Publications by authors named "Mohamad Zaidan"

39 Publications

Arteriovenous fistulas thrombosis in hemodialysis patients with COVID-19.

J Vasc Access 2021 Feb 24:1129729821996091. Epub 2021 Feb 24.

Nephrology and Hemodialysis Department, Hôpital Privé de Thiais, Thiais, France.

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.
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http://dx.doi.org/10.1177/1129729821996091DOI Listing
February 2021

The spectrum of kidney biopsies in hospitalized patients with COVID-19, acute kidney injury, and/or proteinuria.

Nephrol Dial Transplant 2021 Feb 12. Epub 2021 Feb 12.

Université Paris Saclay, Université Paris-Sud, UVSQ, Villejuif, France.

We report a multicentric retrospective case series of patients with COVID-19 who developed acute kidney injury and/or proteinuria and underwent a kidney biopsy in the Paris and its metropolitan area. Forty-seven patients (80.9% men) with COVID-19 who underwent a kidney biopsy between March 08 and May 19, 2020 were included. Median age was 63 years IQR [52-69]. Comorbidities included hypertension (66.0%), diabetes mellitus (27.7%), obesity (27.7%), history of chronic kidney (25.5%), cardiac (38.6%) and respiratory (27.3%) diseases. Initial symptoms were fever (85.1%), cough (63.8%), shortness of breath (55.3%), and diarrhea (23.4%). Almost all patients developed acute kidney injury (97.9%) and 63.8% required renal replacement therapy. Kidney biopsy showed two main histopathological patterns, including acute tubular injury in 20 (42.6%) patients, and glomerular injury consisting of collapsing glomerulopathy and focal segmental glomerulosclerosis in 17 (36.2%) patients. Two (4.3%) patients had acute vascular nephropathy, while eight (17%) had alternative diagnosis most likely unrelated to COVID-19. Acute tubular injury occurred almost invariably in the setting of severe forms of COVID-19, whereas patients with glomerular injury had various profiles of COVID-19 severity and collapsing glomerulopathy was only observed in patients harboring a combination of APOL1 risk variants. At last follow-up, 16 of the 30 patients who initially required dialysis were still on dialysis, and 9 died. The present study describes the spectrum of kidney lesions in patients with COVID-19. While acute tubular injury is correlated with COVID-19 severity, the pattern of glomerular injury is intimately associated with the expression of APOL1 risk variants.
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http://dx.doi.org/10.1093/ndt/gfab042DOI Listing
February 2021

Encrusted Urinary Tract Infections Due to Corynebacteria Species.

Kidney Int Rep 2021 Jan 4;6(1):179-186. Epub 2020 Nov 4.

Department of Nephrology‒Transplantation, Hôpital Bicêtre, APHP, Le Kremlin‒Bicêtre, France.

Introduction: Encrusted pyelitis and cystitis are peculiar disorders characterized by the calcification of the vesical, the pyelic, and/or the ureteral walls. These calcifications are composed of struvite and calcium carbonate‒apatite due to the presence of .

Methods: We have identified the clinical features and outcomes of 17 patients with encrusted pyelitis (n = 15) or encrusted cystitis (n = 2). Diagnosis was based on computed tomography scan and sonography including thickening and calcified lesions of the urinary tract.

Results: The main clinical presentation was suggestive of subacute urinary tract infection with fever and urologic symptoms, mostly gross hematuria. Biologic features were characterized by the presence of struvite crystals and alkaline urine. Acute kidney injury was reported in 70.6% of cases. Predisposing factors were mostly due to urologic background (82.4%) with a history of urologic procedure (71%) and prior exposure to antibiotics (59%). All patients received appropriate antibiotherapy and 15 were treated with topical urinary acidification. A significant reduction of encrusted calcifications was observed in 88% of cases. Renal function improved in 71% of the patients. Nevertheless, poor tolerance of the treatment and side effects were common, affecting 71% of patients, with Gram-negative bacilli urinary tract infections (53%) being the most frequent. At last follow-up, 4 patients (23.5%) progressed to end-stage renal disease and only 1 had a clinical relapse.

Conclusions: Encrusted urinary tract infections are rare, characterized by a severe renal and overall prognosis in the absence of appropriate treatment. Topical urinary acidification and appropriate antibiotherapy are efficient but may be burdened by significant adverse events.
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http://dx.doi.org/10.1016/j.ekir.2020.10.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783559PMC
January 2021

COVID-19 severity in kidney transplant recipients is similar to nontransplant patients with similar comorbidities.

Am J Transplant 2021 03 4;21(3):1285-1294. Epub 2021 Jan 4.

