Consensus document on autosomal dominant polycystic kindey disease from the Spanish Working Group on Inherited Kindey Diseases. Review 2020.

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6-10% of patients on kidney replacement therapy (KRT). Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a revised consensus statement from the previous 2014 version, presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence mostly are C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease (CKD) and KRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are provided as well as the recommendation to assess rapid progression.

Documento de consenso de poliquistosis renal autosómica dominante del grupo de trabajo de enfermedades hereditarias de la Sociedad Española de Nefrología. Revisión 2020 / Consensus document on autosomal dominant polycystic kindey disease from the Spanish Working Group on Inherited Kindey Diseases. Review 2020

La poliquistosis renal autosómica dominante (PQRAD) es la causa más frecuente de nefropatía genética y representa entre el 6 y el 10% de los pacientes en terapia de reemplazo renal (TRR).Muy pocos ensayos prospectivos, aleatorizados o estudios clínicos abordan el diagnóstico y el tratamiento de este trastorno relativamente frecuente. No hay guías clínicas disponibles hasta la fecha. Este es un documento de consenso revisada de la versión anterior del 2014, que presenta las recomendaciones del Grupo de Trabajo Español de Enfermedades Renales Hereditarias, acordadas tras la búsqueda bibliográfica y discusiones. Los niveles de evidencia en su mayoría son C y D según el Centro de Medicina Basada en Evidencia (Universidad de Oxford). Las recomendaciones se relacionan, entre otros temas, con el uso de diagnóstico por imágenes y genético, el manejo de la hipertensión, el dolor, las infecciones y el sangrado quístico, la afectación extrarrenal, incluida la enfermedad poliquística hepática y los aneurismas craneales, el manejo de la enfermedad renal crónica y el TRR, así como el seguimiento de niños con PQRAD. Se proporcionan recomendaciones sobre terapias específicas para la PQRAD, así como la recomendación para evaluar la rápida progresión. (AU)

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6–10% of patients on kidney replacement therapy (KRT).Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a revised consensus statement from the previous 2014 version, presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence mostly are C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease and KRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are provided as well as the recommendation to assess rapid progression. (AU)

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.

Aspirin for Primary Prevention of Cardiovascular Disease and Renal Disease Progression in Chronic Kidney Disease Patients: a Multicenter Randomized Clinical Trial (AASER Study).

BACKGROUND: Patients with chronic kidney disease (CKD) are at high risk for developing cardiovascular events. However, limited evidence is available regarding the use of aspirin in CKD patients to decrease cardiovascular risk and to slow renal disease progression. STUDY DESIGN: Prospective, multicenter, open-label randomized controlled trial. SETTING AND PARTICIPANTS: One hundred eleven patients with estimated glomerular filtration rate (eGFR) 15-60 ml/min/1.73 m2 without previous cardiovascular events. INTERVENTION: Aspirin treatment (100 mg/day) (n = 50) or usual therapy (n = 61). Mean follow-up time was 64.8 ± 16.4 months. OUTCOMES: The primary endpoint was composed of cardiovascular death, acute coronary syndrome (nonfatal MI, coronary revascularization, or unstable angina pectoris), cerebrovascular disease, heart failure, or nonfatal peripheral arterial disease. Secondary endpoints were fatal and nonfatal coronary events, renal events (defined as doubling of serum creatinine, ≥ 50% decrease in eGFR, or renal replacement therapy), and bleeding episodes. RESULTS: During follow-up, 17 and 5 participants suffered from a primary endpoint in the control and aspirin groups, respectively. Aspirin did not significantly reduce primary composite endpoint (HR, 0.396 (0.146-1.076), p = 0.069. Eight patients suffered from a fatal or nonfatal coronary event in the control group compared to no patients in the aspirin group. Aspirin significantly reduced the risk of coronary events (log-rank, 5.997; p = 0.014). Seventeen patients in the control group reached the renal outcome in comparison with 3 patients in the aspirin group. Aspirin treatment decreased renal disease progression in a model adjusted for age, baseline kidney function, and diabetes mellitus (HR, 0.272; 95% CI, 0.077-0.955; p = 0.043) but did not when adjusted for albuminuria. No differences were found in minor bleeding episodes between groups and no major bleeding was registered. LIMITATIONS: Small sample size and open-label trial. CONCLUSIONS: Long-term treatment with low-dose aspirin did not reduce the composite primary endpoint; however, there were reductions in secondary endpoints with fewer coronary events and renal outcomes. ClinicalTrials.gov Identifier: NCT01709994.

