Clinical Presentation, Pathological Spectrum, and Outcomes of Alcoholic Cirrhosis-Related Immunoglobulin A Nephropathy.

Introduction: Immunoglobulin A nephropathy (IgAN) associated with cirrhosis is frequent but often overlooked because it is largely considered silent. Until now, little has been known about their presentation and outcomes. Methods: We conducted a retrospective multicenter study on patients with kidney biopsy-proven cirrhosis-related IgAN (cirrhosis-IgAN), diagnosed between 2009 and 2022. We mixed them up with 83 primary IgAN (pIgAN) diagnosed during the same period, using a partitioning clustering approach, to determine common clinicopathological profiles. Results: All the 46 patients with cirrhosis-IgAN had an excessive alcoholic consumption. Clinical presentation was severe with acute kidney injury (AKI) in 79%; alternative causes of AKI was found in 62% of cases. Three clinicopathological clusters were identified as follows: the first one represented chronic involvement, the second one could be assimilated to mild disease, and the third one corresponded to a membranoproliferative glomerulonephritis (MPGN) pattern and was associated with heavy proteinuria and intrinsic AKI (without alternative causes). Whereas the first 2 clusters were equally distributed between pIgAN and cirrhosis-IgAN, the third was more frequent in patients with cirrhosis. The cumulative mortality rate in cirrhosis-IgAN was 26% and 46% at 1-year and 3-years, respectively. Steroid exposure and moderate or severe AKI were associated with higher mortality and steroid exposure was associated with the occurrence of severe infection. Conclusion: Our results suggest that high AKI incidence is related to extrinsic causes in most cases but can also be driven by IgA-dominant MPGN in a subset of patients. Steroid use was associated with infectious disease and mortality. Further studies are needed to clarify the role of immunosuppressive treatment in cirrhosis-IgAN patients.

Assessment of epidemiology and outcomes of adult patients with kidney-limited thrombotic microangiopathies.

Thrombotic microangiopathies (TMA) are usually associated with hematological features (RH-TMA). The epidemiology of TMA limited to kidneys (RL-TMA) is unclear Therefore, patients with TMA and native kidney biopsies were identified during 2009-2022 in 20 French hospitals and results evaluated. RL-TMA was present in 341/757 (45%) patients and associated with lower creatinine levels (median 184 vs 346 µmol/L) than RH-TMA. RL-TMA resulted from virtually all identified causes, more frequently from anti-VEGF treatment and hematological malignancies but less frequently from shigatoxin-associated hemolytic uremic syndrome (HUS), systemic sclerosis, gemcitabine and bacterial infection, and even less frequently when three or more causes/triggers were combined (RL-TMA: 5%; RH-TMA: 12%). RL-TMA was associated with significantly lower major cardiovascular events (10% vs 20%), kidney replacement therapy (23% vs 43%) and death (12% vs 20%) than RH-TMA during follow-up (median 28 months). Atypical HUS (aHUS) was found in 326 patients (RL-TMA: 43%, RH-TMA: 44%). Among the 69 patients with proven complement-mediated aHUS, eculizumab (anti-C5 therapy) was used in 43 (62%) (RL-TMA: 35%; RH-TMA: 71%). Among the 257 other patients with aHUS, including 51% with RL-TMA, eculizumab was used in 29 but with unclear effects of this treatment. Thus, RL-TMA represents a very high proportion of patients with TMA and results from virtually all known causes of TMA and includes 25% of patients with complement-mediated aHUS. Adverse outcomes of RL-TMA are lower compared to RH-TMA but remain significant. Anti-C5 therapy was rarely used in RL-TMA, even in proven complement-mediated aHUS, and its effects remain to be assessed.

Very Low Dose Anti-Thymocyte Globulins Versus Basiliximab in Non-Immunized Kidney Transplant Recipients.

