, and 3 AKI were 35%, 20%, 45%, respectively. In those needing intensive care, the respective proportions were 20%, 17%, 63%, and 34% received acute renal replacement therapy. Independent predictors of severe AKI were chronic kidney disease, systolic blood pressure, and potassium at baseline. In-hospital mortality in patients with AKI was 41% overall and 52% in intensive care. The aOR for mortality associated with AKI was 9.6 (95% CI 7.4-12.3) overall and 20.9 (95% CI 11.7-37.3) in patients receiving intensive care. 56% of patients with AKI who were discharged alive recovered kidney function back to baseline. The area under the curve (AUC) for the machine learned predictive model using baseline features for dialysis requirement was 0.79 in a validation test.Conclusions and RelevanceAKI is common in patients hospitalized with COVID-19, associated with worse mortality, and the majority of patients that survive do not recover kidney function. A machine-learned model using admission features had good performance for dialysis prediction and could be used for resource allocation.Key PointsQuestionWhat is incidence and outcomes of acute kidney injury (AKI) in patients hospitalized with COVID-19?FindingsIn this observational study of 3,235 hospitalized patients with COVID-19 in New York City, AKI occurred in 46% of patients and 20% of those patients required dialysis. AKI was associated with increased mortality. 44% of patients discharged alive had residual acute kidney disease. A machine learned predictive model using baseline features for dialysis requirement had an AUC Of 0.79.MeaningAKI was common in patients with COVID-19, associated with increased mortality, and nearly half of patients had acute kidney disease on discharge.

Background There is an unmet need for noninvasive methods to diagnose and stage renal allograft fibrosis. Purpose To investigate the utility of T1ρ measured with MRI for the assessment of fibrosis in renal allografts. Study type Institutional Review Board (IRB)-approved prospective. Subjects Fifteen patients with stable functional allograft (M/F 9/6, mean age 56 years) and 12 patients with allograft dysfunction and established fibrosis (M/F 6/6, mean age 51 years). Field strength/sequence T1ρ imaging at 1.5T using a custom-developed sequence. Assessment Average T1ρ in the cortex and medulla was quantified and T1ρ repeatability (expressed by the coefficient of variation [CV]) was measured in four patients. Statistical tests Differences in T1ρ values between the 2 groups were assessed using Mann-Whitney U-tests. Diagnostic performance of T1ρ for differentiation between functional and fibrotic allografts was evaluated using receiver operating characteristic (ROC) analysis. Spearman correlations of T1ρ with Masson's trichrome-stained fractions and serum estimated glomerular filtration rate (eGFR) were assessed. Results Higher T1ρ repeatability was found for cortex compared with medulla (mean CV T1ρ cortex 7.4%, medulla 13.3%). T1ρ values were significantly higher in the cortex of fibrotic vs. functional allografts (111.8 ± 17.2 msec vs. 99.0 ± 11.0 msec, P = 0.027), while there was no difference in medullary T1ρ values (122.6 ± 20.8 msec vs. 124.3 ± 20.8 msec, P = 0.789). Cortical T1ρ significantly correlated with Masson's trichrome-stained fractions (r = 0.515, P = 0.044) and eGFR (r = -0.546, P = 0.004), and demonstrated an area under the curve (AUC) of 0.77 for differentiating between functional and fibrotic allografts (sensitivity and specificity of 75.0% and 86.7%, using threshold of 106.9 msec). Data conclusion Our preliminary results suggest that T1ρ is a potential imaging biomarker of renal allograft fibrosis. These results should be verified in a larger study. Level of evidence 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:1085-1091.

Purpose To investigate the utility of magnetic resonance elastography (MRE) vs. ultrasound (US) point shear wave elastography (pSWE) for the assessment of chronic renal allograft dysfunction, prediction of outcome and determine the correlation with Banff pathology scores. Methods In this IRB approved prospective study, 27 enrolled patients with functional (n = 15) and chronic dysfunctional (n = 12) renal allografts underwent same day 2D MRE and pSWE. Histogram parameters [including mean, median, standard deviation, kurtosis and skewness] of the magnitude of the complex shear modulus (MRE) and median Young’s modulus (pSWE) were measured in the cortex (MRE and pSWE) and combined corticomedullary regions (MRE). Histopathology was available for 16 patients (4 functional, 12 dysfunctional). Results MRE and pSWE stiffness were not significantly different between functional and dysfunctional groups (p range 0.139-0.347). The skewness of MRE corticomedullary stiffness was significantly lower (p = 0.04) in patients with chronic dysfunction and correlated significantly with Banff histopathologic scores (range r=-0.518–0.567, p = 0.035–0.040). MRE cortical and corticomedullary mean stiffness showed strong performance in predicting graft loss/relist (AUC 0.958, p = 0.011 for both). Reliable pSWE measurements were obtained in 13 patients (48 %). pSWE stiffness did not correlate with Banff scores and did not predict outcome. Conclusions The skewness of MRE corticomedullary stiffness is sensitive to changes in chronic allograft dysfunction, while mean/median MRE renal stiffness and median US stiffness did not differentiate patients with stable function vs those with chronic renal allograft dysfunction. MRE corticomedullary mean stiffness appears to be a predictor of graft loss/relist. pSWE was not found to be a useful method for assessing renal allografts.

