Kidney International

BackgroundKidney transplant recipients with COVID-19 are at high risk of poor outcome because of comorbidities and immunosuppression. The effects of immunosuppressive therapy reduction are unclear in patients with COVID-19. MethodsWe conducted a retrospective study on 45 consecutive kidney transplant recipients followed at the University Hospital of Modena who tested positive for COVID-19 by RT-PCR analysis. ResultsThe median age of patients was 56.1 (interquartile range, [IQR] 47.3-61.1) years with a predominance of male (64.4%). Kidney transplantation vintage was 10.1 (2.7-16) years, and more than half of patients (55.6%) was on triple immunosuppressive therapy. Early reduction of immunosuppression occurred in 62.8% of patients and included antimetabolite (88.8%) and calcineurin inhibitor withdrawal (22.2%). Of the 45 patients, 88.9% became symptomatic and 40% required hospitalization. Overall mortality was 17.8%. There were no differences in outcomes between full- and reduced-dose immunosuppressive therapy at the end of follow-up. One hospitalized patient experienced irreversible graft failure. There were no differences in serum creatinine level and proteinuria in non-hospitalized patients with COVID-19. Admitted patients had better kidney function after dismission (P=0.019). Risk factors for death were age (odds ratio [OR]: 1.19; 95%CI: 1.01-1.39), and duration of kidney transplant (OR: 1.17; 95%CI: 1.01-1.35). One kidney transplant recipient experienced symptomatic COVID-19 reinfection after primary infection and anti-SARS-CoV-2 mRNA vaccine. ConclusionsDespite the reduction of immunosuppression, COVID-19 affected survival of kidney transplant recipients with COVID-19. Age and duration of kidney transplant were independent predictors of death in COVID-19. Early kidney function was favorable in most survivors after COVID-19.

BackgroundKidney transplant recipients (KTRs) were given a 3-dose primary series of COVID-19 vaccination as they were vulnerable to infection due to immunosuppression. MethodsThis study was a longitudinal evaluation of nAB dynamics in 43 KTRs in a low-middle income setting receiving 3-dose homologous (mRNA-1273- mRNA-1273- BNT162b2) vaccination against COVID-19. Samples were obtained at time-points (TP) 0- pre-vaccination, TP1- 1 month post first dose(mRNA-1273), TP2-1-month post second dose (mRNA-1273), TP3- 4 months post-second dose, TP4- 2 weeks post-third dose(BNT162b2), TP5-5 months post-third dose and TP6-12 months-post third dose. Anti-SARS-CoV-2 nAB were detected using Genscript cPassTM pseudoviral neutralization kit. Demographic and clinical details were obtained through interviewer administered questionnaires. ResultsPre-vaccination serum analysis showed n=7 KTRs had prior COVID-19 infection, classified as infected+vaccinated, while others were vaccinated. Both groups were similar in age(41.7years vs 46.7years,p=0.2383), gender, and transplant characteristics. Seroconversion and MAB in the vaccinated and infected+vaccinated KTRs were:TP1-8.3% vs 100%(p<0.001), MAB-64.3IU/ml vs 1424IU/ml(p=0.0167TP2-52.7% vs 100%(p=0.0194), MAB-175IU/ml vs 2790IU/ml(p<0.0001), TP3-100% vs 100%, MAB-106IU/ml vs 2153IU/ml(p=0.0002), TP4-100% vs 100%, MAB-736 IU/ml vs 2152IU/ml(p=0.0307) and TP6-100% vs 100%, MAB >2565IU/ml vs >3028IU/ml(p=0.5238) No factors were associated with seroconversion or MAB. ConclusionKTRs receiving a three-dose mRNA COVID-19 vaccine regime maintained strong nAB levels at one-year follow-up, with comparable antibody levels seen between KTRs with prior infection + vaccination and vaccination alone.

BackgroundC3 glomerulopathy (C3G) and immune-complex membranoproliferative glomerulonephritis (IC-MPGN) are rare disorders that frequently result in kidney failure over the long-term. At present, there are no disease-specific treatments approved for these disorders, although there is much interest in the therapeutic potential of complement inhibition. However, the limited duration and necessarily small size of controlled trials means there is a need to quantify how well short-term changes in eGFR and proteinuria predict the clinically important outcome of kidney failure. We aimed to address this using longitudinal data from the UK National Registry of Rare Kidney Diseases (RaDaR). MethodsRaDaR involves both retrospective and prospective data collection with linkage to hospital laboratories via automated feeds. 667 patients were included. Analyses of kidney survival were conducted using Kaplan-Meier and Cox regression. eGFR slope was estimated using linear mixed models. ResultsOver a median of 10.1 (IQR 6.9-14.3) years follow-up, 253/667 (38%) reached kidney failure. There was no difference in progression to kidney failure between C3G, IC-MPGN and Primary MPGN Not Otherwise Specified subgroups (p=0.75). Baseline urine protein creatinine ratio (UPCR), although high, was not associated with kidney failure risk. 2-year eGFR slope had a modest effect on kidney failure risk. In contrast, both 20-50% and 0.44g/g (50mg/mmol) reductions in time-averaged UPCR at 12 months were strongly associated with lower kidney failure risk (p[&le;]0.002). Most notably, those with a UPCR <0.88g/g (<100mg/mmol) at 12 months had a substantially lower risk of kidney failure (HR 0.15 (95%CI 0.05-0.41). ConclusionsWe quantified the relationships between early changes in both eGFR and proteinuria with long-term kidney survival. We demonstrate that proteinuria a short time after diagnosis is a strong predictor of long-term outcome and that a UPCR <0.88g/g (<100mg/mmol) at 1 year is associated with a substantially lower kidney failure risk.