The choice between Basiliximab (BSX) or Anti-Thymocyte Globulin (ATG) as induction therapy in non-immunized kidney transplant recipients remains uncertain. Whilst ATG may allow steroid withdrawal and a decrease in tacrolimus, it also increases infectious complications. We investigated outcomes in non-immunized patients receiving a very low dosage of ATG versus BSX as induction. Study outcomes were patient/graft survival, cumulative probabilities of biopsy proven acute rejection (BPAR), infectious episode including CMV and post-transplant diabetes (PTD). Cox, logistic or linear statistical models were used depending on the studied outcome and models were weighted on propensity scores. 100 patients received ATG (mean total dose of 2.0 mg/kg) and 83 received BSX. Maintenance therapy was comparable. Patient and graft survival did not differ between groups, nor did infectious complications. There was a trend for a higher occurrence of a first BPAR in the BSX group (HR at 1.92; 95%CI: [0.77; 4.78]; p = 0.15) with a significantly higher BPAR episodes (17% vs 7.3%, p = 0.01). PTD occurrence was significantly higher in the BSX group (HR at 2.44; 95%CI: [1.09; 5.46]; p = 0.03). Induction with a very low dose of ATG in non-immunized recipients was safe and associated with a lower rate of BPAR and PTD without increasing infectious complications.

Hypomagnesemia, Hypocalcemia, and Tubulointerstitial Nephropathy Caused by Claudin-16 Autoantibodies.

BACKGROUND: Chronic hypomagnesemia is commonly due to diarrhea, alcoholism, and drugs. More rarely, it is caused by genetic defects in the effectors of renal magnesium reabsorption. METHODS: In an adult patient with acquired severe hypomagnesemia, hypocalcemia, tubulointerstitial nephropathy, and rapidly progressing kidney injury, similarities between the patient's presentation and features of genetic disorders of renal magnesium transport prompted us to investigate whether the patient had an acquired autoimmune cause of renal magnesium wasting. To determine if the patient's condition might be explained by autoantibodies directed against claudin-16 or claudin-19, transmembrane paracellular proteins involved in renal magnesium absorption, we conducted experiments with claudin knockout mice and transfected mouse kidney cells expressing human claudin-16 or claudin-19. We also examined effects on renal magnesium handling in rats given intravenous injections of IgG purified from sera from the patient or controls. RESULTS: Experiments with the knockout mice and in vitro transfected cells demonstrated that hypomagnesemia in the patient was causally linked to autoantibodies directed against claudin-16, which controls paracellular magnesium reabsorption in the thick ascending limb of Henle's loop. Intravenous injection of IgG purified from the patient's serum induced a marked urinary waste of magnesium in rats. Immunosuppressive treatment combining plasma exchange and rituximab was associated with improvement in the patient's GFR, but hypomagnesemia persisted. The patient was subsequently diagnosed with a renal carcinoma that expressed a high level of claudin-16 mRNA. CONCLUSIONS: Pathogenic claudin-16 autoantibodies represent a novel autoimmune cause of specific renal tubular transport disturbances and tubulointerstitial nephropathy. Screening for autoantibodies targeting claudin-16, and potentially other magnesium transporters or channels in the kidney, may be warranted in patients with acquired unexplained hypomagnesemia.

Incidence, Risk Factors and Outcomes of Kidney and Liver Cyst Infection in Kidney Transplant Recipient With ADPKD.

Introduction: Cyst infection is a known complication of autosomal dominant polycystic kidney disease (ADPKD). Here, we describe incidence, risk factors, clinical presentation, and outcomes of cyst infection in kidney transplant recipient. Methods: We conducted a single-center retrospective cohort study of patients with ADPKD with renal allografts between January 1, 2009, and October 31, 2020. Cyst infection diagnosis was based on previously described clinical and radiological criteria, using positron emission tomography when available. Results: A total of 296 patients with ADPKD with renal allografts were included, and 21 patients experienced 22 episodes of cyst infection over a median follow-up of 4 (2-7) years. The cumulative incidence rate was 3% at 1 year, 6 % at 5 years, and 12% at 10 years after transplantation. In multivariate analysis, history of cyst infection before transplantation was the only significant risk factor identified to predict the occurrence of cyst infection after kidney transplantation (hazard ratio [HR] 3.47, 95% CI 1.29-9.31). The clinical presentation at diagnosis of cyst infection included isolated fever in 5 (23%) episodes, acute kidney injury in 12 (55%), and severe sepsis/septic shock in 3 (14%) episodes. Among the 16 (73%) episodes with culture positivity, Escherichia coli was the most common pathogen. There was no difference between early (≤1 year after transplantation) and late (>1 year) cyst infection episodes in terms of clinical presentation and outcomes. Cyst infection was significantly associated with graft loss (HR 3.93, 95% CI 1.21-12.80), but no causal relationship could be established. Conclusion: Incidence of cyst infection in ADPKD after kidney transplantation is low, history of cyst infection representing the main risk factor.

