Nuclear Factor Erythroid 2-Related Factor 2 Drives Podocyte-Specific Expression of Peroxisome Proliferator-Activated Receptor γ Essential for Resistance to Crescentic GN.

Necrotizing and crescentic rapidly progressive GN (RPGN) is a life-threatening syndrome characterized by a rapid loss of renal function. Evidence suggests that podocyte expression of the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) may prevent podocyte injury, but the function of glomerular PPARγ in acute, severe inflammatory GN is unknown. Here, we observed marked loss of PPARγ abundance and transcriptional activity in glomerular podocytes in experimental RPGN. Blunted expression of PPARγ in podocyte nuclei was also found in kidneys from patients diagnosed with crescentic GN. Podocyte-specific Pparγ gene targeting accentuated glomerular damage, with increased urinary loss of albumin and severe kidney failure. Furthermore, a PPARγ gain-of-function approach achieved by systemic administration of thiazolidinedione (TZD) failed to prevent severe RPGN in mice with podocyte-specific Pparγ gene deficiency. In nuclear factor erythroid 2-related factor 2 (NRF2)-deficient mice, loss of podocyte PPARγ was observed at baseline. NRF2 deficiency markedly aggravated the course of RPGN, an effect that was partially prevented by TZD administration. Furthermore, delayed administration of TZD, initiated after the onset of RPGN, still alleviated the severity of experimental RPGN. These findings establish a requirement for the NRF2-PPARγ cascade in podocytes, and we suggest that these transcription factors have a role in augmenting the tolerance of glomeruli to severe immune-complex mediated injury. The NRF2-PPARγ pathway may be a therapeutic target for RPGN.

Renal safety of high-dose, sucrose-free intravenous immunoglobulin in kidney transplant recipients: an observational study.

High-dose intravenous immunoglobulin (IVIg) is commonly used during kidney transplantation. Its nephrotoxicity has been attributed to sucrose stabilizers. We evaluated the renal safety of newer formulations of sucrose-free IVIg. We retrospectively studied clinical and histological data from 75 kidney recipients receiving high-dose, sucrose-free IVIg courses. This group was compared with 75 matched kidney recipients not treated with IVIg. Sucrose-free IVIg treatment was not associated with any acute kidney injury episode at 3 months, but an increased frequency of tubular macrovacuoles (28% vs. 2.8%, P < 0.001) was observed. Among IVIg-treated patients, the presence of macrovacuoles at 3 months was associated with increased IF/TA scores at 3 months (1.7 ± 1 vs. 1 ± 1, P = 0.005) and was more often observed in kidneys with higher IF/TA scores on day 0 (0.6 ± 0.9 vs. 0.3 ± 0.8, P = 0.03) at 3 months. Finally, patients treated with amino-acid-stabilized formulations developed fewer macrovacuoles at 3 months (12% vs. 60%; P < 0.001) than those treated with carbohydrate-stabilized IVIg. Our study shows that high-dose, sucrose-free IVIg use in early kidney recipients is clinically well tolerated. Among sucrose-free IVIg, amino-acid-stabilized formulations are associated with less tubular toxicity than carbohydrate-stabilized IVIg.

A Prospective Study on Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change Disease.

Introduction: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are related podocytopathies with distinct kidney outcomes. Surprisingly, elevated urinary activation fragments have been found in FSGS despite little complement deposition on immunofluorescence (IF) staining. Whether complement activation distinguishes FSGS from MCD, participating in the development of segmental lesions, remains unknown. Methods: We performed an observational study in patients with MCD and FSGS, and proteinuria ≥1 g/g of creatinine. We included both primary and secondary or unknown causes. We compared urinary fragments of terminal pathway activation, sC5b9, and C5a expressed as creatinine ratios, between MCD and FSGS. Results: Patients with FSGS (n = 41) had a serum albumin of 31±10 g/l and proteinuria of 5.1 (2.6-9.1) g/g at sampling, whereas those with MCD (n = 15) had a lower serum albumin (22 ± 9 g/l; P = 0.002), and a proteinuria of 3.8 (1.9-7.7) g/g (P = 0.40). Urinary sC5b9 and C5a were 8.7 (1.7-52.3) and 1.26 (0.45-1.84) µg/mmol of creatinine, respectively in patients with FSGS; compared to 0.8 (0.0-1.5) and 0.06 (0.01-0.15) µg/mmol of creatinine in MCD (P < 0.001), respectively. We found no association between urinary complement fragments and age, estimated glomerular filtration rate (eGFR), or chronic kidney lesions. When analyzing samples with proteinuria ≥ 3 g/g, the c-statistics for urinary sC5b9 and C5a were 0.96 and 1.00, respectively, in differentiating FSGS from MCD. Conclusion: We found no urinary complement activation fragments in MCD, in comparison to FSGS, despite similar levels of proteinuria. This suggests a role for complement activation in the pathogenesis of FSGS and provides an additional tool for distinguishing these 2 entities.