Low dose aspirin increases 15-epi-lipoxin A4 levels in diabetic chronic kidney disease patients.

BACKGROUND: Resolution of inflammation is regulated by endogenous lipid mediators, such as lipoxins and their epimers, including 15-epi-lipoxin A4 (15-epi-LXA4). However, there is no information on 15-epi-LXA4 and its in vivo regulation in chronic kidney disease (CKD) patients. STUDY DESIGN: Open label randomized clinical trial. SETTING AND PARTICIPANTS: 50 participants with chronic kidney disease (CKD) stage 3 and 4 without prior cardiovascular disease (25 in the aspirin group and 25 in the standard group) followed for 46 months. INTERVENTION: Aspirin (100mg/day) or standard treatment. AIM: To analyze the effect of aspirin on plasma 15-epi-LXA4 levels and inflammatory markers in CKD patients. RESULTS: Baseline plasma15-epi-LXA4 levels were lower in diabetic (1.22 ± 0.99ng/ml) than in non-diabetic CKD patients (2.05 ± 1.06ng/ml, p < 0.001) and inversely correlated with glycosylated hemoglobin levels (r = -0.303, p = 0.006). In multivariate analysis, diabetes was associated with lower 15-epi-LXA4 levels, adjusted for age, inflammatory markers and renal function (p = 0.005). In the whole study population, 15-epi-LXA4 levels tended to increase, but not significantly (p = 0.45), after twelve months on aspirin (from mean ± SD 1.84 ± 1.06 to 2.04 ± 0.75ng/ml) and decreased in the standard care group (1.60 ± 1.15 to 1.52 ± 0.68ng/ml, p = 0.04). The aspirin effect on 15-epi-LXA4 levels was more striking in diabetic patients, increasing from 0.94 ± 0.70 to 1.93 ± 0.74ng/ml, p = 0.017. CONCLUSIONS: Diabetic patients with CKD have lower circulating 15-epi-LXA4 levels than non-diabetic CKD patients. Low dose aspirin for 12 months increased 15-epi-LXA4 levels in diabetic patients. Given its anti-inflammatory properties, this increase in 15-epi-LXA4 levels may contribute to the beneficial effects of low dose aspirin.

Markers of endothelial damage in patients with chronic kidney disease on hemodialysis.

Patients with Stage 5 chronic kidney disease who are on hemodialysis (HD) remain in a chronic inflammatory state, characterized by the accumulation of uremic toxins that induce endothelial damage and cardiovascular disease (CVD). Our aim was to examine microvesicles (MVs), monocyte subpopulations, and angiopoietins (Ang) to identify prognostic markers in HD patients with or without diabetes mellitus (DM). A total of 160 prevalent HD patients from 10 centers across Spain were obtained from the Biobank of the Nephrology Renal Network (Madrid, Spain): 80 patients with DM and 80 patients without DM who were matched for clinical and demographic criteria. MVs from plasma and several monocyte subpopulations (CD142+/CD16+, CD14+/CD162+) were analyzed by flow cytometry, and the plasma concentrations of Ang1 and Ang2 were quantified by ELISA. Data on CVD were gathered over the 5.5 yr after these samples were obtained. MV level, monocyte subpopulations (CD14+/CD162+ and CD142+/CD16+), and Ang2-to-Ang1 ratios increased in HD patients with DM compared with non-DM patients. Moreover, MV level above the median (264 MVs/µl) was associated independently with greater mortality. MVs, monocyte subpopulations, and Ang2-to-Ang1 ratio can be used as predictors for CVD. In addition, MV level has a potential predictive value in the prevention of CVD in HD patients. These parameters undergo more extensive changes in patients with DM.