Départment de Néphrologie et transplantation rénale, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.

Higher rates of severe COVID-19 have been reported in kidney transplant recipients (KTRs) compared to nontransplant patients. We aimed to determine if poorer outcomes were specifically related to chronic immunosuppression or underlying comorbidities. We used a 1:1 propensity score-matching method to compare survival and severe disease-free survival (defined as death and/or need for intensive care unit [ICU]) incidence in hospitalized KTRs and nontransplant control patients between February 26 and May 22, 2020. Patients were matched for risk factors of severe COVID-19: age, sex, body mass index, diabetes mellitus, preexisting cardiopathy, chronic lung disease, and basal renal function. We included 100 KTRs (median age [interquartile range (IQR)]) 64.7 years (55.3-73.1) in three French transplant centers. After a median follow-up of 13 days (7-30), transfer to ICU was required for 34 patients (34%) and death occurred in 26 patients (26%). Overall, 43 patients (43%) developed a severe disease during a median follow-up of 8.5 days (2-14). Propensity score matching to a large French cohort of 2017 patients hospitalized in 24 centers, revealed that survival was similar between KTRs and matched nontransplant patients with respective 30-day survival of 62.9% and 71% (p = .38) and severe disease-free 30-day survival of 50.6% and 47.5% (p = .91). These findings suggest that severity of COVID-19 in KTRs is related to their associated comorbidities and not to chronic immunosuppression.
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http://dx.doi.org/10.1111/ajt.16416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753406PMC
March 2021

Circulating plasmablasts and high level of BAFF are hallmarks of minimal change nephrotic syndrome in adults.

Nephrol Dial Transplant 2020 Nov 26. Epub 2020 Nov 26.

Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, Service de Néphrologie et Transplantation, Centre de Référence Maladie Rare « Syndrome Néphrotique Idiopathique », Fédération Hospitalo-Universitaire « Innovative Therapy for Immune Disorders », Créteil, France.

Background: The recent success achieved with the use of B cell-depleting agents in some patients with minimal change nephrotic syndrome (MCNS) suggests an unexpected role for B lymphocytes in the pathogenesis of this immune-mediated glomerular disease. Nevertheless, no extensive B-cell phenotyping analysis has ever been performed in untreated adult patients soon after MCNS diagnosis.

Methods: We investigated the distribution of the different B-cell subpopulations in 22 untreated adult patients with biopsy-proven MCNS [MCNS relapse (MCNS-Rel)]. We compared these data with those for 24 healthy controls, 13 MCNS patients in remission (with no specific treatment) and 19 patients with idiopathic membranous nephropathy (IMN).

Results: Patients with MCNS-Rel or IMN had higher proteinuria and lower serum albumin and gammaglobulin levels (P < 0.0001 for all comparisons) than MCNS patients in remission. Plasmablasts were the only B-cell subsets present at significantly higher levels in MCNS-Rel patients than in the patients of the other three groups (P < 0.05 for all comparisons). The lower albumin levels and higher proteinuria levels were positively correlated with the percentage of circulating plasmablasts (Spearman test's ρ = -0.54, P = 0.01 and ρ = 0.65, P = 0.002, respectively). Similarly, the increase of immunoglobulin M (IgM) and the decrease of IgG levels were significantly associated with the percentage of plasmablasts in MCNS-Rel patients (Spearman's ρ = 0.36, P = 0.01 and Spearman's ρ = -0.60, P = 0.01, respectively). Increased production of interleukin (IL)-21, IL-6 and B-cell activating factor (BAFF) in the serum of MCNS-Rel patients was found significantly correlated with the percentage of plasmablasts (ρ = 0.72, P = 0.0002, ρ = 0.49, P = 0.04 and ρ = 0.62, P = 0.009, respectively).

Conclusions: An increase in the proportion of circulating plasmablasts seems to be a hallmark of untreated MCNS in adult patients. Further studies are required to more precisely determine the phenotype and functions of these cells.
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http://dx.doi.org/10.1093/ndt/gfaa279DOI Listing
November 2020

Solid Organ Transplantation in the Era of COVID-19: Lessons from France.

Transplantation 2021 01;105(1):61-66

Service de Néphrologie, Dialyse et Transplantation, Hôpital Necker, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.

