Pre-gestational counselling for women living with CKD: starting from the bright side.

Pregnancy in women living with chronic kidney disease (CKD) was often discouraged due to the risk of adverse maternal-fetal outcomes and the progression of kidney disease. This negative attitude has changed in recent years, with greater emphasis on patient empowerment than on the imperative 'non nocere'. Although risks persist, pregnancy outcomes even in advanced CKD have significantly improved, for both the mother and the newborn. Adequate counselling can help to minimize risks and support a more conscious and informed approach to those risks that are unavoidable. Pre-conception counselling enables a woman to plan the most appropriate moment for her to try to become pregnant. Counselling is context sensitive and needs to be discussed also within an ethical framework. Classically, counselling is more focused on risks than on the probability of a successful outcome. 'Positive counselling', highlighting also the chances of a favourable outcome, can help to strengthen the patient-physician relationship, which is a powerful means of optimizing adherence and compliance. Since, due to the heterogeneity of CKD, giving exact figures in single cases is difficult and may even be impossible, a scenario-based approach may help understanding and facing favourable outcomes and adverse events. Pregnancy outcomes modulate the future life of the mother and of her baby; hence the concept of 'post partum' counselling is also introduced, discussing how pregnancy results may modulate the long-term prognosis of the mother and the child and the future pregnancies.

Shepherds View of Large Carnivore Recovery in the Pyrenees, Spain.

The studied farms are small family businesses, and so, in more than half of the cases, their continuity is not guaranteed. Livestock management is typical of a mountain system, in which the animals graze throughout the year in cultivated fields, sown meadows, forests near the farms, and mountain pastures during the three summer months. The herds always have the constant surveillance of a shepherd. Farmers consider the current infrastructure present in mountain grasslands insufficient to facilitate the management and care of their herd. Their activity conflicts with various species of wildlife, such as the wild boar, Sus scrofa, roe deer, Capreolus capreolus, or griffon vulture, Gyps fulvus, and large carnivores such as the brown bear, Ursus arctos, or the grey wolf Canis lupus, despite all of them taking preventive measures to defend their herds from predators. The most widely used prevention measures are the presence of mastiff dogs, Canis lupus familiaris, next to the herds and the use of electric fencing to lock up livestock at night. Farmers reject the presence of bears and wolves in their area, considering it a real threat to the continuity of their economic activity, which presents a high degree of vulnerability.

Pregnancy in Pateints With Exstrophy-Epispadias Complex: Are Higher Rates of Complications and Spontaneous Abortion Inevitable?

OBJECTIVE: To report on the characteristics of pregnancy in female patients with EEC (exstrophy-epispadias complex), determining in particular whether they are at higher risk of spontaneous abortion or complications. MATERIALS AND METHOD: Fifty patients diagnosed with EEC and treated in a reference center for this pathology were reviewed. Those with an incomplete medical history were excluded, leaving a total of 37 women with a median follow-up of 26 years (1-48 years). The outcome measurements were successful pregnancies, miscarriages, urological, gynecological and obstetric complications, impaired renal function, newborn characteristics, and postpartum urogynecological complications. Descriptive statistics was used. RESULTS: Eight patients achieved 17 pregnancies (88.2% spontaneous). Of these pregnancies, 10 (58.8%) were successful, while 7 (41.2%) terminated in miscarriages. Urinary tract infection (UTI) was the most frequent complication (41.6%) and intestinal occlusion was the most severe. A total of 62.5% of the patients presented genital prolapses after pregnancies. A total of 85.7% of patients were dry during the follow-up after their pregnancies. No newborn presented EEC or any other type of malformation. Our study has the limitation of being a retrospective review of a very heterogeneous and small group of patients. CONCLUSION: EEC patients can achieve spontaneous pregnancies but have an increased risk of miscarriage. For this reason, monitoring and control by a specialized and integrated multidisciplinary team is required to minimize complications.

From Inflammation to the Onset of Fibrosis through A2A Receptors in Kidneys from Deceased Donors.