Background We previously showed that the presence of a CKD-associated locus in SHROOM3 in a donor kidney results in increased expression of SHROOM3 (an F-actin–binding protein important for epithelial morphogenesis, via rho-kinase [ROCK] binding); this facilitates TGF-b signaling and allograft fibrosis. However, other evidence suggests Shroom3 may have a protective role in glomerular development. Methods We used human data, Shroom3 knockdown podocytes, and inducible shRNA-mediated knockdown mice to study the role of Shroom3 in adult glomeruli. Results Expression data from the Nephroseq database showed glomerular and nonglomerular SHROOM3 had opposing associations with renal function in CKD biopsy samples. In human allografts, homozygosity at rs17319721, the SHROOM3 locus linked with lower GFR, was associated with reduced albuminuria by 2 years after transplant. Although our previous data showed reduced renal fibrosis with tubular Shroom3 knockdown, this study found that glomerular but not tubular Shroom3 knockdown induced albuminuria. Electron microscopy revealed diffuse foot process effacement, and glomerular RNA-sequencing showed enrichment of tyrosine kinase signaling and podocyte actin cytoskeleton pathways in knockdown mice. Screening SHROOM3-interacting proteins identified FYN (a src-kinase) as a candidate.We confirmed the interaction of endogenous SHROOM3 with FYN in human podocytes via a critical Src homology 3–binding domain, distinct from its ROCK-binding domain. Shroom3-Fyn interaction was required in vitro and in vivo for activation of Fyn kinase and downstream nephrin phosphorylation in podocytes. SHROOM3 knockdown altered podocyte morphology, cytoskeleton, adhesion, and migration. Conclusions We demonstrate a novel mechanism that may explain SHROOM3’s dichotomous associations in glomerular versus nonglomerular compartments in CKD

Background An early posttransplant biomarker/surrogate marker for kidney allograft loss has the potential to guide targeted interventions. Previously published findings, including results from the Clinical Trials in Organ Transplantation (CTOT)-01 study, showed that elevated urinary chemokine CXCL9 levels and elevated frequencies of donor-reactive interferon gamma (IFNγ)-producing T cells by enzyme-linked immunosorbent spot (ELISPOT) assay associated with acute cellular rejection within the first year and with lower 1-year posttransplant estimated glomerular filtration rate (eGFR). How well these biomarkers correlate with late outcomes, including graft loss, is unclear. Methods In CTOT-17, we obtained 5-year outcomes in the CTOT-01 cohort and correlated them with (a) biomarker results and (b) changes in eGFR (Chronic Kidney Disease Epidemiology Collaboration formula) over the initial 2 years posttransplant using univariable analysis and multivariable logistic regression. Results Graft loss occurred in 14 (7.6%) of 184 subjects 2 to 5 years posttransplant. Neither IFNγ ELISPOTs nor urinary CXCL9 were informative. In contrast, a 40% or greater decline in eGFR from 6 months to 2 years posttransplant independently correlated with 13-fold odds of 5-year graft loss (adjusted odds ratio, 13.1; 95% confidence interval, 3.0-56.6), a result that was validated in the independent Genomics of Chronic Allograft Rejection cohort (n = 165; adjusted odds ratio, 11.2). Conclusions We conclude that although pretransplant and early posttransplant ELISPOT and chemokine measurements associate with outcomes within 2 years posttransplant, changes in eGFR between 3 or 6 months and 24 months are better surrogates for 5-year outcomes, including graft loss.

Mice devoid of T, B, and NK cells distinguish between self and allogeneic non-self despite the absence of an adaptive immune system. When challenged with an allograft they mount an innate response characterized by accumulation of mature, monocyte-derived dendritic cells (DCs) that produce IL-12 and initiate graft rejection. The molecular mechanisms, however, by which the innate immune system detects allogeneic non-self to generate these DCs are not known. To address this question, we studied the innate response of Rag2−/−γc−/− mice, which lack T, B, NK cells, to grafts from allogeneic donors. We identified by positional cloning that donor polymorphism in the gene encoding signal regulatory protein alpha (SIRPα) is a key modulator of the recipient’s innate allorecognition response. Donors that differed from the recipient in one or both Sirpa alleles elicited an innate alloresponse. The response was mediated by binding of donor SIRPα to recipient CD47 and was modulated by the strength of the SIRPα-CD47 interaction. Therefore, sensing SIRPα polymorphism by CD47 provides a molecular mechanism by which the innate immune system distinguishes between self and allogeneic non-self independently of T, B, and NK cells.