Coronavirus disease 2019 (COVID-19) outbreak has significantly upended solid organ transplant (SOT) practice around the world. Early reports confirmed the heavy burden of COVID-19 in SOT recipients with mortality rates reaching up to 35%. Because most transplant recipients harbored multiple comorbidities known to be associated with a severe course of COVID-19, the true impact of immunosuppression by itself remained an unsolved issue. Transplant societies have initially recommended to postpone nonurgent renal transplantations, while trying to maintain life-saving transplant programs, such as heart, lung, and liver transplantations. The pandemic thus resulted in an unprecedented and sudden drop of transplant activity worldwide. Moreover, the best treatment strategy in infected patients was challenging. Both reduction of immunosuppression and use of targeted therapies aiming at counteracting severe acute respiratory syndrome coronavirus 2 infection were the 2 faces of the therapeutic armamentarium. Recent controlled studies have better delineated the basis of mitigating and management strategies to improve patients' outcome. Nevertheless, and given the persistence of circulating virus, evidence-based recommendations in SOT recipients remain unclear. The resumption of transplant activity should be tailored with careful selection of both donors and recipients. Transplant decision should be made on a case-by-case basis after thorough assessment of the risks and benefits.
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http://dx.doi.org/10.1097/TP.0000000000003536DOI Listing
January 2021

Three-dimensional architecture of nephrons in the normal and cystic kidney.

Kidney Int 2021 Mar 31;99(3):632-645. Epub 2020 Oct 31.

Institut National de la Santé et de la Recherche Médicale U1151, Centre National de la Recherche Scientifique UMR8253, Université de Paris, Institut Necker Enfants Malades, Département « Croissance et Signalisation », Paris, France. Electronic address:

Kidney function is crucially dependent on the complex three-dimensional structure of nephrons. Any distortion of their shape may lead to kidney dysfunction. Traditional histological methods present major limitations for three-dimensional tissue reconstruction. Here, we combined tissue clearing, multi-photon microscopy and digital tracing for the reconstruction of single nephrons under physiological and pathological conditions. Sets of nephrons differing in location, shape and size according to their function were identified. Interestingly, nephrons tend to lie in planes. When this technique was applied to a model of cystic kidney disease, cysts were found to develop only in specific nephron segments. Along the same segment, cysts are contiguous within normal non-dilated tubules. Moreover, the shapes of cysts varied according to the nephron segment. Thus, our findings provide a valuable strategy for visualizing the complex structure of kidneys at the single nephron level and, more importantly, provide a basis for understanding pathological processes such as cystogenesis.
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http://dx.doi.org/10.1016/j.kint.2020.09.032DOI Listing
March 2021

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

Kidney Int Rep 2020 Sep 18;5(9):1535-1544. Epub 2020 Jul 18.

Service de Néphrologie, Dialyse et Transplantation, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris (APHP), Le Kremlin Bicêtre, France.

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.
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http://dx.doi.org/10.1016/j.ekir.2020.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368159PMC
September 2020

An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes.

Kidney Int 2020 12 1;98(6):1589-1604. Epub 2020 Aug 1.

Research Unit of Rare Diseases, Department of Pediatric and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, Prague, Czech Republic; Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. Electronic address:

There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.
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http://dx.doi.org/10.1016/j.kint.2020.06.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719087PMC
December 2020

Indirect effects of severe acute respiratory syndrome coronavirus 2 on the kidney in coronavirus disease patients.

Clin Kidney J 2020 Jun 22;13(3):347-353. Epub 2020 May 22.

Service de Néphrologie et Dialyse, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Universitaire Ambroise Paré, Boulogne Billancourt, France.

Among patients hospitalized for novel coronavirus disease (COVID-19), between 10 and 14% develop an acute kidney injury and around half display marked proteinuria and haematuria. Post-mortem analyses of COVID-19 kidney tissue suggest that renal tubular cells and podocytes are affected. Here we report two cases of collapsing glomerulopathy and tubulointerstitial lesions in living COVID-19 patients. Despite our use of sensitive reverse transcription polymerase chain reaction techniques in this study, we failed to detect the virus in blood, urine and kidney tissues. Our observations suggest that these kidney lesions are probably not due to direct infection of the kidney by severe acute respiratory syndrome coronavirus 2.
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http://dx.doi.org/10.1093/ckj/sfaa088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314263PMC
June 2020

Signaling pathways predisposing to chronic kidney disease progression.

JCI Insight 2020 05 7;5(9). Epub 2020 May 7.

Institut National de la Santé et de la Recherche Médicale (INSERM), U1151, CNRS UMR 8253, Institut Necker Enfants Malades (INEM), Department of Growth and Signaling, Université de Paris, Paris, France.