Effectiveness of mycophenolate mofetil in C3 glomerulonephritis.

C3 glomerulonephritis is a clinicopathologic entity defined by the presence of isolated or dominant deposits of C3 on immunofluorescence. To explore the effect of immunosuppression on C3 glomerulonephritis, we studied a series of 60 patients in whom a complete registry of treatments was available over a median follow-up of 47 months. Twenty patients had not received immunosuppressive treatments. In the remaining 40 patients, 22 had been treated with corticosteroids plus mycophenolate mofetil while 18 were treated with other immunosuppressive regimens (corticosteroids alone or corticosteroids plus cyclophosphamide). The number of patients developing end-stage renal disease was significantly lower among treated compared with untreated patients (3 vs. 7 patients, respectively). No patient in the corticosteroids plus mycophenolate mofetil group doubled serum creatinine nor developed end-stage renal disease, as compared with 7 (significant) and 3 (not significant), respectively, in patients treated with other immunosuppressive regimens. Renal survival (100, 80, and 72% at 5 years) and the number of patients achieving clinical remission (86, 50, and 25%) were significantly higher in patients treated with corticosteroids plus mycophenolate mofetil as compared with patients treated with other immunosuppressive regimens and untreated patients, respectively. Thus, immunosuppressive treatments, particularly corticosteroids plus mycophenolate mofetil, can be beneficial in C3 glomerulonephritis.

Spanish guidelines for the management of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6-10% of patients on renal replacement therapy (RRT). Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a consensus statement presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence found were C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease (CKD) and RRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are not provided since no drug has regulatory approval for this indication.

High prevalence of occult hepatitis C virus infection in patients with primary and secondary glomerular nephropathies.

The association of hepatitis C virus (HCV) infection and glomerulonephritis is well known. However, the relationship between immune-mediated glomerulonephritis and occult HCV, characterized by the presence of HCV-RNA in liver or in peripheral blood mononuclear cells in the absence of serological markers, is unknown. We tested this in 113 anti-HCV-negative patients; 87 with immune-mediated glomerulonephritis and 26 controls with hereditary glomerular nephropathies. All patients were serum HCV-RNA negative by conventional real-time PCR. Significantly, occult HCV-RNA (detectable viral RNA in peripheral blood mononuclear cells or in serum after ultracentrifugation) was found in 34 of 87 patients with immune-mediated glomerulonephritis versus 1 of 26 control patients. The serum creatinine levels were significantly higher in patients with immune-mediated glomerulonephritis with than in those without occult HCV (1.5 versus 1.1 mg/dl, respectively). A multivariate analysis adjusted for gender showed a significantly increased risk of occult HCV in patients with immune-mediated glomerulonephritis versus the controls (odds ratio of 13.29). Progression to end-stage renal disease tended to be faster in patients with immune-mediated glomerulonephritis and occult HCV than in the negative cases. Thus, occult HCV is strongly associated with immune-mediated glomerulonephritis and may have a role in the progression of the disease.

Oral paricalcitol as antiproteinuric agent in chronic kidney disease.