Spectrum of Kidney Involvement in Patients with Myelodysplastic Syndromes.

INTRODUCTION: Myelodysplastic syndromes (MDS) are characterized by a high prevalence of associated autoimmune manifestations. Kidney involvement has been rarely reported in MDS patients. We report on the spectrum of kidney pathological findings in MDS patients. METHODS: We retrospectively identified MDS patients who had undergone a kidney biopsy between 2001 and 2019 in nine Swiss and French nephrology centres. RESULTS: Nineteen patients (median age 74 years [63-83]) were included. At the time of kidney biopsy, eleven (58%) patients had extra-renal auto-immune manifestations and sixteen (84%) presented with acute kidney injury. Median serum creatinine at diagnosis was 2.8 mg/dL [0.6-8.3] and median urinary protein to creatinine ratio was 1.2 g/g [0.2-11]. Acute tubulo-interstitial nephritis (TIN) was present in seven (37%) patients. Immunofluorescence study in one patient with acute TIN disclosed intense IgG deposits along the tubular basement membrane and Bowman's capsule. Other kidney pathological features included ANCA-negative pauci-immune necrotizing and crescentic glomerulonephritis (n = 3), membranous nephropathy (n = 2), IgA nephropathy (n = 1), IgA vasculitis (n = 1), immunoglobulin-associated membrano-proliferative glomerulonephritis type I (n=1), crescentic C3 glomerulopathy (n = 1), fibrillary glomerulonephritis (n = 1) and minimal change disease (n = 1). Eleven (58%) patients received immunosuppressive treatments, among whom one developed a severe infectious complication. After a median follow-up of 7 month [1-96], nine (47%) patients had chronic kidney disease stage 3 (n = 6) or 4 (n = 3) and five (26%) progressed to end-stage kidney disease. Three patients died. CONCLUSIONS: MDS are associated to several autoimmune kidney manifestations, predominantly acute TIN. MDS are to be listed among the potential causes of autoimmune TIN.

Clinical utility of C-peptide measurement after pancreas transplantation with especial focus on early graft thrombosis.

Since the beginning of our pancreas transplant programme, plasma C-peptide was routinely measured daily during the postoperative period. We aimed to evaluate the clinical interest of the C-peptide in the follow-up of pancreas transplantation with a particular look on early graft failure. From 2000 to 2016, 384 pancreas transplantations were evaluated. We collected and compared C-peptide, glycaemia and adjusted C-peptide (aCP; calculated based on C-peptide, glycaemia and creatininaemia) in patients with and without pancreas failure within 30 days after surgery. Variations of glycaemia, C-peptide and aCP between the day before and the day of failure were also recorded. The difference of aCP was significant during the first week after transplantation between patients with thrombosis and those with functional allograft: 63.2 vs. 26.7 on day 1, P = 0.0003; 61.4 vs. 26.7 on day 3, P < 0.0001; 64.8 vs. 5.7 on day 7, P < 0.0001, respectively. Glycaemia had a median increase of 8% on the day of failure, whereas C-peptide and aCP had, respectively, a median decrease of 88% and 83%. C-peptide monitoring after pancreas transplantation may help to identify graft function and early failure. This sensitive biomarker could allow pre-emptive diagnosis of an early thrombotic event allowing the possibility of rescue interventions.

Resurgence of BK virus following Covid-19 in kidney transplant recipients.

Kidney transplant recipients have been supposed vulnerable to severe Covid-19 infection, due to their comorbidities and immunosuppressive therapies. Mild-term complications of Covid-19 are currently unknown, especially in this population. Herein, we report two cases of BKV replication after non-severe SARS-CoV-2 infection. The first case was a 59-year-old man, transplanted 3 months ago, with recent history of slight BKV viremia (3.3 log10 DNA copies/ml). Despite strong reduction of maintenance immunosuppression (interruption of mycophenolic acid and important decrease of calcineurin inhibitors), BKV replication largely increased after Covid-19 and viremia persisted at 4.5 log copy/ml few months later. The second case was a 53-year-old woman, transplanted 15 years ago. She had a recent history of BKV cystitis, which resolved with a decrease of MPA dosage. Few weeks after SARS-CoV-2 infection, she presented recurrence of lower urinary tract symptoms. Our reports highlight that SARS-CoV-2 infection, even without severity, could disrupt immune system and particularly lymphocytes, thus leading to viral replication. Monitoring of viral replications after Covid-19 in kidney transplant recipients could permit to confirm these preliminary observations.