Atypical ADPKD Due to a DNAJB11 Pathogenic Variant: An Educational Case Report.

Rationale: Due to next-generation sequencing, variants in new genes such as DNAJB11 are recently being identified as causing atypical autosomal dominant polycystic kidney disease (ADPKD). It is important to describe phenotypes associated with these variants in order to increase awareness among clinicians, especially since genetic variability affects ADPKD severity. Presenting Concerns of the Patient: We describe a 55-year-old female patient of Haitian origin who presented with slowly deteriorating kidney function, microscopic hematuria, proteinuria, enlarged kidneys with innumerable small cysts, and a family history of chronic kidney disease and cysts. The phenotype was atypical for ADPKD caused by PKD1 or PKD2 variants, since cysts were of small size, kidneys were only moderately enlarged, and the patient had no extra-renal involvement suggestive of typical ADPKD such as liver cysts, pancreatic cysts, cranial aneurysms, or cardiac abnormalities. Diagnoses: A panel of genes was analyzed by next-generation massive sequencing techniques, including DNAJB11, DZIP1L, GANAB, HNF1B, PKD1, PKD2, and PKHD1. Genetic testing revealed a heterozygous variant in the DNAJB11 gene (c.123 dup), which is predicted to result in premature protein termination (p. Lys42*) and was classified by the laboratory as likely pathogenic. Interventions: She was treated with candesartan 16 mg once daily to address her proteinuria. Outcomes: At the time of the most recent follow-up, her proteinuria has increased, and her kidney function continues to slowly deteriorate. Teaching Points: DNAJB11 variants are a rare cause of atypical ADPKD. It is important to recognize the clinical features that help distinguish DNAJB11 from PKD1 and PKD2 variants. Atypical ADPKD due to DNAJB11 variants is usually characterized by small cysts, normal kidney size, proteinuria, progressive chronic kidney disease, and phenotypic overlap with autosomal dominant tubulointerstitial kidney disease (ADTKD). It may, however, present itself with enlarged kidneys as was seen in our patient. Genetic testing should be offered whenever a patient presents atypical features of ADPKD, which also requires increased awareness among clinicians regarding the various phenotypes of atypical ADPKD.

Justification: Grâce au séquençage de nouvelle génération, on a récemment identifié des variants de nouveaux gènes tels que DNAJB11 qui causeraient une forme atypique de polykystose rénale autosomique dominante (PKRAD). Afin de sensibiliser davantage les cliniciens, il est important de décrire les phénotypes associés à ces variants, d'autant plus qu'on sait que la variabilité génétique affecte la gravité de la PKRAD. Présentation du cas: Nous décrivons le cas d'une patiente de 55 ans d'origine haïtienne qui présentait une lente détérioration de la fonction rénale, une hématurie microscopique, une protéinurie et des reins avec d'innombrables petits kystes. La patiente avait également des antécédents familiaux de néphropathie et de kystes. Le phénotype était atypique pour une PKRAD causée par les variants PKD1 ou PKD2, car les kystes étaient petits, que la taille des reins n'était que modérément augmentée et qu'elle ne présentait aucune atteinte extra-rénale suggérant une PKRAD typique tels que des kystes hépatiques, des kystes pancréatiques, des anévrismes crâniens ou des anomalies cardiaques. Diagnostic: Un groupe de gènes a été analysé par des techniques de séquençage massif de nouvelle génération, notamment les gènes DNAJB11, DZIP1L, GANAB, HNF1B, PKD1, PKD2 et PKHD1. Le dépistage génétique a révélé un variant hétérozygote dans le gène DNAJB11 (c.123 dup), qui est prédite comme entraînant une terminaison protéique prématurée (p.Lys42*) et qui a été classé par le laboratoire comme étant probablement pathogène. Interventions: La patiente a reçu 16 mg de candesartan une fois par jour pour traiter sa protéinurie. Résultats: Lors du plus récent suivi, la protéinurie avait augmenté et la fonction rénale avait continué de se détériorer lentement. Enseignements tirés: Les variants de DNAJB11 sont une cause rare de PKRAD atypique. Il est important de reconnaître les caractéristiques cliniques qui aident à distinguer les variants de DNAJB11 des variants PKD1 et PKD2. La PKRAD atypique due à des variants du gène DNAJB11 est généralement caractérisée par de petits kystes, des reins de taille normale, une protéinurie, une insuffisance rénale chronique progressive et un chevauchement phénotypique avec la néphropathie tubulo-interstitielle autosomique dominante. Elle peut cependant se présenter avec des reins de taille augmentée, comme on l'a vu chez cette patiente. Le dépistage génétique devrait être offert dès qu'un patient présente des caractéristiques de PKRAD atypique, ce qui nécessite également une sensibilisation accrue des cliniciens aux divers phénotypes de la PKRAD atypique.