The loss of functional nephrons after kidney injury triggers the compensatory growth of the remaining ones to allow functional adaptation. However, in some cases, these compensatory events activate signaling pathways that lead to pathological alterations and chronic kidney disease. Little is known about the identity of these pathways and how they lead to the development of renal lesions. Here, we combined mouse strains that differently react to nephron reduction with molecular and temporal genome-wide transcriptome studies to elucidate the molecular mechanisms involved in these events. We demonstrated that nephron reduction led to 2 waves of cell proliferation: the first one occurred during the compensatory growth regardless of the genetic background, whereas the second one occurred, after a quiescent phase, exclusively in the sensitive strain and accompanied the development of renal lesions. Similarly, clustering by coinertia analysis revealed the existence of 2 waves of gene expression. Interestingly, we identified type I interferon (IFN) response as an early (first-wave) and specific signature of the sensitive (FVB/N) mice. Activation of type I IFN response was associated with G1/S cell cycle arrest, which correlated with p21 nuclear translocation. Remarkably, the transient induction of type I IFN response by poly(I:C) injections during the compensatory growth resulted in renal lesions in otherwise-resistant C57BL6 mice. Collectively, these results suggest that the early molecular and cellular events occurring after nephron reduction determine the risk of developing late renal lesions and point to type I IFN response as a crucial event of the deterioration process.
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http://dx.doi.org/10.1172/jci.insight.126183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253021PMC
May 2020

Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation.

J Immunol Res 2019 30;2019:1324804. Epub 2019 Dec 30.

Université Côte d'Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275, Valbonne Sophia Antipolis, France.

The phospholipase A2 receptor (PLA2R1) is the major autoantigen in idiopathic membranous nephropathy (MN). However, the pathogenic role of anti-PLA2R1 autoantibodies is unclear. Our aim was to evaluate the in vitro cytotoxicity of anti-PLA2R1 antibodies mediated by complement. Forty-eight patients with PLA2R1-related MN from the prospective cohort SOURIS were included. Anti-PLA2R1 titer, epitope profile, and anti-PLA2R1 IgG subclasses were characterized by ELISA. Cell cytotoxicity was evaluated by immunofluorescence in HEK293 cells overexpressing PLA2R1 incubated with patient or healthy donor sera in the presence or absence of rabbit complement or complement inhibitors. Mean cytotoxicity of anti-PLA2R1 sera for HEK293 cells overexpressing PLA2R1 was 2 ± 2%, which increased to 24 ± 6% after addition of rabbit complement ( < 0.001) ( = 48). GVB-EDTA, which inhibits all complement activation pathways, completely blocked cell cytotoxicity, whereas Mg-EGTA, which only inhibits the classical and lectin pathways, highly decreased suggesting a limited role of the alternative pathway. A higher diversity of IgG subclasses beyond IgG4 and high titer of total IgG anti-PLA2R1 were associated with increased cytotoxicity ( = 0.01 and = 0.03 respectively). In a cohort of 37 patients treated with rituximab, high level of complement-mediated cytotoxicity was associated with less and delayed remission at month 6 after rituximab therapy (5/12 vs. 20/25 ( = 0.03) in 8.5 months ± 4.4 vs. 4.8 ± 4.0 ( = 0.02)). Kaplan-Meier analysis demonstrated that high level of cytotoxicity (≥40%) ( = 0.005), epitope spreading (defined by immunization beyond the immunodominant CysR domain) ( = 0.002), and high titer of anti-PLA2R1 total IgG ( = 0.01) were factors of poor renal prognosis. Anti-PLA2R1 antibodies containing sera can induce in vitro cytotoxicity mediated by complement activation, and the level of cytotoxicity increases with the diversity and the titer of anti-PLA2R1 IgG subclasses. These patients with high level of complement-mediated cytotoxicity could benefit from adjuvant therapy using complement inhibitor associated with rituximab to induce earlier remission and less podocyte injury.
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http://dx.doi.org/10.1155/2019/1324804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012209PMC
June 2020

Lymphomas with kidney involvement: the French multicenter retrospective LyKID study.

Leuk Lymphoma 2020 04 10;61(4):887-895. Epub 2020 Feb 10.

Hémato-Oncologie, APHP, Hôpital Saint-Louis, Paris, France.

The LyKID study is a nationwide survey in France of lymphoma patients with renal involvement based on biopsy and/or imaging, to evaluate its impact on disease outcome and renal function. A total of 87 adult cases of B or T-cell lymphomas were retrospectively analyzed. Interstitial topography was observed in most of the kidney biopsies (54/66; 80%). Kidney failure (glomerular filtration rate <60 mL/min/1.73 m) was present in 47% of patients and was associated with non-significantly different outcome. After lymphoma treatment, 44% of patients had persistent chronic kidney failure (CKF); kidney failure at diagnosis was the only parameter associated with CKF in multivariate analysis. DLBCL (diffuse large B-cell lymphomas) represented half of the series, with noticeably CNS (central neurological system) relapse in 17% patients, while fewer than one of two patients had received CNS prophylaxis. To our knowledge, the LyKID study represents the largest published non-autopsy lymphoma series with renal involvement.
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http://dx.doi.org/10.1080/10428194.2019.1697811DOI Listing
April 2020

Efficacy and tolerance of immune checkpoint inhibitors in transplant patients with cancer: A systematic review.