IntroductionConventional markers are not reliable predictors of histological activity of lupus nephritis (LN). We aimed to examine the utility of urine {gamma}-interferon-inducible protein (IP-10) in predicting LN flares, diagnosis of LN, and forecasting treatment response. MethodsSLE patients who fulfilled the ACR 1997 criteria with history of LN were enrolled. Urine IP-10 was measured at least once during routine quarterly visits, at the time of diagnosis of active LN, and monthly during induction therapy for 6 months. ResultsThere were 65 active LN and 46 inactive LN included. The mean urine IP-10 levels among the active and inactive LN were 2.69 (95%CI 2.53-2.86) and 2.18 (95%CI 1.96-2.39) log copies/mcg total RNA respectively (p-value < 0.0001). Clinicopathological discordance was observed in 9 of 55 (16%) biopsied patients (5 with proliferative LN without proteinuric flare and 4 with nephrotic-range proteinuria from glomerulosclerosis). Urine IP-10 predicted histological activity of LN with 91% accuracy, compared to 84% with proteinuric flare. Within two years, half of the clinically inactive LN patients with positive baseline urine IP-10 developed LN flare, whereas no flares were observed in patients with negative baseline urine IP-10. Urine IP-10 levels were not associated with treatment response at 6 months. ConclusionUrine IP-10 may reflect histological activity of LN more accurately than conventional markers, especially in patients with clinicopathologic discrepancy. Clinically inactive LN patients with positive urine IP-10 were at a higher risk of developing LN flare. Key messages- The majority of the studies on novel biomarkers in LN lacked renal biopsy and relied on clinical indicators to determine histological activity. As a result, the validity of these studies may be jeopardized. - According to this study, clinicopathological discordance was found in 16% of LN patients who underwent renal biopsy. Urine IP-10 outperformed urinary protein level in differentiating histologically active LN from inactive LN (accuracy 91% versus 84%). - Within two years, half of the clinically inactive LN patients who had positive urine IP-10 developed LN flares, whereas none of those who had negative urine IP-10 did. - Urine IP-10 may aid in the diagnosis of histologically active LN, particularly in patients with clinicopathologic discrepancy. Urine IP-10 monitoring in clinically inactive LN patients may predict the risk of future LN flares.

IntroductionGlomerulonephritis (GN) with crescents and IgA deposits on kidney biopsy poses a frequent diagnostic and therapeutic dilemma because of multiple possibilities. MethodsNative kidney biopsies showing IgA deposition and crescents (excluding lupus nephritis) were identified from our biopsy archives between January 2010 and December 2021. Detailed clinico-pathologic features were assessed. One-year clinical follow-up on a subset of cases was performed. ResultsA total of 285 cases were identified and these clustered into IgA nephropathy (IgAN, n=108), Staphylococcus or other infection-associated-GN (SAGN/IRGN, n=46), and anti-neutrophil cytoplasmic antibody associated-GN (ANCA-GN, n=24) based on constellation of clinico-pathologic features, but 101 cases (Group X) could not be definitively differentiated. The reasons have been elucidated, most important being atypical combination of clinico-pathologic features and lack of definitive evidence of active infection. Follow-up (on 72/101 cases), revealed that clinicians working diagnosis was IgAN in 42%, SAGN/IRGN in 24%, ANCA-GN in 24%, and others in 7% of the cases, but treatment approach varied from supportive/antibiotics to immunosuppression in each subgroup. Comparing these cases as "received immunosuppression" versus "no-immunosuppression", only two features - C3-dominant staining; and possibility of recent infection differed (higher in the no-immunosuppression group [p<0.05]). Renal loss was higher in the no-immunosuppression subgroup, but not statistically significant (p=0.11). ConclusionDiagnostic overlap may remain unresolved in a substantial number of kidney biopsies with glomerular crescents and IgA deposits. A case-by-case approach, appropriate antibiotics if infection is ongoing, and consideration for cautious immunosuppressive treatment for progressive renal dysfunction may be needed for best chance of renal recovery.