Pretransplant graft inflammation could be involved in the worse prognosis of deceased donor (DD) kidney transplants. A2A adenosine receptor (A2AR) can stimulate anti-inflammatory M2 macrophages, leading to fibrosis if injury and inflammation persist. Pre-implantation biopsies of kidney donors (47 DD and 21 living donors (LD)) were used to analyze expression levels and activated intracellular pathways related to inflammatory and pro-fibrotic processes. A2AR expression and PKA pathway were enhanced in DD kidneys. A2AR gene expression correlated with TGF-ß1 and other profibrotic markers, as well as CD163, C/EBPß, and Col1A1, which are highly expressed in DD kidneys. TNF-α mRNA levels correlated with profibrotic and anti-inflammatory factors such as TGF-ß1 and A2AR. Experiments with THP-1 cells point to the involvement of the TNF-α/NF-κB pathway in the up-regulation of A2AR, which induces the M2 phenotype increasing CD163 and TGF-ß1 expression. In DD kidneys, the TNF-α/NF-κB pathway could be involved in the increase of A2AR expression, which would activate the PKA-CREB axis, inducing the macrophage M2 phenotype, TGF-ß1 production, and ultimately, fibrosis. Thus, in inflamed DD kidneys, an increase in A2AR expression is associated with the onset of fibrosis, which may contribute to graft dysfunction and prognostic differences between DD and LD transplants.

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis.

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10-12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10-14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10-93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10-23 and OR = 3.39, P = 5.2 × 10-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.

Loci associated with genomic damage levels in chronic kidney disease patients and controls.

Chronic kidney disease (CKD) is a multifactorial disorder with an important genetic component, and several studies have demonstrated potential associations with allelic variants. In addition, CKD patients are also characterized by high levels of genomic damage. Nevertheless, no studies have established relationships between DNA damage, or genomic instability present in CKD patients, and gene polymorphisms. To fill in this gap, the potential role of polymorphisms in genes involved in base excision repair (OGG1, rs1052133; MUTYH, rs3219489; XRCC1, rs25487), nucleotide excision repair (ERCC2/XPD, rs1799793, rs171140, rs13181; ERCC4, rs3136166); phase II metabolism (GSTP1, rs749174; GSTO1, rs2164624; GSTO2, rs156697), and antioxidant enzymes (SOD1, rs17880135, rs1041740, rs202446; SOD2, rs4880; CAT, rs1001179; GPX1, rs17080528; GPX3, rs870406: GPX4, rs713041) were inquired. In addition, some genes involved in CKD (AGT, rs5050; GLO1, rs386572987; SHROOM3, rs17319721) were also evaluated. The genomic damage, the genomic instability, and oxidative damage were evaluated by using the micronucleus and the comet assay in 589 donors (415 CKD patients and 174 controls). Our results showed significant associations between genomic damage and genes directly involved in DNA repair pathways (XRCC1, and ERCC2), and with genes encoding for antioxidant enzymes (SOD1 and GPX1). GSTO2, as a gene involved in phase II metabolism, and MUTYH showed also an association with genomic instability. Interestingly, the three genes associated with CKD (AGT, GLO1, and SHROOM3) showed associations with both the high levels of oxidatively damaged DNA and genomic instability. These results support our view that genomic instability can be considered a biomarker of the CKD status.

Genetic Variants Associated with Chronic Kidney Disease in a Spanish Population.

Chronic kidney disease (CKD) patients have many affected physiological pathways. Variations in the genes regulating these pathways might affect the incidence and predisposition to this disease. A total of 722 Spanish adults, including 548 patients and 174 controls, were genotyped to better understand the effects of genetic risk loci on the susceptibility to CKD. We analyzed 38 single nucleotide polymorphisms (SNPs) in candidate genes associated with the inflammatory response (interleukins IL-1A, IL-4, IL-6, IL-10, TNF-α, ICAM-1), fibrogenesis (TGFB1), homocysteine synthesis (MTHFR), DNA repair (OGG1, MUTYH, XRCC1, ERCC2, ERCC4), renin-angiotensin-aldosterone system (CYP11B2, AGT), phase-II metabolism (GSTP1, GSTO1, GSTO2), antioxidant capacity (SOD1, SOD2, CAT, GPX1, GPX3, GPX4), and some other genes previously reported to be associated with CKD (GLO1, SLC7A9, SHROOM3, UMOD, VEGFA, MGP, KL). The results showed associations of GPX1, GSTO1, GSTO2, UMOD, and MGP with CKD. Additionally, associations with CKD related pathologies, such as hypertension (GPX4, CYP11B2, ERCC4), cardiovascular disease, diabetes and cancer predisposition (ERCC2) were also observed. Different genes showed association with biochemical parameters characteristic for CKD, such as creatinine (GPX1, GSTO1, GSTO2, KL, MGP), glomerular filtration rate (GPX1, GSTO1, KL, ICAM-1, MGP), hemoglobin (ERCC2, SHROOM3), resistance index erythropoietin (SOD2, VEGFA, MTHFR, KL), albumin (SOD1, GSTO2, ERCC2, SOD2), phosphorus (IL-4, ERCC4 SOD1, GPX4, GPX1), parathyroid hormone (IL-1A, IL-6, SHROOM3, UMOD, ICAM-1), C-reactive protein (SOD2, TGFB1,GSTP1, XRCC1), and ferritin (SOD2, GSTP1, SLC7A9, GPX4). To our knowledge, this is the second comprehensive study carried out in Spanish patients linking genetic polymorphisms and CKD.