Am J Transplant 2020 09 21;20(9):2457-2465. Epub 2020 Mar 21.

Department of Nephrology-Dialysis-Trans, Bicêtre Hospital, APHP, Le Kremlin Bicêtre, France.

Solid organ transplant (SOT) is frequently complicated by cancers, which render immunosuppression challenging. Immune checkpoint inhibitors have emerged as treatments for many cancers. Data are lacking regarding efficacy and rejection risk in the SOT population. We conducted a systematic literature review and analyzed 83 cases of immune checkpoint inhibitor use for cancer in SOT. Two thirds of these patients received anti-programmed death ligand 1 therapy, 15.7% received anti-cytotoxic T lymphocyte-associated protein 4 therapy, and 10.8% received a combination. Allograft rejection occurred in 39.8% of patients, leading to end-stage organ failure in 71.0% of cases. Outcomes were similar across organs and immunotherapy regimens. The use of immunosuppressants other than steroids, time since transplant, and prior episodes of rejection were associated with the risk of rejection. The median overall survival of patients was 36 weeks. Most of the deaths were related to cancer progression. In nonkidney recipients, graft rejection was strongly associated with worse survival. At the end of the study, 19.3% of the patients were alive, free from rejection and tumor progression. This study highlights the difficult tradeoff facing oncologists and transplant specialists managing transplant recipients with cancer, and the need for prospective data and novel biomarkers for identifying the patients likely to benefit from immunotherapy in the SOT setting.
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http://dx.doi.org/10.1111/ajt.15811DOI Listing
September 2020

The Case | A 69-year-old man with purpura and acute renal failure.

Kidney Int 2018 08;94(2):435-436

Department of Nephrology-Transplantation, Necker Hospital, APHP, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Paris, France.

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http://dx.doi.org/10.1016/j.kint.2018.03.020DOI Listing
August 2018

The Case | A 69-year-old man with bladder carcinoma and renal lesions.

Kidney Int 2018 Jun;93(6):1493-1494

Department of Nephrology-Transplantation, Necker Hospital, APHP, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2017.12.024DOI Listing
June 2018

The Case | Acute kidney injury, flank pain, and kidney calcifications in an 80-year-old woman.

Kidney Int 2018 02;93(2):527-528

Department of Nephrology-Transplantation, Hôpital Necker, APHP, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2017.08.017DOI Listing
February 2018

[Not Available].

Rev Prat 2016 Jun;66(6 Suppl):e246

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June 2016

[Not Available].

Rev Prat 2016 Jun;66(6 Suppl):e239-45

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June 2016

Primary-cilium-dependent autophagy controls epithelial cell volume in response to fluid flow.

Nat Cell Biol 2016 Jun 23;18(6):657-67. Epub 2016 May 23.

Institut Necker Enfants-Malades (INEM), INSERM U1151-CNRS UMR 8253, Université Paris Descartes-Sorbonne Paris Cité, Paris F-75993, France.

Autophagy is an adaptation mechanism that is vital for cellular homeostasis in response to various stress conditions. Previous reports indicate that there is a functional interaction between the primary cilium (PC) and autophagy. The PC, a microtubule-based structure present at the surface of numerous cell types, is a mechanical sensor. Here we show that autophagy induced by fluid flow regulates kidney epithelial cell volume in vitro and in vivo. PC ablation blocked autophagy induction and cell-volume regulation. In addition, inhibition of autophagy in ciliated cells impaired the flow-dependent regulation of cell volume. PC-dependent autophagy can be triggered either by mTOR inhibition or a mechanism dependent on the polycystin 2 channel. Only the LKB1-AMPK-mTOR signalling pathway was required for the flow-dependent regulation of cell volume by autophagy. These findings suggest that therapies regulating autophagy should be considered in developing treatments for PC-related diseases.
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http://dx.doi.org/10.1038/ncb3360DOI Listing
June 2016

Karyomegalic Interstitial Nephritis: A Case Report and Review of the Literature.

