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.

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.

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.

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.

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.

Genetic and pharmacological inhibition of microRNA-92a maintains podocyte cell cycle quiescence and limits crescentic glomerulonephritis.

Crescentic rapidly progressive glomerulonephritis (RPGN) represents the most aggressive form of acquired glomerular disease. While most therapeutic approaches involve potentially toxic immunosuppressive strategies, the pathophysiology remains incompletely understood. Podocytes are glomerular epithelial cells that are normally growth-arrested because of the expression of cyclin-dependent kinase (CDK) inhibitors. An exception is in RPGN where podocytes undergo a deregulation of their differentiated phenotype and proliferate. Here we demonstrate that microRNA-92a (miR-92a) is enriched in podocytes of patients and mice with RPGN. The CDK inhibitor p57Kip2 is a major target of miR-92a that constitutively safeguards podocyte cell cycle quiescence. Podocyte-specific deletion of miR-92a in mice de-repressed the expression of p57Kip2 and prevented glomerular injury in RPGN. Administration of an anti-miR-92a after disease initiation prevented albuminuria and kidney failure, indicating miR-92a inhibition as a potential therapeutic strategy for RPGN. We demonstrate that miRNA induction in epithelial cells can break glomerular tolerance to immune injury.

Clinical and molecular characterization of cystinuria in a French cohort: relevance of assessing large-scale rearrangements and splicing variants.

BACKGROUND: Cystinuria is an autosomal recessive disorder of dibasic amino acid transport in the kidney and the intestine leading to increased urinary cystine excretion and nephrolithiasis. Two genes, SLC3A1 and SLC7A9, coding respectively for rBAT and b0,+AT, account for the genetic basis of cystinuria. METHODS: This study reports the clinical and molecular characterization of a French cohort including 112 cystinuria patients and 25 relatives from 99 families. Molecular screening was performed using sequencing and Quantitative Multiplex PCR of Short Fluorescent Fragments analyses. Functional minigene-based assays have been used to characterize splicing variants. RESULTS: Eighty-eight pathogenic nucleotide changes were identified in SLC3A1 (63) and SLC7A9 (25) genes, of which 42 were novel. Interestingly, 17% (15/88) and 11% (10/88) of the total number of variants correspond, respectively, to large-scale rearrangements and splicing mutations. Functional minigene-based assays were performed for six variants located outside the most conserved sequences of the splice sites; three variants affect splice sites, while three others modify exonic splicing regulatory elements (ESR), in good agreement with a new in silico prediction based on ΔtESRseq values. CONCLUSION: This report expands the spectrum of SLC3A1 and SLC7A9 variants and supports that digenic inheritance is unlikely. Furthermore, it highlights the relevance of assessing large-scale rearrangements and splicing mutations to fully characterize cystinuria patients at the molecular level.

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.

The use of gallium-67 scintigraphy in the diagnosis of acute interstitial nephritis.

BACKGROUND: Gallium-67 scintigraphy has been suggested as a noninvasive method to diagnose acute interstitial nephritis (AIN). However, its diagnostic performance and usefulness remain controversial. METHODS: We retrospectively reviewed the charts of 76 patients who underwent gallium-67 scintigraphy for a suspicion of AIN. Patients were classified based on kidney biopsy and/or clinical probability of AIN. Gallium-67 scintigraphy results were reinterpreted blindly using both posterior planar and single photon emission computed tomography (SPECT) imaging. Intensity of radioisotope uptake in the kidney was graded from 0 to 5. RESULTS: The diagnosis of AIN was confirmed in 23 patients and excluded in 44. Nine patients with an uncertain diagnosis were excluded from subsequent analysis. A gallium-67 kidney uptake cutoff of 1 gave a negative predictive value of 100%, whereas a cutoff of 5 had an excellent specificity and positive predictive value for the diagnosis of AIN. When using a cutoff of 3, which had previously been used in the literature, we obtained a sensitivity of 61% and a specificity of 75% with posterior planar imaging. The results of both SPECT and posterior planar imaging modalities were comparable. CONCLUSIONS: Gallium-67 scintigraphy may be of interest in patients with a clinical suspicion of AIN, especially in those who are unable to undergo kidney biopsy. However, results need to be interpreted with caution and depend on the intensity of gallium-67 kidney uptake.

Clinical, Genetic, and Urinary Factors Associated with Uromodulin Excretion.