Is there long-term value of pathology scoring in immunoglobulin A nephropathy? A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update.

BACKGROUND: It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up. METHODS: In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1-10.8)]. RESULTS: In this extended analysis, M1, S1 and T1-T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P < 0.01), and there was no effect modification by age for these associations, suggesting that they may be valid in children and in adults as well. Only T lesions were associated with the rate of eGFR loss in the whole cohort, whereas C showed this association only in patients not treated with immunosuppression. In separate prognostic analyses, the whole set of pathology lesions provided a gain in discrimination power over the clinical variables alone, which was similar at 5 years (+2.0%) and for the whole follow-up (+1.8%). A similar benefit was observed for risk reclassification analyses (+2.7% and +2.4%). CONCLUSION: Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy.

IgA Nephropathy in Elderly Patients.

BACKGROUND AND OBJECTIVES: Some studies suggest that the incidence of IgA nephropathy is increasing in older adults, but there is a lack of information about the epidemiology and behavior of the disease in that age group. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this retrospective multicentric study, we analyzed the incidence, forms of presentation, clinical and histologic characteristics, treatments received, and outcomes in a cohort of 151 patients ≥65 years old with biopsy-proven IgA nephropathy diagnosed between 1990 and 2015. The main outcome was a composite end point of kidney replacement therapy or death before kidney replacement therapy. RESULTS: We found a significant increase in the diagnosis of IgA nephropathy over time from six patients in 1990-1995 to 62 in 2011-2015 (P value for trend =0.03). After asymptomatic urinary abnormalities (84 patients; 55%), AKI was the most common form of presentation (61 patients; 40%). Within the latter, 53 (86%) patients presented with hematuria-related AKI (gross hematuria and tubular necrosis associated with erythrocyte casts as the most important lesions in kidney biopsy), and eight patients presented with crescentic IgA nephropathy. Six (4%) patients presented with nephrotic syndrome. Among hematuria-related AKI, 18 (34%) patients were receiving oral anticoagulants, and this proportion rose to 42% among the 34 patients older than 72 years old who presented with hematuria-related AKI. For the whole cohort, survival rates without the composite end point were 74%, 48%, and 26% at 1, 2, and 5 years, respectively. Age, serum creatinine at presentation, and the degree of interstitial fibrosis in kidney biopsy were risk factors significantly associated with the outcome, whereas treatment with renin-angiotensin-aldosterone blockers was associated with a lower risk. Immunosuppressive treatments were not significantly associated with the outcome. CONCLUSIONS: The diagnosis of IgA nephropathy among older adults in Spain has progressively increased in recent years, and anticoagulant therapy may be partially responsible for this trend. Prognosis was poor. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_07_16_CJASNPodcast_19_08_.mp3.

Nefropatía asociada a mutación del gen MYH9 / MYH9 Associated nephropathy

Las enfermedades relacionadas con mutaciones del gen MYH9 son un grupo de patologías genéticas raras. Su herencia sigue un patrón autosómico dominante en donde el gen MYH9, codifica la cadena pesada de la miosina IIA no muscular que se expresa en diferentes tejidos pero especialmente en los podocitos y en las células mesangiales. Este trastorno se caracteriza por la presencia de macrotrombocitopenia, inclusiones leucocitarias y un riesgo variable de desarrollar insuficiencia renal, hipoacusia y cataratas en edad juvenil o adulta. Describimos el caso de una mujer de 27 años, de raza caucásica, diagnosticada inicialmente de púrpura trombocitopénica idiopática. Tras una detallada historia familiar y el desarrollo de síntomas clínicos posteriores con afectación renal e hipoacusia, se le realizó un estudio genético que nos permitió el diagnóstico de nefropatía asociada a la mutación en el gen MYH9. Este caso destaca el retraso del diagnóstico y la utilidad del estudio genético en pacientes con enfermedades muy poco frecuentes. Se procede a la revisión de la enfermedad en este artículo

