Kidney Histopathology Can Predict Kidney Function in ANCA-Associated Vasculitides with Acute Kidney Injury Treated with Plasma Exchanges.

BACKGROUND: Data from the PEXIVAS trial challenged the role of plasma exchange (PLEX) in ANCA-associated vasculitides (AAV). We aimed to describe kidney biopsy from patients with AAV treated with PLEX, evaluate whether histopathologic findings could predict kidney function, and identify which patients would most benefit from PLEX. METHODS: We performed a multicenter, retrospective study on 188 patients with AAV and AKI treated with PLEX and 237 not treated with PLEX. The primary outcome was mortality or KRT at 12 months (M12). RESULTS: No significant benefit of PLEX for the primary outcome was found. To identify patients benefitting from PLEX, we developed a model predicting the average treatment effect of PLEX for an individual depending on covariables. Using the prediction model, 223 patients had a better predicted outcome with PLEX than without PLEX, and 177 of them had >5% increased predicted probability with PLEX compared with without PLEX of being alive and free from KRT at M12, which defined the PLEX-recommended group. Risk difference for death or KRT at M12 was significantly lower with PLEX in the PLEX-recommended group (-15.9%; 95% CI, -29.4 to -2.5) compared with the PLEX not recommended group (-4.8%; 95% CI, 14.9 to 5.3). Microscopic polyangiitis, MPO-ANCA, higher serum creatinine, crescentic and sclerotic classes, and higher Brix score were more frequent in the PLEX-recommended group. An easy to use score identified patients who would benefit from PLEX. The average treatment effect of PLEX for those with recommended treatment corresponded to an absolute risk reduction for death or KRT at M12 of 24.6%. CONCLUSIONS: PLEX was not associated with a better primary outcome in the whole study population, but we identified a subset of patients who could benefit from PLEX. However, these findings must be validated before utilized in clinical decision making.

MicroRNA-146a in Human and Experimental Ischemic AKI: CXCL8-Dependent Mechanism of Action.

AKI leads to tubular injury and interstitial inflammation that must be controlled to avoid the development of fibrosis. We hypothesized that microRNAs are involved in the regulation of the balance between lesion formation and adaptive repair. We found that, under proinflammatory conditions, microRNA-146a (miR-146a) is transcriptionally upregulated by ligands of IL-1 receptor/Toll-like receptor family members via the activation of NF-κB in cultured renal proximal tubular cells. In vivo, more severe renal ischemia-reperfusion injury (IRI) associated with increased expression of miR-146a in both allografts and urine of human kidney transplant recipients, and unilateral IRI in mice induced miR-146a expression in injured kidneys. After unilateral IRI, miR-146a-/- mice exhibited more extensive tubular injury, inflammatory infiltrates, and fibrosis than wild-type mice. In vitro, overexpression or downregulation of miR-146a diminished or enhanced, respectively, IL-1 receptor-associated kinase 1 expression and induced similar effects on C-X-C motif ligand 8 (CXCL8)/CXCL1 expression by injured tubular cells. Moreover, inhibition of CXCL8/CXCL1 signaling prevented the development of inflammation and fibrosis after IRI in miR-146a-/- mice. In conclusion, these results indicate that miR-146a is a key mediator of the renal tubular response to IRI that limits the consequences of inflammation, a key process in the development of AKI and CKD.

A Novel Extrinsic Pathway for the Unfolded Protein Response in the Kidney.