BACKGROUND AND OBJECTIVES: The urinary excretion of uromodulin is influenced by common variants in the UMOD gene, and it may be related to NaCl retention and hypertension. Levels of uromodulin are also dependent of the renal function, but other determinants remain unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We tested associations between the urinary excretion of uromodulin; medical history and medication; serum and urinary levels of electrolytes, glucose, and uric acid; and the genotype at the UMOD/Protein Disulfide Isomerase-Like, Testis Expressed locus (rs4293393 and rs12446492); 943 participants from the CARTaGENE Cohort, a random sample from the Canadian population of 20,004 individuals, were analyzed. Participants with available genotyping were obtained from a substudy addressing associations between common variants and cardiovascular disease in paired participants with high and low Framingham risk scores and vascular rigidity indexes. RESULTS: The population studied was 54±9 years old, with 51% women and eGFR of 9±14 ml/min per 1.73 m(2). Uromodulin excretion was 25 (11-42) mg/g creatinine. Using linear regression, it was independently higher among patients with higher eGFR, the TT genotype of rs4293393, and the TT genotype of rs12446492. The fractional excretions of urate and sodium showed a strong positive correlation with uromodulin, likely linked to the extracellular volume status. The presence of glycosuria and the use of uricosuric drugs, which both increased the fraction excretion of urate, were independently associated with a lower uromodulin excretion, suggesting novel interactions between uric acid and uromodulin excretion. CONCLUSIONS: In this large cohort, the excretion of uromodulin correlates with clinical, genetic, and urinary factors. The strongest associations were between uric acid, sodium, and uromodulin excretions and are likely linked to the extracellular volume status.

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.

Recurrence of crystalline nephropathy after kidney transplantation in APRT deficiency and primary hyperoxaluria.

PURPOSE OF REVIEW: To provide transplant physicians with a summary of the pathogenesis and diagnosis of adenine phosphoribosyl transferase (APRT) deficiency and primary hyperoxaluria and, focussed on kidney transplantation, and to discuss interventions aimed at preventing and treating the recurrence of crystalline nephropathy in renal transplant recipients. SOURCE OF INFORMATION: Pubmed literature search. SETTING: Primary hyperoxaluria and APRT deficiency are rare inborn errors of human metabolism. The hallmark of these diseases is the overproduction and urinary excretion of compounds (2,8 dihydroxyadenine in APRT deficiency, oxalate in primary hyperoxaluria) that form urinary crystals. Although recurrent urolithiasis represents the main clinical feature of these diseases, kidney injury can occur as a result of crystal precipitation within the tubules and interstitium, a condition referred to as crystalline nephropathy. Some patients develop end-stage renal disease (ESRD) and may become candidates for kidney transplantation. Since kidney transplantation does not correct the underlying metabolic defect, transplant recipients have a high risk of recurrence of crystalline nephropathy, which can lead to graft loss. In some instances, the disease remains undiagnosed until after the occurrence of ESRD or even after kidney transplantation. KEY MESSAGES: Patients with APRT deficiency or primary hyperoxaluria may develop ESRD as a result of crystalline nephropathy. In the absence of diagnosis and adequate management, the disease is likely to recur after kidney transplantation, which often leads to rapid loss of renal allograft function. Primary hyperoxaluria, but not APRT deficiency, becomes a systemic disease at low GFR with oxalate deposition leading to malfunction in non-renal organs (systemic oxalosis). We suggest that these diagnoses should be considered in patients with low glomerular filtration rate (GFR) and a history of kidney stones. In APRT deficiency, stones may be confused with uric acid stones, unless specialized techniques are used (infrared spectroscopy or X-ray crystallography for urinary crystals or stone analysis; Fourier transform infrared microscopy for crystals in kidney biopsy). Where these are unavailable, and for confirmation, the diagnosis can be made by measurement of enzyme activity in red blood cell lysates or by genetic testing. In patients with primary hyperoxaluria, levels of urinary and plasma oxalate; and the presence of nearly pure calcium oxalate monohydrate in stones, which often also have an unusually pale colour and unorganized structure, increase diagnostic suspicion. Molecular genetic testing is the criterion measure. Lifelong allopurinol therapy, with high fluid intake if appropriate, may stabilize kidney function in APRT deficiency; if ESRD has occurred or is near, results with kidney transplantation after initiation of allopurinol are excellent. In primary hyperoxaluria recognized before ESRD, pyridoxine treatment and high fluid intake may lead to a substantial decrease in urinary calcium oxalate supersaturation and prevent renal failure. In non-responsive patients or those recognized later in their disease, liver transplantation cures the underlying defect and should be considered when the GFR falls below 30 ml/min/1.73 m(2); in those which or near ESRD, liver transplantation and intensive dialysis before kidney transplantation may be considered to reduce the total body oxalate burden before kidney transplantation. LIMITATIONS: The availability of diagnostic tests varies between countries and centres. Data on long term outcomes after kidney transplantation are limited, especially for APRT deficiency patients. IMPLICATIONS: Increasing transplant physicians knowledge of APRT deficiency and primary hyperoxaluria should enable them to implement adequate diagnostic and therapeutic interventions, thereby achieving good outcomes after kidney transplantation.