(1) Determine inter-observer reproducibility and test-retest repeatability of 4D flow parameters in renal allograft vessels; (2) determine if 4D flow measurements in the renal artery (RA) and renal vein (RV) can distinguish between functional and dysfunctional allografts; (3) correlate haemodynamic parameters with estimated glomerular filtration rate (eGFR), perfusion measured with dynamic contrast-enhanced MRI (DCE-MRI) and histopathology.Twenty-five prospectively recruited renal transplant patients (stable function/chronic renal allograft dysfunction, 12/13) underwent 4D flow MRI at 1.5 T. 4D flow coronal oblique acquisitions were performed in the transplant renal artery (RA) (velocity encoding parameter, VENC = 120 cm/s) and renal vein (RV) (VENC = 45 cm/s). Test-retest repeatability (n = 3) and inter-observer reproducibility (n = 10) were assessed by Cohen's kappa, coefficient of variation (CoV) and Bland-Altman statistics. Haemodynamic parameters were compared between patients and correlated to the estimated glomerular filtration rate, DCE-MRI parameters (n = 10) and histopathology from allograft biopsies (n = 15).For inter-observer reproducibility, kappa was 0.99 and 0.62 and CoV of flow was 12.6% and 7.8% for RA and RV, respectively. For test-retest repeatability, kappa was 0.99 and 0.5 and CoV of flow was 27.3% and 59.4%, for RA and RV, respectively. RA (p = 0.039) and RV (p = 0.019) flow were both significantly reduced in dysfunctional allografts. Both identified chronic allograft dysfunction with good diagnostic performance (RA: AUC = 0.76, p = 0.036; RV: AUC = 0.8, p = 0.018). RA flow correlated negatively with histopathologic interstitial fibrosis score ci (ρ = - 0.6, p = 0.03).4D flow parameters had better repeatability in the RA than in the RV. RA and RV flow can identify chronic renal allograft dysfunction, with RA flow correlating with histopathologic interstitial fibrosis score.• Inter-observer reproducibility of 4D flow measurements was acceptable in both the transplant renal artery and vein, but test-retest repeatability was better in the renal artery than in the renal vein. • Blood flow measurements obtained with 4D flow MRI in the renal artery and renal vein are significantly reduced in dysfunctional renal transplants. • Renal transplant artery flow correlated negatively with histopathologic interstitial fibrosis score.

In kidney transplantation, short-term allograft survival has improved due to improvements in acute rejection episodes without corresponding improvements in long-term survival. Although current organ allocation algorithms take into account human leukocyte antigen (HLA) matching to reduce antidonor alloimmune responses, it is likely that genomic variation at non-HLA loci (ie, non-HLA donor-recipient [D-R] pair mismatches) play a role in the "non-self" responses and ultimately affect long-term allograft survival. Existing data from both animal models and human studies suggest an association between non-HLA D-R mismatches and kidney allograft outcomes. In this minireview, we examine existing and emerging data and discuss putative mechanisms on the role of non-HLA D-R mismatches on long-term allograft outcomes in kidney transplantation.

Commonly available clinical parameters fail to predict early acute cellular rejection (EAR, occurring within 6 months after transplant), a major risk factor for graft loss after kidney transplantation. We performed whole-blood RNA sequencing at the time of transplant in 235 kidney transplant recipients enrolled in a prospective cohort study (Genomics of Chronic Allograft Rejection [GoCAR]) and evaluated the relationship of pretransplant transcriptomic profiles with EAR. EAR was associated with downregulation of NK and CD8(+) T cell gene signatures in pretransplant blood. We identified a 23-gene set that predicted EAR in the discovery (n = 81, and AUC = 0.80) and validation (n = 74, and AUC = 0.74) sets. Exclusion of recipients with 5 or 6 HLA donor mismatches increased the AUC to 0.89. The risk score derived from the gene set was also significantly associated with acute cellular rejection after 6 months, antibody-mediated rejection and/or de novo donor-specific antibodies, and graft loss in a cohort of 154 patients, combining the validation set and additional GoCAR patients with surveillance biopsies between 6 and 24 months (n = 80) posttransplant. This 23-gene set is a potentially important new tool for determination of the recipient’s immunological risk before kidney transplantation, and facilitation of an individualized approach to immunosuppressive therapy.