Medicine (Baltimore) 2016 May;95(20):e3349

From the Department of Nephrology-Transplantation (PI, BK, MZ), Necker Hospital, APHP, Paris; Department of Pathology (MR), Necker Hospital, APHP, Paris; Paris Descartes-Sorbonne Paris Cité University (MR, BK, MZ), Paris; Department of Nephrology (JL), Armed Forces Hospital of Val de Grâce, Paris; Department of Genetics (CA), Necker Hospital, APHP, Paris; Laboratory of Hereditary Kidney Diseases (CA), INSERM U1163, Paris; Imagine Institute (CA), Paris Descartes-Sorbonne Paris Cité University, Paris; and Department of Cell biology (BK, MZ), Institut Necker Enfants Malades, INSERM U1151, Paris, France.

Karyomegalic interstitial nephritis is a rare cause of hereditary chronic interstitial nephritis, described for the first time over 40 years ago.A 36-year-old woman, of Turkish origin, presented with chronic kidney disease and high blood pressure. She had a history of recurrent upper respiratory tract infections but no familial history of nephropathy. Physical examination was unremarkable. Laboratory tests showed serum creatinine at 2.3 mg/dL with an estimated glomerular filtration rate of 26 mL/min/1.73m, and gamma-glutamyl transpeptidase and alkaline phosphatase at 3 and 1.5 times the upper normal limit. Urinalysis showed 0.8 g/day of nonselective proteinuria, microscopic hematuria, and aseptic leukocyturia. Immunological tests and tests for human immunodeficiency and hepatitis B and C viruses were negative. Complement level and serum proteins electrophoresis were normal. Analysis of the renal biopsy showed severe interstitial fibrosis and tubular atrophy. Numerous tubular cells had nuclear enlargement with irregular outlines, hyperchromatic aspect, and prominent nucleoli. These findings were highly suggestive of karyomegalic interstitial nephritis, which was further confirmed by exome sequencing of FAN1 gene showing an identified homozygous frameshift mutation due to a one-base-pair deletion in exon 12 (c.2616delA).The present case illustrates a rare but severe cause of hereditary interstitial nephritis, sometimes accompanied by subtle extrarenal manifestations. Identification of mutations in FAN1 gene underscores recent insights linking inadequate DNA repair and susceptibility to chronic kidney disease.
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http://dx.doi.org/10.1097/MD.0000000000003349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902386PMC
May 2016

[Renal involvement during type 1 cryoglobulinemia].

Nephrol Ther 2016 Apr 10;12 Suppl 1:S71-81. Epub 2016 Mar 10.

Service de néphrologie, CHU de Poitiers, 2, rue de la Milétrie, 86021 Poitiers, France; Centre national de référence amylose AL et autres maladies à dépôts d'immunoglobulines monoclonales, CHU de Poitiers, 2, rue de la Milétrie, 86021 Poitiers, France.

Cryoglobulins are circulating immunoglobulins that precipitate with cold temperature and dissolve with rewarming. Type 1 cryoglobulinemia is composed of a single monoclonal immunoglobulin and is associated with renal involvement in up to 40% of cases. Type 1 cryoglobulinemia is related to an underlying B-cell haematological malignancy in 60% of patients. In the remaining cases, in the absence of criteria for malignancy, the diagnosis of monoclonal gammopathy of renal significance should be established. The clinical and biological setting and histological features of type 1 cryoglobulinemia are globally similar to those of mixed cryoglobulinemia. In case of haematological malignancy, the treatment is guided by the nature of the underlying disease, and aims at inducing haematological remission, which is necessary for the renal response. The management of monoclonal gammopathy of renal significance has been clarified by an international consensus group and is based on the nature of the underlying clone. In case of monoclonal cryoglobulinemia associated with a plasma-cell clone (IgG or IgA), the treatment is based on the combination of bortezomib, cyclophosphamide and dexamethasone. In case of IgM monoclonal cryoglobulinemia, the treatment is similar to that of Waldenström macroglobulinemia, and is based on rituximab. The clinical course of renal monoclonal cryoglobulinemia is intimately associated with the haematological response, and is usually favourable.
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http://dx.doi.org/10.1016/j.nephro.2016.01.010DOI Listing
April 2016

Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation.

PLoS Genet 2016 Mar 11;12(3):e1005894. Epub 2016 Mar 11.

INSERM UMR1163, Laboratory of Inherited Kidney Diseases, Necker-Enfants Malades Hospital, Paris, France.