Association between Use of Hydrochlorothiazide and Risk of Keratinocyte Cancers in Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: Keratinocyte cancers, which primarily comprise squamous cell carcinomas and basal cell carcinomas, represent a major concern and potential risk for kidney transplant recipients. Hydrochlorothiazide, a diuretic widely used to treat hypertension, has been implicated in skin photosensitivity reaction. Recent studies conducted in the general population have found that hydrochlorothiazide use is associated with a higher risk of keratinocyte cancer, especially squamous cell carcinomas. High-risk groups, however, including transplant recipients were excluded from these. Our aim was to investigate whether hydrochlorothiazide use was associated with keratinocyte cancer in kidney transplant recipients on immunosuppressive therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a single-center cohort of kidney (n=2155), combined kidney-pancreas (n=282), and pancreas (n=59) transplant recipients from the Données Informatisées VAlidées Transplantation (DIVAT) database transplanted between 2000 and 2017 in Nantes, France, we evaluated the association between hydrochlorothiazide exposure and keratinocyte cancers. Multivariable cause-specific, time-varying Cox models were used to estimate the relationship between hydrochlorothiazide exposure and the hazard of squamous cell carcinoma and basal cell carcinoma, with hydrochlorothiazide designated as the time-dependent variable. RESULTS: Among the participants, 279 of 2496 (11%) were exposed to hydrochlorothiazide after the transplantation. Cumulative incidence rates of keratinocyte cancer by 10 and 15 years were 7% and 9% for squamous cell carcinomas, respectively, and 8% and 11% for basal cell carcinomas, respectively. We found a relationship between exposure to hydrochlorothiazide and the risk of squamous cell carcinomas (hazard ratio, 2.04; 95% confidence interval, 1.27 to 3.28). In contrast, we found no association between hydrochlorothiazide exposure and basal cell carcinomas (hazard ratio, 0.63; 95% confidence interval, 0.35 to 1.15). CONCLUSIONS: In a single-center cohort of kidney, combined kidney-pancreas, and pancreas transplant recipients, exposure to hydrochlorothiazide was associated with a two-fold higher risk of squamous cell carcinoma and no higher risk of basal cell carcinoma.

The weekend effect in kidney transplantation outcomes: a French cohort-based study.

Numerous studies have reported a weekend effect on outcomes for diseases treated at hospitals. No study has been conducted in France for kidney transplantation. We therefore performed a cohort-based study to evaluate whether outcomes of kidney transplant recipients display a weekend effect. Data were extracted from the French DIVAT cohort. Patients aged 18 years and older, transplanted with a single kidney from deceased donors between 2005 and 2017 were studied. Linear regression, logistic regression, and cause-specific Cox model were used. Among the 6652 studied patients, 4653 patients were transplanted during weekdays (69.9%) versus 1999 during weekends (30.1%). The only statistically significant difference was the percentage of patients with vascular surgical complication(s) at 30 days: 13.3% in the weekend group versus 16.2% in the weekday group 0.79 (95% CI: 0.68; 0.92). We did not observe other significant differences for the other outcomes: patient or graft survival, the risk of acute rejection episodes, the 30-day percentage of urological complications, and the 1-year estimated glomerular filtration rate. Our study highlights a small protective weekend effect with less post-surgery vascular complications compared to weekdays. This paradox might be explained by a different handling of weekend transplantations.

An extension of the RITUX-ERAH study, multicenter randomized clinical trial comparing rituximab to placebo in acute antibody-mediated rejection after renal transplantation.