The ribonuclease angiogenin is a component of the mammalian stress response, and functions in both cell-autonomous and non-cell-autonomous ways to promote tissue adaptation to injury. We recently showed that angiogenin regulates tissue homeostasis during AKI associated with endoplasmic reticulum (ER) stress through the production of transfer RNA fragments that interfere with translation initiation and thereby alleviate ER stress. However, whether the paracrine signaling mediated by angiogenin secretion is a genuine component of the ER stress response to kidney injury is unknown. Here, we explored the molecular mechanisms by which angiogenin is secreted upon ER stress, and determined how it modulates the inflammatory microenvironment. In cultured renal epithelial cells, ER stress specifically induced angiogenin secretion under the selective control of inositol-requiring enzyme 1α, a key activator of the unfolded protein response. The transcription factors spliced X-box-binding protein 1 and p65, which are activated by inositol-requiring enzyme 1α upon ER stress, each bound the angiogenin promoter and controlled the amount of angiogenin secreted. Furthermore, p65 promoted angiogenin transcription in an ER stress-dependent manner. Similar to secretion of the ER stress-induced proinflammatory cytokine IL-6, secretion of angiogenin required the ER-Golgi pathway. Notably, incubation of human macrophages with angiogenin promoted macrophage reprogramming toward an activated and proinflammatory phenotype. In patients, angiogenin expression increased upon renal inflammation, and the urinary concentration of angiogenin correlated with the extent of immune-mediated kidney injury. Collectively, our data identify angiogenin as a mediator of the ER stress-dependent inflammatory response and as a potential noninvasive biomarker of AKI.

Successful twin pregnancy in a woman undergoing alternate diurnal and nocturnal hemodialysis.

Although pregnancy has become more frequent in patients undergoing hemodialysis, it remains a relatively rare event and carries a high risk of complications for both the mother and the fetus. In parallel, multiple pregnancies are also associated with a high risk of complications for the mother and the fetus, even in healthy women. The presence of a twin pregnancy in a woman with chronic renal failure undergoing hemodialysis is an even rarer event and is considered a very high-risk situation. We describe the case of a 31-year-old hemodialysis patient who successfully gave birth to twins at 29 weeks after a period of alternate diurnal and nocturnal hemodialysis.

Use of a Belatacept-based Immunosuppression for Kidney Transplantation From Donors After Circulatory Death: A Paired Kidney Analysis.

Background: Efficacy and safety of belatacept have not been specifically reported for kidney transplantations from donors after circulatory death. Methods: In this retrospective multicenter paired kidney study, we compared the outcome of kidney transplantations with a belatacept-based to a calcineurin inhibitor (CNI)-based immunosuppression. We included all kidney transplant recipients from donors after uncontrolled or controlled circulatory death performed in our center between February 2015 and October 2020 and treated with belatacept (n = 31). The control group included the recipients of the contralateral kidney that were treated with CNI in 8 other centers (tacrolimus n = 29, cyclosporine n = 2). Results: There was no difference in the rate of delayed graft function. A higher incidence of biopsy-proven rejections was noted in the belatacept group (24 versus 6 episodes). Estimated glomerular filtration rate (eGFR) was significantly higher in the belatacept group at 3-, 12-, and 36-mo posttransplant, but the slope of eGFR was similar in the 2 groups. During a mean follow-up of 4.1 y, 12 patients discontinued belatacept and 2 patients were switched from CNI to belatacept. For patients who remained on belatacept, eGFR mean value and slope were significantly higher during the whole follow-up. At 5 y, eGFR was 80.7 ± 18.5 with belatacept versus 56.3 ± 22.0 mL/min/1.73 m2 with CNI (P = 0.003). No significant difference in graft and patient survival was observed. Conclusions: The use of belatacept for kidney transplants from either uncontrolled or controlled donors after circulatory death resulted in a better medium-term renal function for patients remaining on belatacept despite similar rates of delayed graft function and higher rates of cellular rejection.

Sirolimus therapy may cause cardiac tamponade.

The side-effects associated with the immunosuppressive drug sirolimus are numerous and constitute a major limitation for its use in renal transplantation. In this study, we describe two cases of renal transplant recipients treated with sirolimus who developed pericardial tamponade associated with interstitial pneumonia, proteinuria, microcytic anemia and, in one case, lymphocytic meningitidis. An extensive search for infectious agents was negative, and all symptoms disappeared after sirolimus interruption. Therefore, this case demonstrates for the first time that sirolimus can cause pericardial tamponade as well as lymphocytic meningitidis.

Arteriovenous fistulas thrombosis in hemodialysis patients with COVID-19.