Ciliopathies are a group of genetic multi-systemic disorders related to dysfunction of the primary cilium, a sensory organelle present at the cell surface that regulates key signaling pathways during development and tissue homeostasis. In order to identify novel genes whose mutations would cause severe developmental ciliopathies, >500 patients/fetuses were analyzed by a targeted high throughput sequencing approach allowing exome sequencing of >1200 ciliary genes. NEK8/NPHP9 mutations were identified in five cases with severe overlapping phenotypes including renal cystic dysplasia/hypodysplasia, situs inversus, cardiopathy with hypertrophic septum and bile duct paucity. These cases highlight a genotype-phenotype correlation, with missense and nonsense mutations associated with hypodysplasia and enlarged cystic organs, respectively. Functional analyses of NEK8 mutations in patient fibroblasts and mIMCD3 cells showed that these mutations differentially affect ciliogenesis, proliferation/apoptosis/DNA damage response, as well as epithelial morphogenesis. Notably, missense mutations exacerbated some of the defects due to NEK8 loss of function, highlighting their likely gain-of-function effect. We also showed that NEK8 missense and loss-of-function mutations differentially affect the regulation of the main Hippo signaling effector, YAP, as well as the expression of its target genes in patient fibroblasts and renal cells. YAP imbalance was also observed in enlarged spheroids of Nek8-invalidated renal epithelial cells grown in 3D culture, as well as in cystic kidneys of Jck mice. Moreover, co-injection of nek8 MO with WT or mutated NEK8-GFP RNA in zebrafish embryos led to shortened dorsally curved body axis, similar to embryos injected with human YAP RNA. Finally, treatment with Verteporfin, an inhibitor of YAP transcriptional activity, partially rescued the 3D spheroid defects of Nek8-invalidated cells and the abnormalities of NEK8-overexpressing zebrafish embryos. Altogether, our study demonstrates that NEK8 human mutations cause major organ developmental defects due to altered ciliogenesis and cell differentiation/proliferation through deregulation of the Hippo pathway.
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http://dx.doi.org/10.1371/journal.pgen.1005894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788435PMC
March 2016

Long-term effects of lithium on renal function.

Authors:
Mohamad Zaidan

Lancet 2015 Nov 13;386(10007):1943. Epub 2015 Nov 13.

Department of Nephrology-Transplantation, Necker Hospital, APHP, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Paris, France; INSERM U1151, Institut Necker Enfants-Malades, Department of Cell Biology, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(15)00833-8DOI Listing
November 2015

The Case | A man with hypertension, respiratory distress, and rapidly progressive renal failure.

Kidney Int 2016 Feb;89(2):509-10

Department of Pathology, Hôpital Européen Georges Pompidou, APHP, Paris, France.

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http://dx.doi.org/10.1016/j.kint.2015.12.014DOI Listing
February 2016

Spectrum and Prognosis of Noninfectious Renal Mixed Cryoglobulinemic GN.

J Am Soc Nephrol 2016 Apr 10;27(4):1213-24. Epub 2015 Aug 10.

Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S 1155, Paris, France; Nephrology and Dialysis, Assistance Publique - Hôpitaux de Paris, Tenon Hospital, Paris, France; Sorbonne Universités, Tenon Hospital, Paris, France

Noninfectious mixed cryoglobulinemic GN (MCGN) has been poorly investigated. We analyzed presentation and outcome of 80 patients with biopsy-proven MCGN, which were identified in the retrospective French CryoVas survey. MCGN was related to primary Sjögren's syndrome in 22.5% of patients and to lymphoproliferative disorders in 28.7% of patients, and was defined as essential in 48.8% of patients. At presentation, hematuria, proteinuria ≥1 g/d, hypertension, and renal failure were observed in 97.4%, 84.8%, 85.3%, and 82.3% of cases, respectively. Mean±eGFR was 39.5±20.4 ml/min per 1.73 m(2) Membranoproliferative GN was the predominant histologic pattern, observed in 89.6% of cases. Renal interstitium inflammatory infiltrates were observed in 50% of cases. First-line treatment consisted of steroids alone (27.6%) or in association with rituximab (21.1%), alkylating agents (36.8%) or a combination of cyclophosphamide and rituximab (10.5%). After a mean follow-up of 49.9±45.5 months, 42.7% of patients relapsed with a renal flare in 75% of cases. At last follow-up, mean eGFR was 50.2±26.1 ml/min per 1.73 m(2)with 9% of patients having reached ESRD; 59% and 50% of patients achieved complete clinical and renal remission, respectively. A rituximab+steroids regimen prevented relapses more effectively than steroids alone or a cyclophosphamide+steroids combination did, but was associated with a higher rate of early death when used as first-line therapy. Severe infections and new-onset B-cell lymphoma occurred in 29.1% and 8.9% of cases, respectively; 24% of patients died. In conclusion, noninfectious MCGN has a poor long-term outcome with severe infections as the main cause of death.
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http://dx.doi.org/10.1681/ASN.2015020114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814186PMC
April 2016

HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease.