OBJET DE L'ÉTUDE: Fournir aux médecins transplantologues un résumé de la pathogénie, de même que les diagnostics de déficit en adénine phosphoribosyl transférase (APRT) et d'hyperoxalurie primaire, dans le contexte de la greffe rénale, ainsi que discuter des interventions visant à prévenir et à traiter la récurrence d'une néphropathie cristalline chez les greffés du rein. SOURCE D'INFORMATION: Recherche de documentation dans Pubmed. CONTEXTE: L'hyperoxalurie primaire et déficit en APRT sont des maladies enzymatiques humaines. Ces maladies se caractérisent par la surproduction et l'excrétion urinaire d'éléments (2,8-dihydroxyadénine pour le déficit en APRT et oxalate pour l'hyperoxalurie primaire) qui forment des cristaux urinaires. Bien que l'urolithiase récurrente représente la caractéristique clinique principale de ces maladies, la précipitation des cristaux au niveau tubulo-interstitiel peut entraîner des lésions rénales, un état pathologique appelé néphropathie cristalline. Certains patients développent une insuffisance rénale terminale (IRT) et peuvent devenir candidats à la greffe rénale. Étant donné que la greffe du rein ne corrige pas le défaut métabolique sous-jacent, les greffés présentent un risque élevé de récurrence de néphropathie cristalline, qui peut mener à la perte du greffon. Dans certains cas, la maladie n'est diagnostiquée qu'après l'occurrence de l'IRT, voire à la suite de la greffe du rein. MESSAGES CLÉS: Les patients souffrant d'un déficit en APRT ou d'hyperoxalurie primaire risquent de développer une IRT engendrée par la néphropathie cristalline. En l'absence d'un diagnostic et d'une gestion adéquate, la maladie réapparaîtra probablement suite de la greffe du rein, ce qui entraînera souvent la perte précipitée de l'allogreffe. L'hyperoxalurie primaire, et non le déficit en APRT, devient une maladie systémique à faible débit de filtration glomérulaire (DFG) caractérisée par des dépôts d'oxalate, et menant à la défaillance d'organes autres que le rein (oxalose systémique). Nous suggérons que ces diagnostics soient priss en considération chez les patients comportant un faible DFG, de même que des antécédents de calculs rénaux. Dans le cas d'un déficit en APRT, les calculs rénaux pourraient être confondus avec des calculs d'acide urique, à moins que ne soient employées des techniques spécialisées (spectroscopie infrarouge ou radiocristallographie pour l'analyse des cristaux urinaires ou des calculs par rayon X; microscopie infrarouge à transformer de Fourier pour les cristaux au cours de la biopsie des calculs). Lorsque possible, et à des fins de confirmation, le diagnostic peut être effectué par la mesure de l'activité enzymatique de la lyse des cellules sanguines rouges ou par le dépistage génétique. Chez les patients atteints d'hyperoxalurie primaire, les taux d'oxalates urinaire et plasmique, de même que la présence d'oxalate calcique monohydrate à l'état presque pur dans les calculs, qui présentent aussi généralement une pâleur et une structure désorganisée, éveillent les soupçons quant au diagnostic. Le dépistage génétique moléculaire constitue le critère de mesure. Un traitement d'allopurinol à vie, ainsi qu'un apport élevé en liquides si nécessaire, peut stabiliser la fonction rénale en situation de déficit en APRT. Si l'IRT s'est produite ou approche, les résultats de la greffe du rein à la suite du début du traitement à l'allopurinol sont excellents. Dans le cas d'une hyperoxalurie détectée avant l'IRT, un traitement à la pyridoxine et un apport élevé en liquides peuvent mener à une baisse substantielle de la sursaturation en oxalate calcique urinaire et ainsi, prévenir l'insuffisance rénale. Chez les patients qui ne répondent pas au traitement ou ceux chez qui la maladie est détectée tardivement, la transplantation hépatique enraye le défaut sous-jacent, et devrait être envisagée si le DFG chute en dessous de 30 ml/min/1,73 m2. Chez les patients en IRT ou près de l'être, la transplantation hépatique et la dialyse intensive la précédant sont à envisager afin de réduire la charge corporelle totale d'oxalate avant la transplantation hépatique. LIMITES DE L'ÉTUDE: L'accessibilité à des tests de dépistage varie selon les pays et les unités. Les données sur les résultats à long terme de la greffe rénale sont limitées, particulièrement en ce qui concerne les patients présentant un déficit en APRT. CONSÉQUENCES: Enrichir les connaissances des transplantologues au sujet du déficit en APRT et de l'hyperoxalurie primaire devrait leur permettre de mettre en œuvre des interventions diagnostiques et thérapeutiques adéquates, et ainsi d'obtenir de bons résultats à la suite des greffes rénales.