Endoplasmic reticulum stress in UMOD-related kidney disease: a human pathologic study.

Mutations of the UMOD gene, which encodes the uromodulin protein, are associated with tubulointerstitial nephritis and hyperuricemia. UMOD mutations impair uromodulin folding, resulting in its retention within the endoplasmic reticulum (ER) of renal tubular cells. The aim of this study was to investigate whether mutant uromodulin accumulation in epithelial tubular cells is associated with ER stress. We characterized tubular expression of uromodulin and the ER stress surrogate marker Grp78 by immunohistochemistry in kidney biopsy specimens from 7 patients with UMOD-related kidney disease. We compared this population with 5 patients with familial tubulointerstitial nephritis not related to UMOD mutation. All biopsy specimens from patients carrying the UMOD mutation showed strong heterogeneous cytoplasmic expression of uromodulin in cells of the thick ascending limb of the loop of Henle. In the same tubules, Grp78 was highly expressed in a perinuclear pattern. In contrast, in all kidney biopsy specimens from patients without UMOD mutations, uromodulin staining showed normal apical expression and Grp78 expression was not increased. Our observations support the hypothesis that ER accumulation of mutant uromodulin may cause ER stress, providing a potential mechanism for the progression of UMOD-related kidney disease.

Epidermal growth factor: a new therapeutic target in glomerular disease.

Glomerular kidney diseases are of major public health importance because of their strong impact on the quality of life of patients and of their costly management. A relatively neglected area of study is the local factors that influence development of glomerular demolition. The involvement of a glomerular factor has been now demonstrated in glomerulonephritis with cell proliferation such as crescentic rapidly progressive glomerulonephritis (RPGN). Various unrelated immune disorders promote RPGN, such as antibodies directed against the glomerular basement membrane, deposition of immune complexes or antibodies directed against neutrophils. Despite the heterogeneity of these causing diseases, RPGNs share similar histopathological features, which suggest involvement of common final pathways. De novo expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in glomerular epithelial cells is found specifically in human glomerulonephritis with proliferation of these cells and dedifferentiation of podocytes. A receptor for HB-EGF, the EGF receptor (EGFR), is expressed by parietal epithelial cells and podocytes. Furthermore, in a mouse model of RPGN, HB-EGF deficiency or conditional targeting of the Egfr alleles in podocytes markedly alleviated RPGN, renal failure and death. This indicates that the HB-EGF/EGFR pathway plays a pivotal role in RPGN and opens therapeutic perspectives as EGFR inhibitors are clinically available.

Presentation of HIV-associated nephropathy and outcome in HAART-treated patients.