BackgroundEvidence for involvement of NK cells and monocytes as prime agents in the process of human kidney transplant rejection is expanding quickly. These cells express FCGR3A, used for antibody-dependent cellular cytotoxicity (ADCC) after engagement with donor-specific antibodies on graft cells. A functional genetic polymorphism in the Fc fragment of IgG IIIa receptor (CD16a) gene (FCGR3A) results in a high-affinity (V158 allele) or low-affinity receptor (F158 allele). MethodsWe studied the impact of the FCGR3A F158V genotype on graft histology, function, and outcomes in a large, unselected observational cohort study of 1259 kidney transplants (40% F/F158, 46% F/V158 and 14% V/V158) with 5435 post-transplant transplant biopsies. ResultsPresence of at least one V158 allele was proportionally and significantly associated with a lower rate of C4d without rejection (F/V158, HR=0.51 [0.29-0.92], p=0.026; V/V158, HR=0.28 [0.08-0.90], p=0.033). Additionally, V/V158 was strongly associated with chronic active antibody-mediated rejection (HR=9.13 [1.89-44], p=0.006) and transplant glomerulopathy (HR=1.67 [1.01-2.75], p=0.046). The V/V158 genotype significantly associated with accelerated graft functional decline (-1.68 mL/min/y versus -0.74 mL/min/y (F/F158), p=0.034) and a higher rate of graft failure (HR=1.49 [1.01-2.20], p=0.045). This association was driven by transplants with post-transplant rejection. ConclusionsOur findings suggest that FCGR3A affinity is key in AMR pathobiology. Low affinity of this receptor (F158 allele) might associate with abrogation of effective downstream ADCC, even in the presence of complement activation (C4d deposition), while high affinity of this receptor (V158 allele) might escalate AMR, accelerating evolution to more chronic AMR phenotypes (transplant glomerulopathy). This framework provides an immunobiological link between lower C4d without rejection rates, higher chronic active AMR/ transplant glomerulopathy rates and adverse graft outcomes associated with the FCGR3A V/V158 genotype. Key study findingsO_LIV/V158 associates with higher rates of chronic active AMR/transplant glomerulopathy, and lower rates of C4d without rejection C_LIO_LIV/V158 drives faster graft decline and graft failure, especially in transplants complicated with rejection C_LIO_LIFCGR3A F158V might link complement activation and ADCC in AMR pathobiology, accelerating chronic alloimmune injury C_LI

BackgroundMembranous nephropathy (MN) is a chronic, autoimmune kidney disease characterized by an autoimmune response against podocyte-specific antigens, compromising renal functions. Few studies attempted to mechanistically describe how rituximab influences Th cells and whether this impacts on clinical outcome. MethodsTh cell profile of MN patients was characterized using peripheral blood mononuclear cell samples from a multi-centre, prospective clinical trial. Th cell subsets (Treg, Th17 and Th1) were measured by flow cytometry at baseline and after rituximab treatment during a two years follow-up. In vitro studies on fresh peripheral blood samples and isolated cell populations were performed to investigate the mechanisms through which rituximab induces Treg cells. FindingsBefore rituximab treatment, MN patients had a Th17/Treg imbalance when compared to age-matched healthy donors (p=0.004). Responders had significantly higher proportions of Treg cells post-rituximab than non-responders (p=0.037). In vitro, rituximab treatment induced Treg cells when using peripheral blood samples from MN patients, however the induction was lost when isolated T cells were used instead of whole blood (p=0.02). Rituximab did not directly induce Treg cells but required a specific cellular environment composed by at least B and Natural Killer (NK) cells as observed by treating pooled T, B and NK cells. Finally, using complementation assays, we demonstrated that rituximab-mediated Treg induction relied on cytokines, mainly Transforming growth factor {beta} (TGF{beta}), secreted by activated NK cells. InterpretationRituximab induces Treg through cytokines produced by NK cells probably during the mechanism of B cell depletion by antibody-dependent cell-mediated cytotoxicity. This mechanism could potentiate the likelihood of remission in MN patients by counteracting loss of immune tolerance.

We aimed to describe the outcomes of Omicron infection in kidney transplant recipients (KTR), compare the efficacy of the community therapeutic interventions and report the safety profile of molnupiravir. From 142 KTRs diagnosed with COVID-19 infection after Omicron had become the dominant variant in the UK, 116 (78.9%) cases were diagnosed in the community; 47 receiving sotrovimab, 21 molnupiravir and 48 no treatment. 10 (20.8%) non-treated patients were hospitalised following infection, which was significantly higher than the sotrovimab group (2.1%), p=0.0048, but not the molnupiravir treated group (14.3%), p=0.47. The only admission following sotrovimab occurred in a patient infected with BA.2. One patient from the molnupiravir and no-treatment groups required ICU support, and both subsequently died, with one other death in the no-treatment group. No patient receiving sotrovimab died. 6/116 (5.2%) patients required dialysis following their diagnosis; 2 (9.5%) patients receiving molnupiravir and 4 (8.3%) no-treatment. This requirement was significantly higher in the molnupiravir group compared with the sotrovimab treated patients, in whom no patient required dialysis, p=0.035. Both molnupiravir treated patients requiring dialysis had features of systemic thrombotic microangiopathy. Post-vaccination serostatus was available in 110 patients. Seropositive patients were less likely to require hospital admission compared with seronegative patients, 6 (7.0%) and 6 (25.0%) respectively, p=0.023. Seropositive patients were also less likely to require dialysis therapy, p=0.016. In conclusion, sotrovimab treatment in the community was associated with superior patient and transplant outcomes; its clinical efficacy against the BA.2 variant requires a rapid review. The treatment benefit of molnupiravir was not evident, and wider safety reporting in transplant patients is needed.