The treatment of active antibody-mediated rejection (ABMR) is still a matter of debate, the place of rituximab remaining controversial. The French multicenter double-blind RITUX-ERAH study included 38 patients with ABMR in the first year of renal transplantation. All patients received plasma exchanges, intravenous immunoglobulins, and corticosteroids and were randomly assigned rituximab or placebo infusion at day 5. Additional rituximab infusions were allowed. In the intention-to-treat analysis, 12-month graft survival and renal function were not different between the rituximab and placebo groups. Long-term data are needed to conclude. Evaluation of the 7-year outcomes of the RITUX-ERAH study patients according to the rituximab or placebo treatment received. Eleven patients received placebo and 27 at least one infusion of rituximab. Seven years after ABMR, death-censored kidney allograft survival and renal function were not different between the groups. The evolution of anti-HLA sensitization was similar. There was no statistically significant difference in the incidence of infectious or neoplastic complications, but to be noted, seven cancers developed in six patients treated with rituximab (mean period of 44 months post-ABMR). In this cohort, there was no benefit 7 years after ABMR of rituximab in addition to plasma exchanges, intravenous immunoglobulins, and steroids.

Tacrolimus- versus sirolimus-based immunosuppression after simultaneous pancreas and kidney transplantation: 5-year results of a randomized trial.

Tacrolimus, the cornerstone immunosuppression after simultaneous pancreas and -kidney (SPK) transplantation, may exert nephrotoxic and diabetogenic effects. We therefore prospectively compared in an open-label, randomized, monocentric, 5-year follow-up study, a tacrolimus- and a sirolimus-based immunosuppressive regimen. Randomization using the block method allowing a blind allocation was done at the time of surgery. All patients received anti-thymocyte globulin and maintenance therapy with tacrolimus, mycophenolate mofetil, and steroids. At month 3, tacrolimus was continued or replaced by sirolimus. The primary endpoint was kidney and pancreas graft survival at 1 and 5 years. Fifty patients were included in the final analysis in each group. At 1 year, differences for kidney and pancreas graft survival between sirolimus and tacrolimus were 0% (90% confidence interval -4.61% to 4.61%) and 6% (90% confidence interval -6.32% to 18.32%), respectively. There was no difference in renal and pancreas graft survival at 5 years. Thirty-four patients (68%) in the sirolimus group vs three (6%) in the tacrolimus group needed definitive withdrawal of the study drug. Despite noninferiority of sirolimus compared to tacrolimus for kidney and pancreas graft survival, the high rate of sirolimus discontinuation does not favor its use as cornerstone therapy after SPK transplantation (NCT00693446).

CXCR5+PD1+ICOS+ Circulating T Follicular Helpers Are Associated With de novo Donor-Specific Antibodies After Renal Transplantation.

Donor-specific anti-HLA antibodies (DSAs) are a major risk factor associated with renal allograft outcomes. As a trigger of B cell antibody production, T follicular helper cells (Tfhs) promote DSA appearance. Herein, we evaluated whether circulating Tfhs (cTfhs) are associated with the genesis of antibody-mediated rejection. We measured cTfh levels on the day of transplantation and 1 year after transplantation in blood from a prospective cohort of 237 renal transplantation patients without DSA during the first year post-transplantation. Total cTfhs were characterized as CD4+CD45RA-CXCR5+, and the three following subsets of activated cTfh were analyzed: CXCR5+PD1+, CXCR5+PD1+ICOS+, an CXCR5+PD1+CXCR3-. Immunizing events (previous blood transfusion and/or pregnancy) and the presence of class II anti-HLA antibodies were associated with increased frequencies of activated CXCR5+PD1+, CXCR5+PD1+ICOS+, and CXCR5+PD1+CXCR3- cTfh subsets. In addition, ATG-depleting induction and calcineurin inhibitor treatments were associated with a relative increase of activated cTfh subsets frequencies at 1 year post-transplantation. In multivariate survival analysis, we reported that a decrease in activated CXCR5+PD1+ICOS+ at 1 year after transplantation in the blood of DSA-free patients was significantly associated with the risk of developing de novo DSA after the first year (p = 0.018, HR = 0.39), independently of HLA mismatches (p = 0.003, HR = 3.79). These results highlight the importance of monitoring activated Tfhs in patients early after transplantation and show that current treatments cannot provide early, efficient prevention of Tfh activation and migration. These findings indicate the need to develop innovative treatments to specifically target Tfhs to prevent DSA appearance in renal transplantation.