BACKGROUND: Among the numerous renal diseases observed in human immunodeficiency virus (HIV) patients, HIV-associated nephropathy (HIVAN) is a major cause of end-stage renal disease (ESRD). The purpose of our study was to describe the presentation and outcome of HIVAN in the era of highly active antiretroviral therapy (HAART). METHODS: We analysed clinical features and outcome of 57 patients with histologically proven HIVAN diagnosed between 2000 and 2009 in four teaching hospitals in Paris, France. RESULTS: This series was characterized by median age of 41 years (18-58), frequent African origin (87%), severe renal dysfunction [estimated glomerular filtration rate (eGFR) 20 mL/min/1.73m(2) (1-68)], high-grade proteinuria [4.1 g/day (0.6-16.8)], high proportion of sclerotic glomeruli [31.5% (0-95)], high HIV load [4.5 log copies/mL (0-6.7)] and low CD4+ count [127/mm(3) (3-713)]. Nevertheless, a non-negligible proportion of patients did not present with these typical features. Follow-up data were available for 51 patients. ESRD occurred in 30 patients (58.8%). Median renal survival was 40 months. Baseline characteristics significantly associated with ESRD were as follows: severity of renal dysfunction, percentage of sclerotic glomeruli, time from HIV infection to HIVAN diagnosis longer than 1 year and prior exposure to antiretroviral drugs. There was an insignificant trend towards better renal outcome being associated with viral suppression during follow-up. Use of renin-angiotensin system (RAS) blockers was associated with higher renal survival (P < 0.05). CONCLUSION: Despite HAART, HIVAN led to ESRD in more than half of the cases. Early recognition of the disease is crucial to start HAART and RAS blockers before irreversible renal injury.

Adenine phosphoribosyltransferase deficiency in children.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder characterized by 2,8-dihydroxyadenine (2,8-DHA) crystalluria that can cause nephrolithiasis and chronic kidney disease. The aim of our study was to assess the clinical presentation, diagnosis, and outcome of APRT deficiency in a large pediatric cohort. All pediatric cases of APRT deficiency confirmed at the same French reference laboratories between 1978 and 2010 were retrospectively reviewed. Twenty-one patients from 18 families were identified. The median age at diagnosis was 3 years. Diagnosis was made after one or more episodes of nephrolithiasis (17 patients), after urinary tract infection (1 patient), and by family screening (3 patients). The diagnosis was based on stone analysis and microscopic examination of urine and/or enzymatic determination of APRT on red blood cells. All children had null APRT enzyme activity in erythrocytes. APRT gene sequencing was performed on 18 patients, revealing six homozygous and 12 compound heterozygous mutations. At diagnosis, half of the patients had decreased kidney function, and two children presented with acute renal failure. Allopurinol treatment was given to all patients at a median dose of 9 mg/kg/day. After a median follow-up of 5 years, all patients showed stabilization or improvement of kidney function, normal growth and development, and six patients had recurrence of nephrolithiasis. Based on these results, we conclude that an excellent outcome can be achieved in children with APRT deficiency who receive the proper treatment.

Association between circulating PCSK9 and proteinuria in nephrotic syndrome: A cross-sectional study.

BACKGROUND: Nephrotic syndrome (NS) is associated with both hypercholesterolemia and hypertriglyceridemia, which could exacerbate disease progression and accelerate atherosclerosis. It has been reported that PCSK9, a proprotein convertase involved in hypercholesterolemia, was increased in patients with NS. OBJECTIVE: To investigate the association between PCSK9 concentrations and the magnitude of proteinuria. METHODS: A total of 168 patients from nephrology and lipid clinics of the Centre Hospitalier de l'Université de Montreal were included in this cross-sectional observational study. Proteinuria level was classified in three groups: nephrotic syndrome (n = 51), proteinuria (n = 66), and control (n = 51) according to proteinuria and albuminemia concentrations. Plasma PCSK9 concentration was measured by an in-house ELISA and the lipid profile was assayed using an automated biochemical analyzer (COBAS INTEGRA 400, Roche Diagnostic). RESULTS: Plasma PCSK9 concentration was highest in the NS group (170.9 ng/mL), intermediate in the proteinuria group (156.4 ng/mL) and lowest in the control group (136.0 ng/mL), P = 0.005. We observed an association between the protein/creatinine (P/C) ratio and plasma PCSK9 concentrations in the whole cohort (ß = 0.205, P = 0.006) after adjustment for age, sex, LDL-C, statin use, other lipid-lowering therapy use, diabetes, and eGFR. CONCLUSIONS: Patients with nephrotic syndrome have an increased risk of cardiovascular complications. PCSK9 is significantly elevated in NS and is associated with a detrimental lipid profile that could contribute to a worse prognosis of the disease. Future studies evaluating the efficacy of PCSK9 inhibitors in patients with NS would be justified.

Plasma copeptin is increased and associated with smaller kidney volume in young adults born very preterm.