MYH9 related diseases are caused by mutations in the MYH9 gene and constitute a rare group of genetic entities. Its inheritance follows an autosomal dominant pattern. The MYH9 gene, encodes the nonmuscle myosin heavy chain IIA, expressed in different tissues and especially in podocytes and mesangial cells. The disorder is characterized by the presence of macrothrombocytopenia, leukocyte inclusions and a variable risk of developing renal failure, hearing loss and early-onset cataracts. We describe the case of a 27-year-old Caucasian woman, diagnosed initially with idiopathic thrombocytopenic purpura. After a detailed family history and the appearance of renal involvement and hearing loss, genetic testing allowed to make the diagnosis of nephropathy associated with MYH9 mutation. This case is an example of the delayed diagnosis of uncommon diseases and highlights the usefulness genetic testing. A review of the disease is provided

Tres casos de gammapatía monoclonal de significado renal postrasplante renal: nefropatía c3 de novo / Three cases of monoclonal gammopathy of renal significance after kidney transplantation. De novo C3 glomerulopathy

La gammapatía monoclonal de significado renal incluye todas las enfermedades renales causadas por una inmunoglobulina monoclonal secretada por un clon de célula B no maligno. Por definición, los pacientes con gammapatía monoclonal de significado renal no cumplen criterios de mieloma múltiple y la alteración hematológica es generalmente considerada gammapatía monoclonal de significado incierto. No obstante, la dolencia que pueden causar a nivel renal puede ser importante, requiriendo un tratamiento específico. El espectro de la gammapatía monoclonal de significado renal es amplio, incluyendo una entidad reciente como la nefropatía C3. El desarrollo de una nefropatía C3 en el contexto de una gammapatía monoclonal de significado renal tras el trasplante renal no es frecuente y hasta el momento ha sido poco descrita. A continuación presentamos 3 casos de nefropatía C3 asociados a una gammapatía monoclonal de aparición de novo tras el trasplante renal

Monoclonal gammopathy of renal significance includes all renal disorders caused by a monoclonal immunoglobulin secreted by a non-malignant B-cell clone. Patients with MGRS do not, by definition, meet criteria for multiple myeloma, with haematological disorders generally considered to be monoclonal gammopathy of undetermined significance. Nevertheless, the renal involvement can be serious and require specific treatment. Monoclonal gammopathy of renal significance is associated with a wide spectrum of disorders, including the recently discovered C3 glomerulopathy. Development of C3 glomerulopathy in the context of monoclonal gammopathy of renal significance after kidney transplantation is uncommon and very few cases have been published to date. We report on three cases of C3 glomerulopathy in the context of de novo monoclonal gammopathy after kidney transplantation

Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a randomised, non-inferiority trial.

OBJECTIVES: Cyclophosphamide induction regimens are effective for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but are associated with infections, malignancies and infertility. Mycophenolate mofetil (MMF) has shown high remission rates in small studies of AAV. METHODS: We conducted a randomised controlled trial to investigate whether MMF was non-inferior to cyclophosphamide for remission induction in AAV. 140 newly diagnosed patients were randomly assigned to MMF or pulsed cyclophosphamide. All patients received the same oral glucocorticoid regimen and were switched to azathioprine following remission. The primary endpoint was remission by 6 months requiring compliance with the tapering glucocorticoid regimen. Patients with an eGFR <15 mL/min were excluded from the study. RESULTS: At baseline, ANCA subtype, disease activity and organ involvement were similar between groups. Non-inferiority was demonstrated for the primary remission endpoint, which occurred in 47 patients (67%) in the MMF group and 43 patients (61%) in the cyclophosphamide group (risk difference 5.7%, 90% CI -7.5% to 19%). Following remission, more relapses occurred in the MMF group (23 patients, 33%) compared with the cyclophosphamide group (13 patients, 19%) (incidence rate ratio 1.97, 95% CI 0.96 to 4.23, p=0.049). In MPO-ANCA patients, relapses occurred in 12% of the cyclophosphamide group and 15% of the MMF group. In PR3-ANCA patients, relapses occurred in 24% of the cyclophosphamide group and 48% of the MMF group. Serious infections were similar between groups (26% MMF group, 17% cyclophosphamide group) (OR 1.67, 95% CI 0.68 to 4.19, p=0.3). CONCLUSION: MMF was non-inferior to cyclophosphamide for remission induction in AAV, but resulted in higher relapse rate. TRIAL REGISTRATION NUMBER: NCT00414128.