BackgroundPhospholipase A2 receptor-associated membranous nephropathy (PLA2R-MN) is an anti-PLA2R antibody (PLA2R-Ab) mediated autoimmune kidney disease. Although antibody titer correlates closely with disease activity, whether it can provide longer-term predictions on disease course and progression is unclear. Rituximab, a B-cell depletion therapy, has become the first-line treatment option for PLA2R-MN; however, the response to Rituximab varies among patients. MethodsWe developed a flow cytometry-based test that detects and quantifies PLA2R antigen-specific memory B cells (PLA2R-MBCs) in peripheral blood, the primary source for PLA2R-Ab production upon disease relapse. We applied the test to 159 blood samples collected from 28 patients with PLA2R-MN (at diagnosis, during and after immunosuppressive treatment, immunological remission, and relapse) to evaluate the relationship between circulating PLA2R-MBC levels and disease activity. ResultsThe level of PLA2R-MBCs in healthy controls (n=56) is less than or equal to 1.5% of the total MBC compartment. High circulating PLA2R-MBC levels were detected in two patients post-Rituximab despite achieving immunologic and proteinuric remission, as well as in two patients with negative serum autoantibody but increasing proteinuria. Elimination of these cells with Rituximab improved clinical outcomes. Moreover, five patients exhibited elevated PLA2R-MBC levels before disease relapse, followed by a rapid decline to baseline when relapse became clinically evident. COVID-19 vaccination or SARS-CoV-2 infection significantly affected the dynamics of circulating PLA2R-MBCs. ConclusionsThis study suggests that monitoring PLA2R-MBC levels in patients with PLA2R-MN may help refine and individualize immunosuppressive therapy and predict disease course and progression. The technology and findings may also have broader applications in the clinical management of other autoimmune diseases.

BackgroundImmunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Geographic differences in disease course and treatment response are well recognized. The purpose of this analysis was to study clinical and histological characteristics, treatment practices and outcome of IgAN cases from a Swiss tertiary center. MethodsThis retrospective cohort analysis identified 158 cases of adult biopsy-proven IgAN by chart review diagnosed between 1980 and 2017. Following detailed phenotypisation, standard descriptive methods and univariate analysis corrected by the Bonferroni method were applied. ResultsPatients were majorly male and of Caucasian descent. At diagnosis, mean estimated glomerular filtration rate (eGFR) was 55.4 ml/min/1.73 m2, mean proteinuria was 2.4 g/d, 69.9% of the patients were hypertensive. Clinical presentation varied according to age. Initial biopsies showed moderate to severe tubular atrophy and interstitial fibrosis (IFTA) in 29.1% and crescents in 36.7% of cases. Therapy included renin-angiotensin-aldosterone-inhibitors in 86.7%, immunosuppressive therapy in 46.8% including steroids and other immunosuppressive drugs (28.7%), mainly azathioprin. Outcome included 34.1% complete and 22.2% partial remissions, relapses in 32.0% of patients, while 43.0% of patients progressed to ESKD during follow-up (median 100.0 months). Recurrence rate after transplantation was 18.8%. Immunosuppressive therapy was more frequently used in patients with higher proteinuria level and crescents. Predictors of progression were lower eGFR, higher proteinuria and higher extent of IFTA on the initial biopsy. ConclusionsThis retrospective cohort analysis gives insight into characteristics and outcome of patients with IgAN from a Swiss tertiary center, treatment practices as well as predictors of outcome and therapy choices. Key learning pointsO_ST_ABSWhat was knownC_ST_ABSO_LIA wide range of clinical presentations exists for immunoglobulin A nephropathy (IgAN) pointing to IgAN as a disease spectrum rather than a single disease entity C_LIO_LIAdditional important geographic differences regarding disease prevalence, disease course and response to therapies have been recognized C_LIO_LIProgression to end-stage kidney disease (ESKD) occurs in a substantial part of affected patients C_LI This study addsO_LIIn this cohort, a comparatively high proportion of patients was treated by immunosuppressive therapy including non-steroid treatment underlining the heterogeneous nature of treatment practices worldwide C_LIO_LIPredictors of the use of immunosuppressive therapy in this cohort have been identified C_LIO_LISimilarly to recent UK registry data, a high rate of progression to ESKD has been found including patients with low baseline proteinuria level C_LI Potential impactO_LIThese findings further underline the importance of achieving an improved characterization and pathogenetic understanding of IgAN disease subtypes through ongoing research efforts C_LIO_LIAt the beginning of the current new therapeutic era for patients with IgAN, this goal has now become more relevant than ever C_LI