Background: Plasma copeptin, a surrogate marker for vasopressin levels, is increased in neonates born preterm, particularly in those with a more severe neonatal course, as reflected by bronchopulmonary dysplasia. Copeptin levels in adulthood are unknown. Methods: In this case-control study of 101 adults born very preterm (<30 weeks of gestation) and 105 control adults born full-term, a comprehensive clinical and biological assessment was performed, including blood pressure measurements, kidney ultrasound and determination of plasma copeptin, renin activity, angiotensin II, aldosterone, apelin, sodium and potassium, serum and morning urine osmolality. Results: The median age in the study was 23.1 years [interquartile range (IQR) 21.2-24.8] and 57% were females. In males, the median copeptin levels were 8.2 pmol/L (IQR 6.3-12.4) and 6.1 pmol/L (IQR 4.3-9.0) in the preterm and term groups, respectively (P = 0.022). In females, the median copeptin levels were 5.2 pmol/L (IQR 3.9-7.6) and 4.0 pmol/L (IQR 2.8-5.7) in the preterm and term groups, respectively (P = 0.005). Adults born preterm with a history of bronchopulmonary dysplasia had further increased copeptin levels. The kidney volume, adjusted for height, was smaller and albuminuria was higher in the preterm group, and both were associated with higher plasma copeptin levels. Conclusions: Plasma copeptin is higher in young adults born preterm and is related to a more severe neonatal course and smaller kidney volume.

Phenotype and genotype characterization of adenine phosphoribosyltransferase deficiency.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder causing 2,8-dihydroxyadenine stones and renal failure secondary to intratubular crystalline precipitation. Little is known regarding the clinical presentation of APRT deficiency, especially in the white population. We retrospectively reviewed all 53 cases of APRT deficiency (from 43 families) identified at a single institution between 1978 and 2009. The median age at diagnosis was 36.3 years (range 0.5 to 78.0 years). In many patients, a several-year delay separated the onset of symptoms and diagnosis. Of the 40 patients from 33 families with full clinical data available, 14 (35%) had decreased renal function at diagnosis. Diagnosis occurred in six (15%) patients after reaching ESRD, with five diagnoses made at the time of disease recurrence in a renal allograft. Eight (20%) patients reached ESRD during a median follow-up of 74 months. Thirty-one families underwent APRT sequencing, which identified 54 (87%) mutant alleles on the 62 chromosomes analyzed. We identified 18 distinct mutations. A single T insertion in a splice donor site in intron 4 (IVS4 + 2insT), which produces a truncated protein, accounted for 40.3% of the mutations. We detected the IVS4 + 2insT mutation in two (0.98%) of 204 chromosomes of healthy newborns. This report, which is the largest published series of APRT deficiency to date, highlights the underdiagnosis and potential severity of this disease. Early diagnosis is crucial for initiation of effective treatment with allopurinol and for prevention of renal complications.

Decreased kidney function and crystal deposition in the tubules after kidney transplant.

Adenine phosphoribosyltransferase (APRT) deficiency is an autosomal recessive purine enzyme defect that results in the inability to utilize adenine, which consequently is oxidized by xanthine dehydrogenase to 2,8-dihydroxyadenine (2,8-DHA), an extremely insoluble substance eventually leading to crystalluria, nephrolithiasis, and kidney injury. We describe a case of APRT deficiency not diagnosed until the evaluation of a poorly functioning kidney transplant in a 67-year-old white woman. After the transplant, there was delayed transplant function, urine specimens showed crystals with unusual appearance, and the transplant biopsy specimen showed intratubular obstruction by crystals identified as 2,8-DHA using infrared spectroscopy. APRT enzymatic activity was undetectable in red blood cell lysates, and analysis of the APRT gene showed 1 heterozygous sequence variant, a duplication of T at position 1832. The patient was treated with allopurinol, 300 mg/d, and transplant function progressively normalized. Because patients with undiagnosed APRT deficiency who undergo kidney transplant may risk losing the transplant because of an otherwise treatable disease, increased physician awareness may hasten the diagnosis and limit the morbidity associated with this disease.

Renal biopsy practice in France: results of a nationwide study.