Three cases of monoclonal gammopathy of renal significance after kidney transplantation. De novo C3 glomerulopathy. / Tres casos de gammapatía monoclonal de significado renal postrasplante renal: nefropatía c3 de novo.

Monoclonal gammopathy of renal significance includes all renal disorders caused by a monoclonal immunoglobulin secreted by a non-malignant B-cell clone. Patients with MGRS do not, by definition, meet criteria for multiple myeloma, with haematological disorders generally considered to be monoclonal gammopathy of undetermined significance. Nevertheless, the renal involvement can be serious and require specific treatment. Monoclonal gammopathy of renal significance is associated with a wide spectrum of disorders, including the recently discovered C3 glomerulopathy. Development of C3 glomerulopathy in the context of monoclonal gammopathy of renal significance after kidney transplantation is uncommon and very few cases have been published to date. We report on three cases of C3 glomerulopathy in the context of de novo monoclonal gammopathy after kidney transplantation.

MYH9 Associated nephropathy. / Nefropatía asociada a mutación del gen MYH9.

MYH9 related diseases are caused by mutations in the MYH9 gene and constitute a rare group of genetic entities. Its inheritance follows an autosomal dominant pattern. The MYH9 gene, encodes the nonmuscle myosin heavy chain IIA, expressed in different tissues and especially in podocytes and mesangial cells. The disorder is characterized by the presence of macrothrombocytopenia, leukocyte inclusions and a variable risk of developing renal failure, hearing loss and early-onset cataracts. We describe the case of a 27-year-old Caucasian woman, diagnosed initially with idiopathic thrombocytopenic purpura. After a detailed family history and the appearance of renal involvement and hearing loss, genetic testing allowed to make the diagnosis of nephropathy associated with MYH9 mutation. This case is an example of the delayed diagnosis of uncommon diseases and highlights the usefulness genetic testing. A review of the disease is provided.

Autosomal Dominant Polycystic Kidney Disease: Clinical Assessment of Rapid Progression.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) causes the development of renal cysts and leads to a decline in renal function. Limited guidance exists in clinical practice on the use of tolvaptan. A decision algorithm from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Working Groups of Inherited Kidney Disorders and European Renal Best Practice (WGIKD/ERBP) has been proposed to identify candidates for tolvaptan treatment; however, this algorithm has not been assessed in clinical practice. METHODS: Eighteen-month cross-sectional, unicenter, observational study assessing 305 consecutive ADPKD patients. The ERA-EDTA WGIKD/ERBP algorithm with a stepwise approach was used to assess rapid progression (RP). Subsequently, expanded criteria based on the REPRISE trial were applied to evaluate the -impact of extended age (≤55 years) and estimated glomerular filtration rate (eGFR; ≥25 mL/min/1.73 m2). RESULTS: Historical eGFR decline, indicative of RP, was fulfilled in 26% of 73 patients who were candidates for RP assessment, mostly aged 31-55 years. Further tests including ultrasound and MRI measurements of kidney volume plus genetic testing enabled the evaluation of the remaining patients. Overall, 15.7% of patients met the criteria for rapid or likely RP using the algorithm, and the percentage increased to 27% when extending age and eGFR. CONCLUSIONS: The ERA-EDTA WGIKD/ERBP algorithm provides a valuable means of identifying in routine clinical practice patients who may be eligible for treatment with tolvaptan. The impact of a new threshold for age and eGFR may increase the percentage of patients to be treated.

Urinary Proteome Analysis Identified Neprilysin and VCAM as Proteins Involved in Diabetic Nephropathy.