BackgroundCOVID-19-associated acute kidney injury frequency, severity and characterisation in critically ill patients has not been reported. MethodsSingle-center cohort performed from March 3, 2020, to April 14, 2020 in 4 intensive care units in Bordeaux University Hospital, France. All patients with COVID19 and pulmonary severity criteria were included. AKI was defined using KDIGO criteria. A systematic urinary analysis was performed. The incidence, severity, clinical presentation, biological characterisation (transient vs. persistent acute kidney injury; proteinuria, hematuria and glycosuria), and short-term outcomes was evaluated. Results71 patients were included, with basal serum creatinine of 69 {+/-} 21 {micro}mol/L. At admission, AKI was present in 8/71 (11%) patients. Median follow-up was 17 [12-23] days. AKI developed in a total of 57/71 (80%) patients with 35% Stage 1, 35% Stage 2, and 30% Stage 3 acute kidney injury; 10/57 (18%) required renal replacement therapy. Transient AKI was present in only 4/55 (7%) patients and persistent AKI was observed in 51/55 (93%). Patients with persistent AKI developed a median urine protein/creatinine of 82 [54-140] (mg/mmol) with an albuminuria/proteinuria ratio of 0.23 {+/-} 20 indicating predominant tubulo-interstitial injury. Only 2 (4%) patients had glycosuria. At Day 7 onset of after AKI, six (11%) patients remained dependent on renal replacement therapy, nine (16%) had SCr > 200 {micro}mol/L, and four (7%) died. Day 7 and day 14 renal recovery occurred in 28% and 52 % respectively. ConclusionCOVID-19-associated AKI is frequent, persistent severe and characterised by an almost exclusive tubulo-interstitial injury without glycosuria.

BackgroundClass switching toward spike (S)-binding IgG4 antibodies after mRNA-based COVID-19 vaccination has been observed, an antibody subclass with strong neutralizing but limited effector activity. While this has been reported in healthy individuals, subclass dynamics in immunocompromised kidney patients are unclear. We assessed IgG subclass patterns and S-specific B-cell phenotypes up to 6 months after a two-dose mRNA-1273 vaccination schedule in kidney transplant recipients (KTRs), dialysis patients, and patients with chronic kidney disease (CKD). MethodsIn this exploratory study, KTRs (n=11), dialysis patients (n=5), CKD stage G4-5 patients (eGFR <30 ml/min/1.73m2, n=5), and controls without known kidney disease (eGFR >45 ml/min/1.73m2, n=8) received two mRNA-1273 doses 28 days apart. Blood was collected pre-vaccination (V1), and at 28 days (V3) and 6 months (V4) after the second dose. S1-specific IgG antibodies were measured by a validated fluorescent bead-based multiplex-immunoassay, and participants seronegative at V1 and seropositive at V3 were included. B cells were phenotyped by flow cytometry. ResultsFive of 11 KTRs had no detectable S-binding B cells, whereas all other groups mounted responses. Across responders, the frequency of S-binding B cells increased from V1 (median 0.08%) to 0.49% at V3 and to 0.84% at V4 (both p<0.0001). S-binding B cells mainly comprised IgG+ plasmablasts. The IgG4:IgG1 log-ratio increased significantly from V3 to V4 (p<0.001), indicating a relative shift toward IgG4; absolute frequencies were comparable across the groups. ConclusionsApproximately half of KTRs lacked detectable S-binding B cells after two mRNA-1273 doses, despite antibody formation. Among responders, S-binding B cells persisted up to 6 months after vaccination with a relative shift toward IgG4, a pattern also observed in dialysis patients, CKD patients and controls. The clinical significance of this subclass skewing requires confirmation in larger cohorts with functional antibody readouts.

