Mohamad Zaidan

Tubulointerstitial Nephropathies in HIV-Infected Patients over the Past 15 Years: A Clinico-Pathological Study

BACKGROUND AND OBJECTIVES The therapy and outcome of HIV infection have dramatically changed over the last 15 years, resulting in a change in renal complications. This study analyzed the characteristics of HIV-infected patients and biopsy-proven tubulointerstitial nephropathies to define disease patterns and therapeutic implications. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A clinico-pathologic retrospective study of 59 consecutive renal biopsies showing predominant tubular and/or interstitial lesions in HIV-infected patients referred to the nephrology department between 1995 and 2011 was performed. HIV-associated nephropathy and vascular diseases were excluded from the study. RESULTS Tubulointerstitial nephropathies accounted for 26.6% of 222 native renal biopsies performed in HIV-infected patients. Two pathologic groups were analyzed, tubulopathy and interstitial nephritis, which represented 49% and 51% of tubulointerstitial nephropathies, respectively. Most patients presented with AKI (76.3%) and high-grade proteinuria (57.7%). Drug-related nephrotoxicity was the leading cause (52.5%). Alternative etiologies included infections (15.2%), dysimmune disorders (8.5%), malignancies (3.4%), and chronic (10.2%) and acute (10.2%) tubulointerstitial nephropathies of undetermined origin. Tubulopathy was strongly associated with antiretroviral drug toxicity (75.9%) and mostly caused by tenofovir (55.2%), which was associated with proximal tubular dysfunction (87.5%), overt Fanconis syndrome (37.5%), and nephrogenic diabetes insipidus (12.5%). Interstitial nephritis was associated with a broader spectrum of pathologic lesions and etiologies. CONCLUSIONS In this series, tubulointerstitial nephropathies accounted for 26.6% of renal diseases in HIV-infected patients. Considering the therapeutic implications of diagnoses of drug toxicity, infection, and dysimmune syndromes, this study underscores the importance of monitoring renal parameters in HIV-infected patients and points to the relevance of kidney biopsy to allow an accurate diagnosis.

Evidence of follicular T-cell implication in a case of IgG4-related systemic disease with interstitial nephritis

IgG4-related systemic disease is a protean disorder that covers a wide variety of lesions. We report on a patient with tubulointerstitial nephritis, lymphadenopathies, sialadenitis and retroperitoneal fibrosis. The salivary gland and kidney interstitium were infiltrated with B lymphocytes and T lymphocytes and IgG3(+) and IgG4(+) plasma cells. The overexpression of IgG1 and IgG3, in addition to IgG4, the unusual abundance of interfollicular plasma cells and CD4(+) T cells in germinal centres of lymph nodes, and the dramatic response to rituximab point to possible roles of follicular helper T cells in enhancing a skewed B-cell terminal maturation and of CD20(+) B cells in disease progression.

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

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.

Renal involvement during type 1 cryoglobulinemia

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.

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

Abstract 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/1.73m2, 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.

Caractéristiques anatomocliniques de l’atteinte rénale au cours des vascularites cryoglobulinémiques mixtes non infectieuses

Introduction.– L’atteinte renale au cours des vascularites cryoglobulinemiques mixtes (VCM) a essentiellement ete decrite dans les formes associees a l’hepatite C, qui en represente la principale cause. L’objectif de cette etude etait d’etudier les caracteristiques anatomocliniques de l’atteinte renale associee aux VCM non infectieuses.Patients et methodes.– Etude multicentrique retrospective avec recueil des donnees cliniques et histopathologiques de patients presentant une VCM non infectieuse compliquee d’une atteinte renale prouvee histologiquement. Ces patients ont ete extraits de la cohorte CryoVas, etude nationale et transdisciplinaire ayant permis d’inclure 242 patients avec une VCM non infectieuse.Resultats.– Quatre-vingt patients ont ete inclus (50 F/30H, âge moyen : 63 ± 14 ans). La VCM etait secondaire a un syndrome de Gougerot-Sjogren (SS) chez 20 patients, a une hemopathie maligne chez 21 patients dont cinq avaient un SS associe. Le diagnostic de VCM essentielle a ete retenu chez 39 patients. L’atteinte renale etait caracterisee par une hematurie, une proteinurie superieure a 1 g/j, une hypertension arterielle et une insuffisance renale dans 97 %, 86 %, 85 % et 82 % des cas, respectivement. Le debit de filtration glomerulaire (DFG) moyen etait de 40 ± 20 mL/min/1,73m2. Les manifestations extrarenales les plus frequentes incluaient l’atteinte cutanee (71 %), neurologique (43 %) et articulaire (35 %). La majorite des patients presentait une glomerulonephrite membrano-proliferative de type 1 (91 %) tandis que sept patients (9 %) avaient une glomerulonephrite mesangio-proliferative. Un infiltrat interstitiel etait observe dans plus de la moitie des cas avec une organisation nodulaire dans pres de 40 % des cas. Ces infiltrats etaient essentiellement constitues de lymphocytes T CD3+ et B CD20+. L’expression faible ou nulle du marquage anti-cellules folliculaires dendritiques au niveau des nodules lymphoides etait en defaveur d’une organisation de type « centre germinatif ectopique ». Une fibrose interstitielle superieure a 25 % etait retrouvee dans 20 % des cas. Les lesions vasculaires comportaient essentiellement des lesions d’atherosclerose et plus rarement des lesions de vascularite. Quatre-vingt-quinze pour cent des patients ont ete traites par corticoides (88 %) et/ou immunosuppresseurs, incluant un agent alkylant (49 %) ± du rituximab (30 %). Des echanges plasmatiques ont ete realises chez 18 patients. La duree moyenne de suivi etait de 49 ± 51 mois. Au dernier suivi, 43 % des patients presentaient une remission renale complete definie par une amelioration d’au moins 20 % du DFG initial, une proteinurie inferieure a 0,5 g/j et une disparition de l’hematurie. Le DFG etait de 54 ± 25 mL/min/1,73m2, 57 % des patients avaient un DFG inferieur a 60 mL/min/1,73 m2 et 5 % avaient atteint le stade terminal. L’evolution a ete marquee par la survenue d’infections severes et d’hemopathies malignes dans 30 et 8 % des cas, respectivement. Pres de 25 % des patients etaient decedes dont la moitie au cours des six premiers mois suivant le diagnostic de l’atteinte renale. Les complications infectieuses (50 %) et hemorragiques (28 %) representaient les principales causes de deces.Discussion et conclusion.– Ce travail collaboratif represente la serie la plus large decrivant l’atteinte renale de la VCM non infectieuse. La VCM essentielle represente pres de 50 % des cas. Toutefois, la recherche d’une hemopathie maligne et d’un SS est indispensable etant donne la frequence elevee des hemopathies au diagnostic et au cours du suivi, notamment en cas de SS associe. Le pronostic est greve par la survenue d’infections severes et de complications hemorragiques.