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BACKGROUND: With current immunosuppressive regimens, BK polyomavirus-associated nephropathy (BKPyVAN) is still a matter of concern. Stratification of patients at risk for allograft loss is of uttermost importance to guide treatment choice and assess prognosis. In 2018, the Banff working group proposed a classification scheme for the prognosis of BKPyVAN, but external application on independent cohorts is yet to be performed. We investigated how the 2018 Banff classification would perform in a multicenter cohort comprising 50 cases of biopsy-proven BKPyVAN compared to previously published classification systems. METHODS: We analyzed consecutive BKPyVAN cases from two Dutch university hospitals between 2002 and 2013, retrieved clinical data, and scored all biopsies according to the Banff 2018 classification, and as a comparison, 4 previously proposed BKPyVAN classification systems. We used estimated glomerular filtration rate trajectories and death-censored graft survival as primary endpoints. RESULTS: The 2018 Banff classification did not associate with estimated glomerular filtration rate decline or graft failure and performed only slightly better than the 4 previously proposed classifiers. Anti-human leukocyte antigen donor-specific antibodies (DSAs), especially in combination with ongoing biopsy-proven BKPyVAN on follow-up, did correlate with graft function and survival. Patients who were DSA+/BKPyVAN+ on follow-up had more inflammation at the baseline biopsy, which by itself was not associated with graft outcomes. CONCLUSIONS: Neither the 2018 Banff BKPyVAN classification nor previously published stratification systems could be applied to our multicenter patient cohort. Our data suggest that there might be a prognostic value for follow-up biopsies and DSA measurements to improve risk stratification after BKPyVAN, although prospective multicenter efforts with protocol measurements are needed to confirm this.

The recent recognition of complex and chronic phenotypes of T cell-mediated rejection (TCMR) has fostered the need to better evaluate the response of acute TCMR-a condition previously considered to lack relevant consequences for allograft survival-to the standard of care. In a prospective cohort of kidney recipients (n = 256) with biopsy-proven acute TCMR receiving corticosteroids, we investigated clinical, histological, and immunological phenotypes at the time of acute TCMR diagnosis and 3 months posttreatment. Independent posttreatment determinants of allograft loss included the glomerular filtration rate (GFR) (HR = 0.94; 95% CI = 0.92-0.96; P

Background Transplant glomerulopathy, a common glomerular lesion observed after kidney transplant that is associated with poor prognosis, is not a specific entity but rather the end stage of overlapping disease pathways. Its heterogeneity has not been precisely characterized to date. Methods Our study included consecutive kidney transplant recipients from three centers in France and one in Canada who presented with a diagnosis of transplant glomerulopathy (Banff cg score ≥1 by light microscopy), on the basis of biopsies performed from January of 2004 through December of 2014. We used an unsupervised archetype analysis of comprehensive pathology findings and clinical, immunologic, and outcome data to identify distinct groups of patients. Results Among the 8207 post-transplant allograft biopsies performed during the inclusion period, we identified 552 biopsy samples (from 385 patients) with transplant glomerulopathy (incidence of 6.7%). The median time from transplant to transplant glomerulopathy diagnosis was 33.18 months. Kidney allograft survival rates at 3, 5, 7, and 10 years after diagnosis were 69.4%, 57.1%, 43.3%, and 25.5%, respectively. An unsupervised learning method integrating clinical, functional, immunologic, and histologic parameters revealed five transplant glomerulopathy archetypes characterized by distinct functional, immunologic, and histologic features and associated causes and distinct allograft survival profiles. These archetypes showed significant differences in allograft outcomes, with allograft survival rates 5 years after diagnosis ranging from 88% to 22%. Based on those results, we built an online application, which can be used in clinical practice on the basis of real patients. Conclusions A probabilistic data-driven archetype analysis approach applied in a large, well defined multicenter cohort refines the diagnostic and prognostic features associated with cases of transplant glomerulopathy. Reducing heterogeneity among such cases can improve disease characterization, enable patient-specific risk stratification, and open new avenues for archetype-based treatment strategies and clinical trials optimization.

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

Novel tools are needed to improve diagnostic accuracy and risk prediction in BK virus nephropathy (BKVN). We assessed the utility of intragraft gene expression testing for these purposes. Eight hundred genes were measured in 110 archival samples, including a discovery cohort of native kidney BKVN (n = 5) vs pure T cell-mediated rejection (TCMR; n = 10). Five polyomavirus genes and seven immune-related genes (five associated with BKVN and two associated with TCMR) were significantly differentially expressed between these entities (FDR < 0.05). These three sets of genes were further evaluated in samples representing a spectrum of BK infection (n = 25), followed by a multicenter validation cohort of allograft BKVN (n = 60) vs TCMR (n = 10). Polyomavirus 5-gene set expression reliably distinguished BKVN from TCMR (validation cohort AUC = 0.992), but the immune gene sets demonstrated suboptimal diagnostic performance (AUC ≤ 0.720). Within the validation cohort, no significant differences in index biopsy gene expression were identified between BKVN patients demonstrating resolution (n = 35), persistent infection (n = 14) or de novo rejection (n = 11) 6 months following a standardized reduction in immunosuppression. These results suggest that, while intragraft polyomavirus gene expression may be useful as an ancillary diagnostic for BKVN, assessment for concurrent TCMR and prediction of clinical outcome may not be feasible with current molecular tools.