BACKGROUND: The current Coronavirus disease 2019 (COVID-19) outbreak is associated with significant mortality, especially in patients suffering from end stage renal disease (ESRD) and hemodialysis patients. Several previous studies reported an over-risk of arterial and venous thrombosis, in particular pulmonary embolism and venous thrombosis of catheter in COVID19 patients in intensive care unit. However, arteriovenous fistula (AVF) thrombosis has rarely been reported yet in these patients. AVF thrombosis is a serious complication that impacts significantly patients outcome. Here, we aim to describe characteristics and prognosis of a cohort of COVID-19 hemodialysis (HD) patients presenting with AVF thrombosis. METHODS: In the Ile de France region (Paris area) during the March 11th-April 30th 2020 period, fistula thrombosis cases were collected among COVID-19 hemodialysis patients in seven dialysis units and in interventional vascular departments. These patients' characteristics were analyzed through a review of the patient's medical records. RESULTS: Seventeen patients were included in our study (median age 69 years). Ten patients (59%) were men. Ten patients (59%) were diabetic and 88% had a high blood pressure. The mortality rate in these patients was 47%. All thrombosis treated with a declotting procedures (64%) were successfully cleared, but with early relapse in 36%. CONCLUSION: Our study highlights AVF thrombosis as a severe complication in COVID-19 hemodialysis patients that contributed to the severity and accelerated death.

Use of proton pump inhibitors in dialysis patients: a double-edged sword?

Large cohort-based studies have shown that proton pump inhibitors (PPIs) are linked to rare but multiple and varied secondary events when used in the general population. Although clinicians accept the negative effects of PPIs on renal function, there is a lack of available data regarding the potential consequences of their use by dialysis patients in whom the risk of gastrointestinal bleeding is quite high. This review aims to highlight the risks and benefits of PPIs use in dialysis patients. To summarize, the benefit on the reduction of high digestive bleeding seems certain, but without any beneficial impact on overall survival. The impact on quality of life seems to be significant. The data on the occurrence of peritonitis during PPIs treatment are very contradictory. There is evidence regarding the occurrence of hypomagnesaemia in haemodialysis patients with PPIs; which may lead to increase bone fragility. New data show an increased cardiovascular risk and even a risk of death linked to the use of PPIs on dialysis. Several mechanisms of IPP toxicity are advanced to explain these findings.

Association of Acute Interstitial Nephritis with Nivolumab in Renal Cell Carcinoma: A Case Report.

Recently, a number of innovative anticancer agents such us the programmed death 1 (PD-1) immune checkpoint inhibitors have been developed. Nevertheless, this type of immunotherapy may be associated with immune-related adverse events whose pathophysiology is considered similar to those found in autoimmune diseases such as nephritis. We report the case of a 71-year-old female with metastatic renal carcinoma who underwent nephrectomy. After three lines of other chemotherapies (VEGF and mTOR inhibitors), the patient was treated by nivolumab (3 mg/kg) for 4 months and developed acute kidney injury 16 weeks after initiating this immunotherapy. Kidney biopsy displayed a diffuse extensive interstitial inflammation associated with moderate interstitial edema. The discontinuation of nivolumab and the administration of prednisone (at 1 mg/kg and tapered over 3 months) was an effective treatment of the interstitial edema and led to the recovery of the kidney function.

IgA Nephropathy Associated with Trifluridine/Tipiracil: A Case Report.

Kidney diseases during chemotherapy treatment are variable, with different manifestations depending on the drugs used. Trifluridine/tipiracil is a treatment used in refractory metastatic digestive cancers. Its renal toxicity is poorly described. We report here the onset of a severe IgA nephropathy requiring hemodialysis which occurred several weeks after trifluridine/tipiracil treatment.

Renal Pathological Findings in Action Myoclonus-Renal Failure Syndrome.

Action myoclonus - renal failure is a rare syndrome associated with a progressive myoclonic epilepsy and renal impairment that may lead to end-stage renal failure. It is an autosomal recessive genetic disease related to a loss-of-function mutation in SCARB2, which encodes for lysosomal integral membrane protein type 2. Renal involvement is poorly described, and we report here the first electron microscopy renal analysis after having performed a kidney biopsy in a 31-year-old Gambian patient.