BACKGROUND: Although several risk factors associated with complications after renal biopsy (RB) have been identified, the gold standard for RB procedures remains to be defined. Practices vary widely among nephrologists, depending on personal experience and the availability of particular techniques. The purpose of our study was to depict the main aspects of the practice of RB in adults in France. METHODS: Members of the Société de Néphrologie in France were asked to participate in a questionnaire survey on RB procedures. RESULTS: Eighty-eight nephrologists from 74 units (27 in teaching hospitals, 35 in public general hospitals and 12 in private centres) participated in our study. Native kidney and graft biopsies were performed in 73 and 35 units, respectively. RB activity was highly variable among units, ranging from several hundred to <10 per year. Transjugular renal biopsy was judged to be smoothly accessible in 28 out of 73 units (38.4%). Significant variations in practices were observed regarding patient information before RB, assessment of haemorrhagic risk factors, management of patients with antiplatelet agents and haemorrhagic risk factors, and radiological guidance. Early discharge (<12 h) was the rule in 3 (4.1%) units for native kidney biopsies and in 10 (28.6%) units for graft biopsies. CONCLUSIONS: Our study is the first to provide a representative picture of 'everyday' RB practices in a country. Important variations in procedures were observed. Our study may represent a preliminary step for the elaboration of guidelines for all aspects of RB practices.

Association of Hyperuricemia With Acute Kidney Injury: Case Series Report Among Patients Hospitalized With General Tonic-Clonic Seizures.

BACKGROUND: Urate nephropathy is a rare cause of acute kidney injury. Although most risk factors are associated with chemotherapy, tumor lysis syndrome or rhabdomyolysis, occurrence following severe seizure has also been reported. Uric acid measurement following convulsion is rarely performed and, therefore, the incidence of hyperuricemia in this context is unknown. OBJECTIVE: The objective is to present a case of urate nephropathy following generalized tonic-clonic seizure (GTCS) and to investigate the kinetics of serum uric acid and creatinine levels in a series of patients admitted for severe seizures. DESIGN: Retrospective case report and prospective case series. SETTING: Emergency room department and neurology unit of a tertiary care hospital. PATIENTS: The study included 13 hospitalized patients for severe GTCS. MEASUREMENTS: Type, timing, and duration of seizure episodes were documented. Demographic data, weight, hypouricemic therapy, and baseline serum creatinine were recorded. Blood samples (uric acid, creatinine, blood gas, lactate, and creatinine kinase) and urine samples (uric acid, creatinine, and dipstick) were prospectively collected at Day 0, 1, 2, and 3 following the GTCS episode. METHODS: We identified and described one rare case of urate nephropathy following GTCS. Then, we presented the kinetic of uric acid and creatinine levels and the acute kidney injury incidence over the follow-up period. All analyses were using descriptive statistics. RESULTS: During the study period, 13 patients with a median tonic-clonic seizure duration of 5.0 minutes (interquartile range [IQR], 2.0-12.5) were included. From day 0 to day 3, the median serum uric acid level decreased from 346.0 µmol/L (IQR, 155.0-377.5) to 178.0 µmol/L (IQR, 140.0-297.5) and median serum creatinine from 73.0 µmol/L (IQR, 51.0-80.0) to 57.0 µmol/L (IQR, 44.0-70.0). Acute kidney injury occurred in four patients. LIMITATIONS: This is a single-center observational study with small sample size, which does not allow us to demonstrate causality between the increase of uric acid levels observed and the occurrence of acute kidney injury. A delay between the first sampling and seizure episodes was observed and could explain the limited increase of uric acid levels captured. CONCLUSIONS: There is a signal for an acute increase of uric acid levels following a severe seizure before returning to baseline within 3 days. During that period, there might be an increased risk of acute kidney injury, although these changes seem to be usually mild and reversible. Our findings suggest that routine serum uric acid measurement in patients presenting with GTCS could help to identify those patients at risk of developing acute kidney injury as a result of acute hyperuricemia. Further larger studies are required to confirm the effectiveness of such screening in acute kidney injury prevention. TRIAL REGISTRATION: As an observational noninterventional study, no registration was required.