Background BK virus nephropathy (BKPyVN) is a major complication after renal transplantation. Little is known about the intra renal immune response during BKPyVN. The role of macrophages remains elusive. The activation of aryl hydrocarbon receptor (AHR) - a transcription factor involved in drug metabolism - plays a key role in inflammation and viral tolerance through modulation of macrophages polarization. Since AHR has not been studied in kidney transplantation, our aim was to compare the AHR expression within renal grafts in BKPyVN with T-cell mediated rejection (TCMR) as a control. Methods We evaluated AHR expression in kidney grafts from BKPyVN (n = 8) with TCMR as control (n = 6) among cases with available frozen material for AHR gene intragraft transcription measurement and stainings for AHR, CD68 and CD45. Results AHR transcription was higher in BKPyVN grafts versus TCMR (p = 0.03). While CD68 + or CD45 + cell expression did not differ within infiltrates (median score = 3 in both groups; p = 1.0 and 0.69, respectively), a higher proportion of nuclear AHR expression was found in BKPyVN for CD68 + and CD45 + cells when compared with TCMR (score median 2 vs 0; p = 0.007 and 1 vs 0; p = 0.013, respectively). Conclusions We describe for the first time a higher expression of AHR in inflammatory cell infiltrates from BKPyVN versus TCMR renal biopsies. Further studies are required to explore AHR as a potential target in the modulation of inflammatory response in BKPyVN with known modulating ligands.

A major hurdle to improving clinical care in the field of kidney transplantation is the lack of biomarkers of the response to antibody-mediated rejection (ABMR) treatment. To discover these we investigated the value of complement-binding donor-specific anti-HLA antibodies (DSAs) for evaluating the response to treatment. The study encompassed a prospective cohort of 139 kidney recipients with ABMR receiving the standard of care treatment, including plasma exchange, intravenous immunoglobulin and rituximab. Patients were systematically assessed at the time of diagnosis and three months after treatment initiation for clinical and allograft histological characteristics and anti-HLA DSAs, including their C1q-binding ability. After adjusting for clinical and histological parameters, post-treatment C1q-binding anti-HLA DSA was an independent and significant determinant of allograft loss (adjusted hazard ratio 2.57 (95% confidence interval 1.29-5.12). In 101 patients without post-treatment C1q-binding anti-HLA DSA there was a significantly improved glomerular filtration rate with significantly reduced glomerulitis, peritubular capillaritis, interstitial inflammation, tubulitis, C4d deposition, and endarteritis compared with 38 patients with posttreatment C1q-binding anti-HLA DSA. A conditional inference tree model identified five prognostic groups at the time of post-treatment evaluation based on glomerular filtration rate, presence of cg lesion and C1q-binding anti-HLA DSA (cross-validated accuracy: 0.77). Thus, circulating complement-binding anti-HLA DSAs are strong and independent predictors of allograft outcome after standard of care treatment in kidney recipients with ABMR.

Anti-angiotensin II type 1 receptor (AT1R) antibodies have been associated with allograft rejection. We hypothesized that circulating AT1R antibodies might identify kidney transplant recipients at increased risk of allograft rejection and loss who are not identified by the HLA system. We prospectively enrolled 1845 kidney transplant recipients from two centers. Donor-specific HLA antibodies (DSAs) and AT1R antibodies were measured at the time of the first acute rejection episode or at 1 year post-transplant. Allograft biopsy was performed to evaluate the rejection phenotype and to assess for endothelial activation. Overall, 371 (20.1%) participants had AT1R antibodies, 334 (18.1%) had DSAs, and 133 (7.2%) had both. AT1R antibodies were associated with an increased risk of allograft loss (adjusted HR 1.49, 95% CI 1.07-2.06 for AT1R antibodies alone and 2.26, 95% CI 1.52-3.36 for AT1R antibodies and DSAs). Participants with AT1R antibodies had a higher incidence of antibody-mediated rejection (AMR) compared with participants without AT1R antibodies (25.0% vs. 12.9%). Among 77 participants with histological features of AMR but without DSAs, 51 (66.2%) had AT1R antibodies. Compared to participants with prototypical DSA-mediated rejection, those with AT1R antibody-associated rejection had a higher prevalence of hypertension, more vascular rejection with arterial inflammation, higher levels of endothelial-associated transcripts, and lack of complement deposition in allograft capillaries. Thus, AT1R antibodies may identify kidney transplant recipients at high risk of allograft rejection and loss, independent of the HLA system. Recognition of complement-independent AT1R antibody-mediated vascular rejection could lead to the development of new treatment strategies to improve allograft survival.