Monoclonal gammopathies have been associated with kidney injury. Nephrotoxicity of the secreted monoclonal (M)-protein relies on a complex interplay between biological characteristics and serum concentration. Little is known about the epidemiology and clinical manifestations of the different types of monoclonal gammopathies in patients with kidney disease. We enrolled all patients with monoclonal gammopathy who underwent kidney biopsy between January 2000 and March 2017. Data about demographics, clinical manifestations and histological lesions were collected retrospectively. Monoclonal gammopathy was detected in 174 (13%) patients with a mean age of 66.4{+/-}13.1 years. M-protein was secreted by monoclonal gammopathy of undetermined significate (MGUS) (52,8%), myeloma multiple (MM) (25.2%), primary amyloidosis (AL) (9,1%), smoldering MM (7 %), non-Hodgkin lymphoma (NHL) (6.8%) and HL (1.7%). Monoclonal gammopathy of renal significance (MGRS) accounted for 6.5% in patients with MGUS and 14.2% in patients with smoldering MM. Evaluation of kidney biopsy revealed that M-protein was directed involved in causing kidney injury in MM (93.1%) and NHL (8,3%). MM was the only gammopathy significantly associated with an increased risk of kidney injury (odds ratio [OR]=47.5, CI95%, 13.7-164.9; P=<0.001). While there were no significant differences in the progression toward end-stage renal disease or dialysis (P=0.776), these disorders were associated with a different risk of death (P=0.047) at the end of the follow-up. Monoclonal gammopathy was a frequent finding in patients with kidney disease. Kidney biopsy had a key role in identifying the underlying monoclonal gammopathy and recognizing the causal relationship between M-protein and kidney injury.

BackgroundOvert proteinuria (>1.0 g/day) is a well-established risk factor for kidney disease progression in IgA nephropathy (IgAN). However, recent evidence suggests that even low-grade proteinuria, typically defined as 0.5-1.0 g/day, may be clinically significant. The prognostic impact of low-grade proteinuria has not been systematically evaluated. MethodsWe conducted a systematic review and meta-analysis to evaluate the association between low-grade proteinuria and adverse kidney outcomes in patients with IgAN. A systematic literature search was performed on PubMed and Web of Science. Eligible studies included those reporting on kidney outcomes such as estimated glomerular filtration rate (eGFR) decline, kidney failure, or eGFR slope in relation to low-grade proteinuria measured either at baseline or during follow-up (e.g., time-averaged proteinuria [TAP]). Data were synthesized using random-effects meta-analysis. No funding was received for this review. The protocol was registered in OSF REGISTRIES [https://osf.io/5dfqr]. ResultsA total of 23 studies involving 15,289 patients met the inclusion criteria. Baseline low-grade proteinuria was significantly associated with an increased risk of adverse kidney outcomes compared to proteinuria below 0.5 g/day (pooled hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.36-2.20). Similarly, low-grade TAP was associated with a higher risk of kidney outcomes (pooled HR 2.87, 95% CI 1.48-5.56) and a significantly steeper annual decline in eGFR (mean difference -1.02 mL/min/1.73 m2/year, 95% CI -1.60 to -0.45). Subgroup analyses based on geographic region and leave-one-out sensitivity analyses were consistent with the overall findings. ConclusionsLow-grade proteinuria, whether assessed at baseline or over time, is an important predictor of kidney disease progression in patients with IgAN. These results reinforce recent clinical guidelines recommending proteinuria control under 0.5 g/day. Long-term suppression of proteinuria should be considered a key therapeutic goal in IgAN.

The response of the immune system to COVID-19 in end stage kidney disease patients who undergo kidney transplantation has yet to be described. We report data on 72 patients who underwent SARS-CoV-2 antibody testing both before and after kidney transplantation and were followed for a median of 186 days (range 83, 277). Of the 25 patients with a positive antibody test at the time of transplant, 17 (68%) remained positive after transplantation. Patients were significantly more likely to have a persistently positive test if they reported a symptomatic COVID-19 infection prior to transplant (p=0.01). SARS-CoV-2 IgG index values were measured in a subset of kidney transplant recipients and compared to wait -listed dialysis patients. These assays demonstrated a more significant decline in IgG (58% versus 14% p = 0.008) in transplant recipients when compared to dialysis patients tested during the same time period. Additional analysis of the quality of the immune response measuring the binding of SARS-CoV-2 antibodies to the receptor-binding domain (RBD binding), the antibody neutralizing capability, and the antibody avidity demonstrated a more pronounced effect when comparing pre-transplant values to post-induction therapy/post transplant values. The attenuated IgG response seen in transplant patients compared to dialysis patients after induction therapy requires further study. These data have important implications for post-transplant management of vaccinated dialysis patients.