COVID-19 in Patients on Maintenance Dialysis in the Paris Region.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) represents a serious threat to patients on maintenance dialysis. The clinical setting, mortality rate, and prognostic factors in these patients have not been well established. METHODS: We included all dialyzed patients with COVID-19 referred to our dialysis center between March 11 and April 11, 2020. Data were obtained through the review of the medical records and were censored at the time of data cutoff, on May 11, 2020. RESULTS: Forty-four patients on maintenance dialysis with COVID-19 were referred to our dialysis unit during the COVID-19 epidemic. Median age was 61 years (interquartile range [IQR]: 51.5-72.5); 65.9% were men. Comorbidities included hypertension (97.7%), diabetes mellitus (50%), and chronic cardiac (38.6%) and respiratory (27.3%) diseases. Initial symptoms were fever (79.5%), shortness of breath (29.5%), cough (43.2%), and diarrhea (13.6%). Three profiles of severity were distinguished based on the World Health Organization (WHO) progression scale. Forty-one (93.2%) were hospitalized and only 3 were maintained on outpatient hemodialysis. Thirty-three (75%) patients required oxygen therapy, including 15 (45.5%) who were referred to the intensive care unit. Overall, 27.3% of patients died, and 58.5% were discharged from hospital, including only 2 (13.3%) of those admitted to the intensive care unit. By multivariate analysis, cough, thrombopenia <120 g/l, lactate dehydrogenase (LDH) level greater than 2 times the upper limit of normal, and blood C-reactive protein (CRP) >175 mg/l were significantly associated with death. CONCLUSION: A major outbreak of COVID-19 occurred in the Paris region, and spread among dialyzed patients. Our study underscores the severity of COVID-19 in these patients and identified prognostic markers.

Oxalate nephropathy is a major cause of kidney injury in surgically treated pancreatic adenocarcinoma patients.

BACKGROUND: Despite new therapeutics, the prognosis for pancreatic cancer remains poor. Pancreatic surgery is a therapeutic option in non-metastatic forms. The consequences for renal function are poorly described. METHODS: Patients who underwent surgery for pancreatic cancer between 1 January 2010 and 1 January 2017 and who experienced kidney biopsy in the Pitié-Salpêtrière Hospital were analysed. RESULTS: Two hundred and ninety-four patients had pancreatic surgery during the period of analysis and five of them had a kidney biopsy (mean ± SD 20 months ±13.6 months after surgery) during the post-operative follow-up. Among these patients, three exhibited oxalate nephropathy (ON), indicating that the prevalence of ON in patients with pancreatectomy is at least 1%. ON may be insidious, with chronic renal failure without urinary abnormalities. All patients had a high oxalate-to-creatinine ratio in urine sample. Renal function improved after specific management of ON in two patients. Pancreaticoduodenectomy may represent a higher risk of ON than left pancreatectomy. CONCLUSION: Although rare and underestimated, ON appears to be a real risk after pancreatic resection. Early detection may preserve renal function.

MicroRNA-146a-deficient mice develop immune complex glomerulonephritis.

MicroRNAs (miRNAs) play an important role in the kidneys under physiological and pathological conditions, but their role in immune glomerulonephritis is unclear. miR-146a has been identified as a key player in innate immunity and inflammatory responses, and in the kidney, this miRNA is involved in the response of injured tubular cells. We studied the renal and immune phenotypes of miR-146a+/+ and miR-146a-/- mice at 12 months of age, and the results showed that miR-146a-/- mice developed autoimmunity during aging, as demonstrated by circulating antibodies targeting double-stranded DNA and an immune complex-mediated glomerulonephritis associated with a mild renal immune infiltrate. In addition, miR-146a-/- mice showed reduced expression of the transmembrane protein Kim1/Tim1, a key regulator of regulatory B cell (Breg) homeostasis, in the kidney and the immune cells. The numbers of memory B cells and plasmablasts were increased in miR-146a-/- mice compared with the numbers in wild-type mice, whereas Bregs were decreased in number and displayed an altered capacity to produce IL-10. Finally, we showed that miR-146a-/- mice develop an autoimmune syndrome with increasing age, and this syndrome includes immune complex glomerulonephritis, which might be due to altered B cell responses associated with Kim1/Tim1 deficiency. This study unravels a link between miR-146a and Kim1 and identifies miR-146a as a significant player in immune-mediated glomerulonephritis pathogenesis.

[Proton pump inhibitors and kidney]. / Inhibiteurs de la pompe à protons et rein.