BACKGROUND: Vitamin D has an important regulatory effect on the renin-angiotensin-aldosterone system, playing a central role in the regulation of proteinuria. We therefore studied the antiproteinuric effect of paricalcitol. METHODS: 36 patients with an estimated GFR of 30-90 mL/min/1.73 m² and proteinuria >400 mg/d with a stable dose of ACE inhibitor or ARB for at least 3 months were recruited. Patients received oral paricalcitol 1 µg/day for 12 months. Primary endpoint was decrease in proteinuria from baseline. Secondary endpoints were changes in creatinine, eGFR, serum levels of calcium, phosphorus, iPTH, 25(OH)vitD, C-Reactive Protein and blood presure. RESULTS: Mean proteinuria was 2806 mg/d and fell to 2199 mg/d at month 6 (p<.0001) and 1931.5 mg/d at month 12 (P<.0001). Patients with >3000 mg/d baseline proteinuria (n=12) saw smaller relative reductions in proteinuria (5956.9±2492.6 mg/d to 4220.4±2613 mg/d at 12 months) than patients with <3000 mg/d baseline proteinuria (1371±627.5 mg/d to 821.3±491.5mg/d at 12 months). There were no changes in BP, eGFR and CRP. We observed significant changes in serum levels of calcium, phosphorus, iPTH, 25(OH) vitamin D. CONCLUSION: Our study shows an important reduction in proteinuria with a low dose of oral paricalcitol in CKD, that is particularly robust with baseline proteinuria between 1-3 g/d.

Oral paricalcitol as antiproteinuric agent in chronic kidney disease

Background: Vitamin D has an important regulatory effect on the renin-angiotensin-aldosterone system, playing a central role in the regulation of proteinuria. We therefore studied the antiproteinuric effect of paricalcitol. Methods: 36 patients with an estimated GFR of 30-90mL/min/1.73m2 and proteinuria >400mg/d with a stable dose of ACE inhibitor or ARB for at least 3 months were recruited. Patients received oral paricalcitol 1µg/day for 12 months. Primary endpoint was decrease in proteinuria from baseline. Secondary endpoints were changes in creatinine, eGFR, serum levels of calcium, phosphorus, iPTH, 25(OH)vitD, C-Reactive Protein and blood presure. Results: Mean proteinuria was 2806mg/d and fell to 2199mg/d at month 6 (p<.0001) and 1931.5mg/d at month 12 (p<.0001). Patients with >3000mg/d baseline proteinuria (n=12) saw smaller relative reductions in proteinuria (5956.9±2492.6mg/d to 4220.4±2613mg/d at 12 months) than patients with <3000mg/d baseline proteinuria (1371±627.5 mg/d to 821.3±491.5mg/d at 12 months). There were no changes in BP, eGFR and CRP. We observed significant changes in serum levels of calcium, phosphorus, iPTH, 25(OH) vitamin D. Conclusion: Our study shows an important reduction in proteinuria with a low dose of oral paricalcitol in CKD, that is particularly robust with baseline proteinuria between 1-3g/d (AU)

Introducción: La vitamina D posee un efecto regulatorio del eje renina-angiotensina-aldosterona, jugando, por lo tanto, un papel importante en cuanto a proteinuria se refiere. Presentamos nuestra experiencia en el uso de paricalcitol como antiproteinúrico. Métodos: Incluimos 36 pacientes con un eGFR of 30-90 ml/min/1,73 m2 y proteinuria > 400 mg/d con dosis estables de inhibidores del SRAA durante 3 meses. Se le admistró durante 12 meses 1 µg/día de paricalcitol. Como objetivo primario estudiamos el descenso de proteinuria; como secundarios cambios en Cr, eFG, calcio, fósforo, iPTH, 25(OH)vitD, PCR y tension arterial. Resultados: La proteinuria media fue 2806 mg/d cayendo hasta 2199 mg/d en el mes 6 (p < 0,0001) y 1931,5 mg/d a los 12 meses (p < 0,0001). Aquellos con una proteinuria basal > 3000 mg/d (n=12) sufrieron una menor disminución (5956,9 ± 2492,6 mg/d a 4220,4 ± 2613 mg/d en mes 12) respecto a aquellos con una proteinuria < 3000 mg/d (1371 ± 627,5 mg/d a 821,3 ± 491,5 mg/d en mes 12). No se objetivaron cambios en tension arterial, eGFR y PCR. Los cambios en calcio, fósforo, iPTH y vitamina D 25(OH) fueron estadísticamente significativos. Conclusión: Nuestro estudio demuestra una reducción importante de proteinuria con dosis bajas de paricalcitol en pacientes con IRC, que es de particular importancia en aquellos con porteinuria basal entre 1-3 g/d (AU)

Anemia control in renal transplant recipients receiving continuous erythropoietin receptor activator (C.E.R.A.) treatment: the AnemiaTrans Study.