Urinary proteome was analyzed and quantified by tandem mass tag (TMT) labeling followed by bioinformatics analysis to study diabetic nephropathy (DN) pathophysiology and to identify biomarkers of a clinical outcome. We included type 2 diabetic normotensive non-obese males with (n = 9) and without (n = 11) incipient DN (microalbuminuria). Sample collection included blood and urine at baseline (control and DN basal) and, in DN patients, after 3 months of losartan treatment (DN treated). Urinary proteome analysis identified 166 differentially abundant proteins between controls and DN patients, 27 comparing DN-treated and DN-basal patients, and 182 between DN-treated patients and controls. The mathematical modeling analysis predicted 80 key proteins involved in DN pathophysiology and 15 in losartan effect, a total of 95 proteins. Out of these 95, 7 are involved in both processes. VCAM-1 and neprilysin stand out of these 7 for being differentially expressed in the urinary proteome. We observed an increase of VCAM-1 urine levels in DN-basal patients compared to diabetic controls and an increase of urinary neprilysin in DN-treated patients with persistent albuminuria; the latter was confirmed by ELISA. Our results point to neprilysin and VCAM-1 as potential candidates in DN pathology and treatment.

Transethnic, Genome-Wide Analysis Reveals Immune-Related Risk Alleles and Phenotypic Correlates in Pediatric Steroid-Sensitive Nephrotic Syndrome.

Background Steroid-sensitive nephrotic syndrome (SSNS) is a childhood disease with unclear pathophysiology and genetic architecture. We investigated the genomic basis of SSNS in children recruited in Europe and the biopsy-based North American NEPTUNE cohort.Methods We performed three ancestry-matched, genome-wide association studies (GWAS) in 273 children with NS (Children Cohort Nephrosis and Virus [NEPHROVIR] cohort: 132 European, 56 African, and 85 Maghrebian) followed by independent replication in 112 European children, transethnic meta-analysis, and conditional analysis. GWAS alleles were used to perform glomerular cis-expression quantitative trait loci studies in 39 children in the NEPTUNE cohort and epidemiologic studies in GWAS and NEPTUNE (97 children) cohorts.Results Transethnic meta-analysis identified one SSNS-associated single-nucleotide polymorphism (SNP) rs1063348 in the 3' untranslated region of HLA-DQB1 (P=9.3×10-23). Conditional analysis identified two additional independent risk alleles upstream of HLA-DRB1 (rs28366266, P=3.7×10-11) and in the 3' untranslated region of BTNL2 (rs9348883, P=9.4×10-7) within introns of HCG23 and LOC101929163 These three risk alleles were independent of the risk haplotype DRB1*07:01-DQA1*02:01-DQB1*02:02 identified in European patients. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS, with younger age of onset across all cohorts, and with increased odds of complete remission across histologies in NEPTUNE children. rs1063348 associated with decreased glomerular expression of HLA-DRB1, HLA-DRB5, and HLA-DQB1.Conclusions Transethnic GWAS empowered discovery of three independent risk SNPs for pediatric SSNS. Characterization of these SNPs provide an entry for understanding immune dysregulation in NS and introducing a genomically defined classification.

A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases.

Molecular diagnosis of inherited kidney diseases remains a challenge due to their expanding phenotypic spectra as well as the constantly growing list of disease-causing genes. Here we develop a comprehensive approach for genetic diagnosis of inherited cystic and glomerular nephropathies. Targeted next generation sequencing of 140 genes causative of or associated with cystic or glomerular nephropathies was performed in 421 patients, a validation cohort of 116 patients with previously known mutations, and a diagnostic cohort of 207 patients with suspected inherited cystic disease and 98 patients with glomerular disease. In the validation cohort, a sensitivity of 99% was achieved. In the diagnostic cohort, causative mutations were found in 78% of patients with cystic disease and 62% of patients with glomerular disease, mostly familial cases, including copy number variants. Results depict the distribution of different cystic and glomerular inherited diseases showing the most likely diagnosis according to perinatal, pediatric and adult disease onset. Of all the genetically diagnosed patients, 15% were referred with an unspecified clinical diagnosis and in 2% genetic testing changed the clinical diagnosis. Therefore, in 17% of cases our genetic analysis was crucial to establish the correct diagnosis. Complex inheritance patterns in autosomal dominant polycystic kidney disease and Alport syndrome were suspected in seven and six patients, respectively. Thus, our kidney-disease gene panel is a comprehensive, noninvasive, and cost-effective tool for genetic diagnosis of cystic and glomerular inherited kidney diseases. This allows etiologic diagnosis in three-quarters of patients and is especially valuable in patients with unspecific or atypical phenotypes.