Assumed for a long time to be very well tolerated, proton pump inhibitors (PPIs) are widely prescribed for inpatients and outpatients; often beyond their validated indications. Nevertheless, many very varied side effects (pneumopathy, ischemic heart disease, dementia) have been associated with the PPIs during the last decade. Renal toxicity is mainly the occurrence of acute interstitial nephritis (AIN), related to a drug-class effect, involving cellular immunity. AINs, which occur especially in elderly patients, can be difficult to diagnose, with frequently isolated acute kidney injury, appearing with variable delay after the introduction of PPIs. Although sensitive to steroid therapy, patients frequently have an incomplete recovery of the kidney function. Very recently, the risk of chronic kidney disease (CKD) and the risk of progression of CKD among PPIs users have been well demonstrated in several large independent epidemiological studies. It is a low, but a significant side effect because of the millions of PPI prescriptions. Although further studies are needed to investigate the pathophysiological mechanisms leading the use of PPI to CKD, it is appropriate for the physicians to limit PPIs to their correct indications and to monitor renal function during these treatments.

[Hyperthyroidism-induced calciphylaxis: A case report]. / Calciphylaxie dans un contexte de maladie de Basedow : à propos d'un cas.

BACKGROUND: Calciphylaxis or calcific uremic arteriolopathy (CUA) is a cutaneous disease with ulcerations secondary to calcification of cutaneous and subcutaneous small arteries and arterioles. It is a rare but severe disease with significant morbidity and mortality affecting 1 to 4% of dialysis patients. The circumstances of occurrence are multiple. CASE: We report the case of a severe bilateral lower limb calciphylaxis in a 69-year-old, obese, hemodialysis patient with a recent diagnosis of Graves' disease complicated with hypercalcemia and cardiac arrhythmia requiring the use of vitamin K antagonist. Complex and multidisciplinary therapeutic management (daily hemodialysis, sodium thiosulfate therapy, treatment of hypercalcemia by denosumab, hyperbaric oxygen therapy, meshed skin autograft) allowed complete healing of the lesions. CONCLUSION: This is the first description of AUC secondary to hyperthyroidism in a dialysis patient. Multidisciplinary care is essential to achieve clinical improvement in those critical situations.

[Hepatorenal syndrome: focus]. / Le syndrome hépatorénal : mise au point.

Hepatorenal syndrome (HRS) is a severe complication of cirrhosis. It develops as a result of abnormal hemodynamics, leading to systemic vasodilatation and renal vasoconstriction. Increased bacterial translocation, various cytokines and systemic inflammatory response system contribute to splanchnic vasodilatation, and altered renal autoregulation. An inadequate cardiac output with systolic incompetence increases the risk of renal failure. Type 1 HRS is usually initiated by a precipitating event associated with an exaggerated systemic inflammatory response, resulting in multiorgan failure. Vasoconstrictors are the basic treatment in patients with type 1 HRS; terlipressin is the superior agent. Norepinephrine can be used as an alternative. Transjugular intrahepatic portosystemic stent shunt may be applicable in a small number of patients with type 1 HRS and in most patients with type 2 HRS. Liver transplantation is the definitive treatment for HRS. The decision to do simultaneous or sequential liver and kidney transplant remains controversial. In general, patients who need more than 8 to 12 weeks of pretransplant dialysis should be considered for combined liver-kidney transplantation.

Acute renal failure and volume overload syndrome secondary to a femorofemoral arteriovenous fistula angioplasty in a kidney transplant recipient.

Experimental and clinical studies analyzing the impact of AVF on cardiovascular and renal parameters, as well as outcomes, in kidney transplant recipients are lacking. On the other hand, it is not known whether AVF ligation after transplantation modifies hemodynamic parameters and kidney function. We report a case of a renal transplant recipient who developed an acute congestive heart failure accompanied by renal failure, which were triggered by femorofemoral AVF angioplasty. Prompt AVF ligation rapidly reversed clinical symptoms and normalized cardiac and renal functions. This paper illustrates the potential deleterious consequences of high-output AVF after kidney transplantation and raises considerations regarding the impact of the fistula on cardiac status and kidney function after kidney transplantation and, consequently, the management AVF after transplantation.