Most data on Alport Syndrome (AS) due to COL4A3 are limited to families with autosomal recessive AS or severe manifestations such as focal segmental glomerulosclerosis (FSGS). Using data from 174,418 participants in the Geisinger MyCode/DiscovEHR study, an unselected health system-based cohort with whole exome sequencing, we identified 403 participants (0.2%) who were heterozygous for likely pathogenic COL4A3 variants. Phenotypic data was evaluated using International Classification of Diseases (ICD) codes, laboratory data, and chart review. To evaluate the phenotypic spectrum of genetically-determined autosomal dominant AS, we matched COL4A3 heterozygotes 1:5 to non-heterozygotes using propensity scores by demographics, hypertension, diabetes, and nephrolithiasis. COL4A3 heterozygotes were at significantly increased risks of hematuria, decreased estimated glomerular filtration rate (eGFR), albuminuria, and end-stage kidney disease (ESKD) (p<0.05 for all comparisons) but not bilateral sensorineural hearing loss (p=0.9). Phenotypic severity tended to be more severe among patients with glycine missense variants located within the collagenous domain. For example, patients with Gly695Arg (n=161) had markedly increased risk of dipstick hematuria (OR 9.47, 95% CI: 6.30, 14.22) and ESKD diagnosis (OR 7.01, 95% CI: 3.48, 14.12) whereas those with PTVs (n=119) had moderately increased risks of dipstick hematuria (OR 1.63, 95% CI: 1.03, 2.58) and ESKD diagnosis (OR 3.43, 95% CI: 1.28, 9.19). Less than a third of patients had albuminuria screening completed, and fewer than 1/3 were taking inhibitors of the renin-angiotensin-aldosterone system (RAASi). Future studies are needed to evaluate the impact of earlier diagnosis, appropriate evaluation, and treatment of ADAS. Significance StatementAlport Syndrome (AS) is the second most common genetic cause of end-stage kidney disease (ESKD), yet little is known about the penetrance and phenotypic spectrum of genetically-determined Autosomal Dominant AS. Using an unselected health system-based cohort, we compared individuals heterozygous for likely pathogenic or pathogenic variants in COL4A3 to a propensity score-matched control group and demonstrate increased risks of hematuria, albuminuria, and ESKD. Risks of kidney disease phenotypes were markedly elevated for missense glycine variants in the collagenous domain and moderately elevated for those with PTVs, compared to controls. The vast majority had not been diagnosed with AS and less than a third ever received albuminuria testing, suggesting opportunities to improve management by early genetic diagnosis.

BackgroundImmune checkpoint inhibitor (ICI)-associated acute interstitial nephritis (ICI-AIN) has emerged as a common cause of acute kidney injury (AKI). However, acute tubular necrosis (ATN) may present with similar clinical features yet requires fundamentally different management. Robust data on the prevalence of ATN among patients with suspected ICI-AIN are limited. The aim of this study was to determine the prevalence of ATN in patients with suspected ICI-AIN and to estimate the risk of diagnostic error associated with empirical corticosteroid therapy in the absence of kidney biopsy. MethodsWe conducted a retrospective multicenter study including ICI-treated patients who developed AKI and underwent kidney biopsy. Patients with glomerular presentations were excluded. Based on histopathological findings, patients were classified into two groups: ICI-AIN and isolated ATN. The primary outcome was the prevalence of ATN among patients with suspected ICI-AIN. Secondary outcomes included the description of clinical characteristics, concomitant medications, and laboratory findings, as well as the identification of factors potentially distinguishing ATN from ICI-AIN. ResultsA total of 132 patients were included. ICI-AIN was diagnosed in 76 patients (58%), while isolated ATN was identified in 56 patients (42%). Among subgroups with known risk factors for ICI-AIN, isolated ATN was observed in 20% (7/35) of patients exposed to proton pump inhibitors (PPIs), 23% (3/13) receiving combination ICI therapy, 31% (5/16) with pre-existing chronic kidney disease (CKD), and 34% (10/34) with concomitant extrarenal immune-related adverse events (irAEs). ATN was also present in 23% (6/26) of patients treated with ICI monotherapy. Patients with AIN had more severe renal impairment, with a higher median serum creatinine level at presentation (200 {micro}mol/L vs. 141 {micro}mol/L, p < 0.001). Leukocyturia and hematuria were significantly more frequent in the AIN group (p = 0.007 and p = 0.009, respectively). PPI use was significantly more common in patients with AIN than in those with ATN (40% vs. 19%, p = 0.027), whereas exposure to platinum-based chemotherapy was more frequent in the ATN group (78% vs. 59%, p = 0.027). ConclusionAlthough certain clinical features are associated with ICI-AIN, they are insufficient to reliably differentiate it from ATN without histological confirmation. An empirical management strategy involving corticosteroid therapy without kidney biopsy carries a diagnostic error risk of approximately 40%, underscoring the importance of kidney biopsy as the diagnostic gold standard.