Renal biopsy practice: What is the gold standard?

Renal biopsy (RB) is useful for diagnosis and therapy guidance of renal diseases but incurs a risk of bleeding complications of variable severity, from transitory haematuria or asymptomatic hematoma to life-threatening hemorrhage. Several risk factors for complications after RB have been identified, including high blood pressure, age, decreased renal function, obesity, anemia, low platelet count and hemostasis disorders. These should be carefully assessed and, whenever possible, corrected before the procedure. The incidence of serious complications has become low with the use of automated biopsy devices and ultrasound guidance, which is currently the "gold standard" procedure for percutaneous RB. An outpatient biopsy may be considered in a carefully selected population with no risk factor for bleeding. However, controversies persist on the duration of observation after biopsy, especially for native kidney biopsy. Transjugular RB and laparoscopic RB represent reliable alternatives to conventional percutaneous biopsy in patients at high risk of bleeding, although some factors limit their use. This aim of this review is to summarize the issues of complications after RB, assessment of hemorrhagic risk factors, optimal biopsy procedure and strategies aimed to minimize the risk of bleeding.

2,8-Dihydroxyadenine urolithiasis: a not so rare inborn error of purine metabolism.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare inherited metabolic disorder that leads to the formation and hyperexcretion of 2,8-dihydroxyadenine (DHA) into urine. The low solubility of DHA results in precipitation and formation of urinary crystals and kidney stones. The disease can be present as recurrent urolithiasis or nephropathy secondary to crystal precipitation into renal parenchyma (DHA nephropathy). The diagnostic tools available, including stone analysis, crystalluria, and APRT activity in red blood cells, make the diagnosis easy to confirm when APRT deficiency is suspected. However, the lack of recognition of this metabolic disorder frequently resulted in a delay in diagnosis and treatment with grave consequences. The early recognition and treatment of APRT deficiency are of crucial importance to prevent irreversible loss of renal function. This review summarizes the genetic and metabolic mechanisms underlying DHA stones formation and chronic kidney disease, along with the issues of diagnosis and management of APRT deficiency. Moreover, we report the mutations in the APRT gene responsible for APRT deficiency in 51 French patients (43 families) including 22 pediatric cases (18 families) among the 64 patients identified in the biochemistry laboratories of Necker Hospital, Paris (1978-2013).

Adenine phosphoribosyltransferase deficiency.

Complete adenine phosphoribosyltransferase (APRT) deficiency is a rare inherited metabolic disorder that leads to the formation and hyperexcretion of 2,8-dihydroxyadenine (DHA) into urine. The low solubility of DHA results in precipitation of this compound and the formation of urinary crystals and stones. The disease can present as recurrent urolithiasis or nephropathy secondary to crystal precipitation into renal parenchyma (DHA nephropathy). The diagnostic tools available-including stone analysis, crystalluria, and APRT activity measurement-make the diagnosis easy to confirm when APRT deficiency is suspected. However, the disease can present at any age, and the variability of symptoms can present a diagnostic challenge to many physicians. The early recognition and treatment of APRT deficiency are of crucial importance for preventing irreversible loss of renal function, which still occurs in a non-negligible proportion of cases. This review summarizes the genetic and metabolic mechanisms underlying stone formation and renal disease, along with the diagnosis and management of APRT deficiency.

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.