Autosomal Dominant Tubulointerstitial Kidney Disease: Clinical Presentation of Patients With ADTKD-UMOD and ADTKD-MUC1.

RATIONALE & OBJECTIVE: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare underdiagnosed cause of end-stage renal disease (ESRD). ADTKD is caused by mutations in at least 4 different genes: MUC1, UMOD, HNF1B, and REN. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 56 families (131 affected individuals) with ADTKD referred from different Spanish hospitals. Clinical, laboratory, radiologic, and pathologic data were collected, and genetic testing for UMOD, MUC1, REN, and HNF1B was performed. PREDICTORS: Hyperuricemia, ultrasound findings, renal histology, genetic mutations. OUTCOMES: Age at ESRD, rate of decline in estimated glomerular filtration rate. RESULTS: ADTKD was diagnosed in 25 families (45%), 9 carried UMOD pathogenic variants (41 affected members), and 16 carried the MUC1 pathogenic mutation c.(428)dupC (90 affected members). No pathogenic variants were identified in REN or HNF1B. Among the 77 individuals who developed ESRD, median age at onset of ESRD was 51 years for those with ADTKD-MUC1 versus 56 years (P=0.1) for those with ADTKD-UMOD. Individuals with the MUC1 duplication presented higher risk for developing ESRD (HR, 2.24; P=0.03). The slope of decline in estimated glomerular filtration rate showed no significant difference between groups (-3.0mL/min/1.73m2 per year in the ADTKD-UMOD group versus -3.9mL/min/1.73m2 per year in the ADTKD-MUC1 group; P=0.2). The prevalence of hyperuricemia was significantly higher in individuals with ADTKD-UMOD (87% vs 54%; P=0.006). Although gout occurred more frequently in this group, the difference was not statistically significant (24% vs 7%; P=0.07). LIMITATIONS: Relatively small Spanish cohort. MUC1 analysis limited to cytosine duplication. CONCLUSIONS: The main genetic cause of ADTKD in our Spanish cohort is the MUC1 pathogenic mutation c.(428)dupC. Renal survival may be worse in individuals with the MUC1 mutation than in those with UMOD mutations. Clinical presentation does not permit distinguishing between these variants. However, hyperuricemia and gout are more frequent in individuals with ADTKD-UMOD.

Efficacy of mycophenolate treatment in adults with steroid-dependent/frequently relapsing idiopathic nephrotic syndrome.

BACKGROUND: This study assessed the efficacy of therapy with mycophenolate (MF) and reduced doses of steroids in adults with steroid-dependent/frequently relapsing idiopathic nephrotic syndrome (SD/FR-INS). METHODS: Twenty-nine nephrotic patients (including 16 males and 13 females; mean age: 40 years, range: 18-74) were treated. Starting doses of MF were 2000 mg/day for mofetil MF (1500 mg/day in one patient) or 1440 mg/day for sodium MF. The initial prednisone (PDN) dose was 10 mg/day in 14 patients, 5 mg/day in two patients and no steroids in one patient. In the remaining 12 patients, moderate initial doses of PDN were administered (mean: 23.7 mg/day, range: 15-40), tapering to 10 mg/day after 1 month. RESULTS: Nephrotic syndrome remission was achieved in 27/29 cases (93.1%) (25 complete, 2 partial). Two patients showed resistance to the prescribed schedule. The first cycle of MF therapy was concluded in 20 patients after a mean (range) of 16.9 months (12-49). Maintenance of remission was observed in 11 of these 20 cases (55%) after a mean follow-up of 32.8 months (12-108). In nine patients with nephrotic syndrome relapse after tapering of MF (MF dependency), the same MF-PDN schedule was restarted, leading again to remission in all nine. The remaining seven MF-sensitive patients are still receiving their first therapeutic cycle. To date, the mean time under therapy in the 27 MF-sensitive patients is 38 months (4-216). Regarding complications, only minor digestive disorders and a slight decrease in blood haemoglobin levels were observed in a few patients. CONCLUSIONS: MF plus reduced doses of PDN is an effective and well-tolerated therapy for adult SD/FR-INS. Though MF dependence is observed, its low toxicity could allow long periods of therapy if it is required to maintain nephrotic syndrome remission.