BackgroundClassification of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies. This approach does not reflect underlying disease biology, limiting the ability to predict progression or treatment response. MethodsSystems biology approaches were used to categorize patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) based on kidney biopsy tissue transcriptomics across three cohorts and assessed association with clinical outcomes. Patient-level tissue pathway activation scores were generated using differential gene expression. Then, functional enrichment and non-invasive urine biomarker candidates were identified. Biomarkers were validated in kidney organoid models and single nucleus RNA-seq (snRNAseq) from kidney biopsies. ResultsTranscriptome-based categorization identified three subgroups of patients with shared molecular signatures across independent North American, European and African cohorts. One subgroup demonstrated worse longterm outcomes (HR 5.2, p = 0.001) which persisted after adjusting for diagnosis and clinical measures (HR 3.8, p = 0.035) at time of biopsy. This subgroups molecular profile was largely (48%) driven by tissue necrosis factor (TNF) activation and could be predicted based on levels of TNF pathway urinary biomarkers TIMP-1 and MCP-1 and clinical features (correlation 0.63, p <0.001 for predicted vs observed score). Kidney organoids confirmed TNF-dependent increase in transcript and protein levels of these markers in kidney cells, as did snRNAseq from NEPTUNE biopsy samples. ConclusionsMolecular profiling identified a patient subgroup within nephrotic syndrome with poor outcome and kidney TNF pathway activation. Clinical trials using non-invasive biomarkers of pathway activation to target therapies are currently being evaluated. Significance StatementMechanistic, targeted therapies are urgently needed for patients with nephrotic syndrome. The inability to target an individuals specific disease mechanism using currently used diagnostic parameters leads to potential treatment failure and toxicity risk. Patients with focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) were grouped by kidney tissue transcriptional profiles and a subgroup associated with poor outcomes defined. The segregation of the poor outcome group was driven by tumor necrosis factor (TNF) pathway activation and could be identified by urine biomarkers, MCP1 and TIMP1. Based on these findings, clinical trials utilizing non-invasive biomarkers of pathway activation to target therapies, improve response rates and facilitate personalized treatment in nephrotic syndrome have been initiated.

BackgroundProteinuria reduction is considered a potential surrogate endpoint predictive of reflecting long-term kidney prognosis in IgA nephropathy (IgAN). However, its association with adverse kidney outcomes and IgAN-related decline in estimated glomerular filtration rate (eGFR) remains uncertain. MethodsPatients with biopsy-proven IgAN from the Japan IgA Nephropathy Cohort Study (J-IGACS) were analyzed. Participants were categorized into tertiles based on their 12-month proteinuria-to-baseline proteinuria ratios. The primary outcome was a composite of [&ge;]40% eGFR decline or initiation of kidney-replacement therapy. Associations between proteinuria ratio and outcomes were assessed using Cox proportional hazards models and restricted cubic splines. Multivariable analyses adjusted for age, sex, baseline eGFR, log-transformed proteinuria, Oxford classification scores, and use of corticosteroids and renin-angiotensin-aldosterone system inhibitors within 12 months. ResultsAmong 793 patients, those in the lowest tertile (greatest proteinuria reduction) had significantly lower risk of the primary endpoint (P for trend <0.001) and a more favorable eGFR slope. Spline analysis showed a continuous, dose-response association between proteinuria ratio and improved outcomes. These findings remained robust in sensitivity analyses restricted to patients likely qualifying for clinical trials. The results showed that patients with lower proteinuria ratios tended to have slower rates of eGFR decline (P for trend <0.001), even after multivariable adjustment. ConclusionProteinuria reduction within the first-year post-diagnosis is independently associated with lower risk of adverse kidney outcomes and a slower decline in kidney function in patients with IgAN. These results support the use of proteinuria reduction as a surrogate endpoint in both clinical trials and disease management.

COVID-19 morbidity and mortality is increased in patients with diabetes and kidney disease via unknown mechanisms. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for entry into host cells. Since ACE2 is a susceptibility factor for infection, we investigated how diabetic kidney disease (DKD) and medications alter ACE2 receptor expression in kidneys. Single cell RNA profiling of healthy living donor (LD) and DKD kidney biopsies revealed ACE2 expression primarily in proximal tubular epithelial cells (PTEC). This cell specific localization was confirmed by in situ hybridization. ACE2 expression levels were unaltered by exposures to renin angiotensin aldosterone system inhibitors in DKD. Bayesian integrative analysis of a large compendium of public -omics datasets identified molecular network modules induced in ACE2-expressing PTEC in DKD (searchable at hb.flatironinstitute.org/covid-kidney) that were linked to viral entry, immune activation, endomembrane reorganization, and RNA processing. The DKD ACE2-positive PTEC module overlapped with expression patterns seen in SARS-CoV-2 infected cells. Similar cellular programs were seen in ACE2-positive PTEC obtained from urine samples of 13 COVID-19 patients who were hospitalized, suggesting a consistent ACE2-coregulated PTEC expression program that may interact with the SARS-CoV-2 infection processes. Thus SARS-CoV-2 receptor networks can seed further research into risk stratification and therapeutic strategies for COVID-19 related kidney damage. Translational statementTo understand the overwhelming burden of kidney disease in COVID-19, we mapped the expression of the SARS-CoV-2 receptor, ACE2, in healthy kidney, early diabetic (DKD) and COVID-19 associated kidney diseases. Single cell RNA sequencing of 111035 cells identified ACE2 predominantly in proximal tubular epithelial cells. ACE2 upregulation was observed in DKD, but was not associated with RAAS inhibition, arguing against an increased risk of COVID-19 among patients taking RAAS inhibitors. Molecular network analysis linked ACE2 expression to innate immune response and viral entry machinery, thereby revealing potential therapeutic strategies against COVID-19.