CONTEXTE: La Néphropathie à l'acide urique est une cause rare d'insuffisance rénale aiguë (IRA). Bien que la plupart des facteurs de risque soient associés à la chimiothérapie, au syndrome de lyse tumorale ou à la rhabdomyolyse, des occurrences ont également été rapportées à la suite d'une grave crise d'épilepsie. Le taux d'acide urique est rarement mesuré après les convulsions et, ainsi, l'incidence de l'hyperuricémie demeure inconnue dans ce contexte. OBJECTIFS: Cette étude a pour objectif de présenter un cas de Néphropathie à l'acide urique à la suite d'une crise généralisée de type tonico-clonique (CGTC) et d'étudier la cinétique des taux sériques d'acide urique et de créatinine chez des patients admis pour une crise d'épilepsie grave. TYPE D'ÉTUDE: Un rapport de cas rétrospectif et une série de cas prospective. CADRE: L'urgence et le service de neurologie d'un hôpital de soins tertiaires. SUJETS: L'étude a inclus treize patients hospitalisés pour une CGTC grave. MESURES: Le type, le moment et la durée des épisodes de crise ont été documentés. Les données démographiques, le poids, le traitement hypo-uricémique et le taux sérique initial de créatinine ont également été colligés. De plus, des échantillons de sang (acide urique, créatinine, gaz sanguin, lactate, créatinine kinase) et d'urine (acide urique, créatinine, bandelette réactive) ont été recueillis de façon prospective aux jours 0, 1, 2 et 3 suivant l'épisode de CGTC. MÉTHODOLOGIE: Nous avons répertorié et décrit un cas rare de Néphropathie à l'acide urique suivant une CGTC, puis nous avons présenté la cinétique des taux d'acide urique et de créatinine ainsi que l'incidence de l'IRA au cours de la période de suivi. Toutes les analyses ont été faites à l'aide de statistiques descriptives. RÉSULTATS: Au cours de la période de suivi, treize patients dont l'épisode de CGTC avait une durée médiane de 5,0 minutes (ÉIQ: 2,0-12,5) ont été inclus. Du jour 0 au jour 3, l'uricémie médiane est passée de 346,0 µmol/L (ÉIQ: 155,0-377,5) à 178,0 µmol/L (ÉIQ: 140,0-297,5) et le taux médian de créatinine sérique de 73,0 µmol/L (ÉIQ: 51,0-80,0) à 57,0 µmol/L (ÉIQ: 44,0-70,0). Quatre patients ont eu un épisode d'IRA. LIMITES: Il s'agit d'une étude observationnelle monocentrique portant sur un faible échantillon, ce qui nous empêche de démontrer une causalité entre l'observation d'une augmentation du taux d'acide urique et l'apparition de l'IRA. Un délai a été observé entre le moment où est survenue la crise et le moment du premier prélèvement, ce qui pourrait expliquer les hausses limitées observées pour les taux d'acide urique. CONCLUSION: Certains signes indiquent une accentuation des taux d'acide urique à la suite d'une crise d'épilepsie grave, avec un retour aux taux initiaux dans les trois jours. Au cours de cette période, le risque d'IRA pourrait s'accroître, bien que ces changements semblent généralement légers et réversibles. Nos résultats donnent à penser que la mesure systématique de l'acide urique dans le sérum des patients admis pour une CGTC pourrait contribuer à identifier les patients susceptibles de développer une IRA découlant d'une hyperuricémie aiguë. Des études supplémentaires de plus grande envergure sont nécessaires pour confirmer l'efficacité de ce dépistage pour prévenir l'IRA.

Plasma exchange for disseminated cryptococcosis.

Acute renal failure is frequent in HIV-infected patients and may be related to HIV-associated nephropathy, drugs, or opportunistic infections. We report a peculiar case of disseminated cryptococcosis complicated by acute renal failure associated with obstruction of intrarenal capillaries by Cryptococus neoformans dead bodies and successfully treated with plasma exchanges.

Pauci-immune crescentic glomerulonephritis associated with ANCA of IgA class.

Pauci-immune renal vasculitis is associated strongly with antineutrophil cytoplasmic antibodies (ANCAs) of the immunoglobulin G (IgG) class, which are detected in 80% to 90% of affected patients. IgA ANCAs have been reported in association with various conditions, but never in the setting of pauci-immune vasculitis. A 28-year-old man with unexplained polyclonal hyper-IgA1 diagnosed in childhood presented with decreased kidney function, nephrotic syndrome, and microscopic hematuria. Kidney biopsy showed pauci-immune crescentic glomerulonephritis. Serum test results were negative for IgG ANCA by means of both indirect immunofluorescence and enzyme-linked immunosorbent assay techniques. Conversely, indirect immunofluorescence performed using anti-IgA antibody was strongly positive with a cytoplasmic ANCA pattern, and an enzyme-linked immunosorbent assay test had positive results for both antimyeloperoxidase and anti-proteinase 3 IgA. IgA ANCAs were not detected in 2 control serum samples from 1 patient with polyclonal hyper-IgA and 1 patient with monoclonal hyper-IgA. The patient received corticosteroids and 4 weekly perfusions of rituximab (375 mg/m2). After a 6-month follow-up, decreased kidney function and nephrotic syndrome persisted and IgA ANCA titers were unchanged. However, a control kidney biopsy showed a decrease in vasculitis activity. This first case of pauci-immune vasculitis associated with ANCA of the IgA class suggests the potential pathogenetic role of these peculiar antibodies. Additional studies are needed to determine whether IgA ANCAs, which are not routinely screened for, can be detected in patients with pauci-immune vasculitis either alone or in association with IgG ANCA.

Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib.

BACKGROUND: Drugs targeting the VEGF pathway are associated with renal adverse events, including proteinuria, hypertension and thrombotic microangiopathy (TMA). Most cases of TMA are reported secondary to bevacizumab. It was shown recently that sunitinib, a small molecule inhibiting several tyrosine kinase receptors, including VEGF receptors, can also induce proteinuria, hypertension and biological features of TMA. Case. A 44-year-old woman with a history of malignant skin hidradenoma was started on sunitinib for refractory disease. She developed hypertension after 2 weeks and low-grade proteinuria after 4 weeks. Renal function remained normal, and biological signs of TMA were absent. A renal biopsy was performed 6 months later as proteinuria persisted, demonstrating typical features of TMA. The patient was given irbesartan, and sunitinib was continued for 3 months after diagnosis. Over this period, blood pressure and renal function remained stable and proteinuria became undetectable. CONCLUSION: We report on the first case of histologically documented TMA secondary to sunitinib and provide detailed description of renal histological involvement. This suggests that all anti-VEGF drugs may share a common risk for developing renal adverse events, including TMA. Our case highlights the possible discrepancy between mild clinical manifestation on one hand and severe TMA features on renal biopsy on the other hand and pleads for large indication of renal biopsy in this setting. The renin-angiotensin system blockers may be considered in patients with mild clinical manifestations and in the absence of therapeutic alternative to anti-VEGF drugs.

Estimating the Change in Renal Function During the First Year of Therapy in ANCA-Associated Vasculitis.

INTRODUCTION: Studies in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) consistently show that the months following diagnosis have the greatest impact on the long-term renal function. Yet, it remains uncertain how much early gain should be expected with treatment. We sought to determine the factors associated with the change in glomerular filtration rate (GFR) throughout the first year. METHODS: We retrospectively reviewed patients from 3 university hospitals who received treatments. We assessed the proportions of glomeruli with crescents, with global sclerosis, the AAV glomerulonephritis classification, the severity of chronic vascular and tubulo-interstitial disease, and the presence of acute tubular injury (ATI). We used repeated-measures analyses of variance (ANOVAs) to determine factors associated with the change in GFR throughout the first year. RESULTS: There were 162 individuals with AAV identified, 96 with a valid renal biopsy and 82 with at least 12 months of follow-up. The initial GFR of 30 ± 25 ml/min per 1.73 m2 rose by 15 ± 20 during the first year. The severity of pathology findings, myeloperoxidase positivity, and those with kidney- and lung-limited disease presented with a lower GFR. Younger patients with a lower initial GFR and the presence of ATI correlated with a greater increase in GFR by 12 months. A higher proportion of crescents did not predict the change in GFR, contrary to global glomerulosclerosis, where each 10% increase added a loss of 2.7 ± 1.3 ml/min per 1.73 m2 per year (P = 0.03). These factors remained independent of each other. CONCLUSION: Multiple factors influence renal recovery during the first year of therapy. Estimating the change in GFR early on will help identify and reassess outliers.

The tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression.

The mechanisms driving the development of extracapillary lesions in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN) remain poorly understood. A key question is how parietal epithelial cells (PECs) invade glomerular capillaries, thereby promoting injury and kidney failure. Here we show that expression of the tetraspanin CD9 increases markedly in PECs in mouse models of CGN and FSGS, and in kidneys from individuals diagnosed with these diseases. Cd9 gene targeting in PECs prevents glomerular damage in CGN and FSGS mouse models. Mechanistically, CD9 deficiency prevents the oriented migration of PECs into the glomerular tuft and their acquisition of CD44 and ß1 integrin expression. These findings highlight a critical role for de novo expression of CD9 as a common pathogenic switch driving the PEC phenotype in CGN and FSGS, while offering a potential therapeutic avenue to treat these conditions.