Background Donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) can be preformed or de novo (dn). Strategies to manage preformed DSA are well described, but data on the management and outcomes of dnDSA are lacking. Methods We performed a retrospective analysis of data from a single centre of the management and outcomes of 22 patients in whom a dnDSA was identified with contemporary and follow up biopsies. Results Evolution from baseline to follow up revealed a statistically significant loss of kidney function (estimated glomerular filtration rate: 45.9 ± 16.7 versus 37.4 ± 13.8 ml/min/1.73 m2; p = 0.005) and increase in the proportion of patients with transplant glomerulopathy (percentage with cg lesion ≥1: 27.2% vs. 45.4%; p = 0.04). Nine patients were not treated at the time of dnDSA identification, and 13 patients received various drug combinations (e.g., corticosteroids, plasmapheresis, thymoglobulins and/or rituximab). No significant pathological changes were observed for the various treatment combinations. Conclusion Our retrospective analysis of a small sample suggests that dnDSA should be considered a risk factor for the loss of kidney function independent of the baseline biopsy, and multidisciplinary evaluations of the transplant patient are a necessary requirement. Further confirmation in a multicentre prospective trial is required.

Kidney graft biopsy is the main diagnostic tool used in kidney transplantation to classify disease processes. Graft biopsies are performed at a predetermined time (protocol) or by indication. However, they bear limitations including the interobserver variability. Intragraft transcriptomics has taken the center stage in the field of biomarkers research in kidney transplantation as it might improve disease stratification. Although already included in the international Banff classification, clinical transition has yet to be confirmed in external validation studies. Also transcriptomics performance could benefit from association with other omics data.La biopsie du greffon rénal est l’un des principaux outils diagnostiques pour la classification des processus pathologiques en transplantation rénale. Les biopsies du greffon sont effectuées à temps fixe (biopsie de protocole) ou sur indication. Toutefois, elles ont plusieurs limitations dont la variabilité interobservateur. La transcriptomique intragreffon a pris une place prépondérante dans la recherche sur les biomarqueurs en transplantation rénale visant à une meilleure stratification des maladies. Bien que déjà incluse dans la classification internationale de Banff, la transition clinique doit être encore confirmée par des études de validation externe. Enfin, l’association à d’autres plateformes omics pourrait permettre une meilleure résolution de cet outil diagnostique.

The handling of electrolytes by the kidney is essential for homeostasis. However, the heritability of these processes, the first step in gene discovery, is poorly known. To help clarify this, we estimated the heritability of serum concentration, urinary excretion, renal clearance, and fractional excretion of sodium, potassium, magnesium, calcium, phosphate, and chloride in a population-based study. Nuclear families were randomly selected from the general population in Lausanne, Geneva, and Bern, Switzerland, and urine collected over 24-hour periods. We used the ASSOC program (S.A.G.E.) to estimate narrow sense heritability, including sex, age, body mass index, and study center as covariates in the model. The 1128 participants, from 273 families, had a mean age of 47 years, body mass index of 25.0 kg/m2, and an estimated glomerular filtration rate (CKD-EPI) of 98 mL/min/1.73 m2. The heritability of serum concentration was highest for calcium, 37% and lowest for sodium, 13%. The heritability of 24-hour urine clearances, excretions, and fractional excretions ranged from 15%, 10%, and 16%, respectively, for potassium to 45%, 44%, and 51%, respectively, for calcium. All probability values were significant. The heritability for phosphate-related phenotypes was lower than that for calcium. Thus, the serum and urine concentrations as well as urinary excretion and renal handling of electrolytes are heritable in the general adult population. The phenotypic variance attributable to additive genetic factors was variable and was higher for calcium. These results pave the way for identifying genetic variants involved in electrolyte homeostasis in the general population. ispartof: Kidney International vol:92 issue:6 pages:1536-1543 ispartof: location:United States status: published

Paraneoplastic nephrotic syndrome is often a complication in patients with cancer, and various histologic lesions have been described in the kidney. We report the case of a 76-year-old woman who presented with a podocytopathy that was found to be associated with a small cell lung carcinoma (SCLC). One cycle of carboplatin-etoposide combination therapy led to resolution of nephrotic syndrome and remission of the lung carcinoma. C-Maf-inducing protein (C-Mip) was overexpressed in both podocytes and cancer cells, but was not found in control kidney and lung tissue samples. C-Mip also was absent in SCLC cells from 30 patients without nephrotic syndrome. Exposing cultured podocytes to a sample of our patient's serum that was collected prior to chemotherapy led to disorganization of the podocyte cytoskeleton and induction of C-Mip expression, which was not observed with control serum or our patient's serum sampled after chemotherapy. These observations suggest that C-Mip may play an important role in SCLC-related podocytopathy and that a circulating factor likely induces its expression in the kidney.