J Am Soc Nephrol 2016 Apr 10;27(4):1042-54. Epub 2015 Aug 10.

Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche (UMR)S 1155, Paris, France; Sorbonne University, Université Pierre et Marie Curie, Paris 06, UMR_S 1155, Paris, France; Assistance Publique-Hôpitaux de Paris, Department of Nephrology and Dialysis, Tenon Hospital, Paris, France

Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the α1 chain of collagen IV, a major component of basement membranes. Patients present with cerebral small vessel disease, retinal tortuosity, muscle cramps, and kidney disease consisting of multiple renal cysts, chronic kidney failure, and sometimes hematuria. Mutations producing HANAC syndrome localize within the integrin binding site containing CB3[IV] fragment of the COL4A1 protein. To investigate the pathophysiology of HANAC syndrome, we generated mice harboring the Col4a1 p.Gly498Val mutation identified in a family with the syndrome. Col4a1 G498V mutation resulted in delayed glomerulogenesis and podocyte differentiation without reduction of nephron number, causing albuminuria and hematuria in newborns. The glomerular defects resolved within the first month, but glomerular cysts developed in 3-month-old mutant mice. Abnormal structure of Bowman's capsule was associated with metalloproteinase induction and activation of the glomerular parietal epithelial cells that abnormally expressed CD44,α-SMA, ILK, and DDR1. Inflammatory infiltrates were observed around glomeruli and arterioles. Homozygous Col4a1 G498V mutant mice additionally showed dysmorphic papillae and urinary concentration defects. These results reveal a developmental role for the α1α1α2 collagen IV molecule in the embryonic glomerular basement membrane, affecting podocyte differentiation. The observed association between molecular alteration of the collagenous network in Bowman's capsule of the mature kidney and activation of parietal epithelial cells, matrix remodeling, and inflammation may account for glomerular cyst development and CKD in patients with COL4A1-related disorders.
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http://dx.doi.org/10.1681/ASN.2014121217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814176PMC
April 2016

Physiological approach to assessment of acid-base disturbances.

Authors:
Mohamad Zaidan

N Engl J Med 2015 01;372(2):193

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http://dx.doi.org/10.1056/NEJMc1413880DOI Listing
January 2015

The authors reply.

Kidney Int 2014 Oct;86(4):857-8

1] Department of Nephrology-Transplantation, Necker Hospital, APHP, Paris Descartes University, Paris, France [2] Paris Descartes University, Sorbonne Paris Cité, Paris, France.

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http://dx.doi.org/10.1038/ki.2014.180DOI Listing
October 2014

Increased risk of solid renal tumors in lithium-treated patients.

Kidney Int 2014 Jul 22;86(1):184-90. Epub 2014 Jan 22.

1] Department of Nephrology-Transplantation, Necker Hospital, APHP, Paris Descartes University, Paris, France [2] Paris Descartes University, Sorbonne Paris Cité, Paris, France.

Cystic kidney diseases and toxic interstitial nephritis may be complicated by renal tumors. Long-term lithium intake is associated with tubulointerstitial nephritis and renal cysts but to date such an association with tumors has not been determined. We evaluated this in a retrospective study to determine whether lithium-treated patients were at higher risk of renal tumors compared with lithium-free patients with chronic kidney disease (CKD), and to the general population. Over a 16-year period, 14 of 170 lithium-treated patients had renal tumors, including seven malignant and seven benign tumors. The mean duration of lithium exposure at diagnosis was 21.4 years. The renal cancers included three clear-cell and two papillary renal cell carcinomas, one hybrid tumor with chromophobe and oncocytoma characteristics, and one clear-cell carcinoma with leiomyomatous stroma. The benign tumors included four oncocytomas, one mixed epithelial and stromal tumor, and two angiomyolipomas. The percentage of renal tumors, particularly cancers and oncocytomas, was significantly higher in lithium-treated patients compared with 340 gender-, age-, and estimated glomerular filtration rate (eGFR)-matched lithium-free patients. Additionally, the Standardized Incidence Ratio of renal cancer was significantly higher in lithium-treated patients compared with the general population: 7.51 (95% confidence interval (CI) (1.51-21.95)) and 13.69 (95% CI (3.68-35.06)) in men and women, respectively. Thus, there is an increased risk of renal tumors in lithium-treated patients.
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http://dx.doi.org/10.1038/ki.2014.2DOI Listing
July 2014