INTRODUCTION: Continuous erythropoietin receptor activator (C.E.R.A.) effectively enables anemia control in patients with chronic kidney disease, but little information is available in renal transplant recipients. The authors aimed to evaluate the effect of C.E.R.A. under clinical practice conditions on anemia control in renal transplant recipients. METHODS: This was a multicenter, retrospective, observational study carried out in adult renal transplant patients in the immediate posttransplant period and at late posttransplant period receiving C.E.R.A. in clinical practice. Patients' data were retrieved from their medical charts at baseline and months 1, 3, and 6. RESULTS: A total of 318 evaluable patients were enrolled into the study: 32 in the immediate posttransplant period and 286 at late posttransplant period (erythropoiesis-stimulating agent [ESA]-naïve, n = 44; converting from other ESAs, n = 242). Patients in the immediate posttransplant period experienced a significant increase in hemoglobin (Hb) levels from baseline to month 1 (9.9±1.5 g/dL vs. 11.5±1.4 g/dL; P< 0.001). ESA-naïve patients showed increasing mean Hb levels from baseline to month 6 (10.1±0.7 g/dL vs. 11.7±1.0 g/dL; P < 0.001) and 94.7% achieved Hb ≥11 g/dL during the study. In patients converted from other ESAs, the percentage of patients with Hb between 11-13 g/dL was maintained from baseline to month 6 with no significant differences (61.0% vs. 62.4%). Mean monthly doses of C.E.R.A. at baseline were 134.4±56.4 µg, 81.3±28.1 µg, and 93.0±44.2 µg in immediate posttransplant, ESA-naïve, and converted patients, respectively. C.E.R.A. was well tolerated. CONCLUSION: C.E.R.A. enables anemia control in renal transplant recipients, allowing target Hb levels to be achieved and maintained with doses even below those described in the Summary of Product Characteristics.

Long-term outcomes of IgA nephropathy presenting with minimal or no proteinuria.

The long-term outcome of patients with IgA nephropathy who present with normal renal function, microscopic hematuria, and minimal or no proteinuria is not well described. Here, we studied 141 Caucasian patients with biopsy-proven IgA nephropathy who had minor abnormalities at presentation and a median follow-up of 108 months. None of the patients received corticosteroids or immunosuppressants. We reviewed renal biopsies using the Oxford classification criteria. In this sample, 46 (32%) patients had mesangial proliferation, whereas endocapillary proliferation, focal glomerulosclerosis, and tubulointerstitial abnormalities were uncommon. Serum creatinine increases >50% and >100% were observed in five (3.5%) patients and one (0.7%) patient, respectively; no patients developed ESRD. After 10, 15, and 20 years, 96.7%, 91.9%, and 91.9% of patients maintained serum creatinine values less than a 50% increase, respectively. Using Cox proportional hazards regression, the presence of segmental glomerulosclerosis was the only factor that significantly associated with a >50% increase in serum creatinine. Clinical remission occurred in 53 (37.5%) patients after a median of 48 months. Proteinuria>0.5 and >1.0 g/24 h developed in 21 (14.9%) and 6 (4.2%) patients, respectively. Median proteinuria at the end of follow-up was 0.1 g/24 h, with 41 (29.1%) patients having no proteinuria. At presentation, 23 (16.3%) patients were hypertensive compared with 30 (21.3%) patients at the end of follow-up; 59 (41.8%) patients were treated with renin-angiotensin blockers because of hypertension or increasing proteinuria. In summary, the long-term prognosis for Caucasian patients with IgA nephropathy who present with minor urinary abnormalities and normal renal function is excellent.

Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy.

Spontaneous remission is a well known characteristic of idiopathic membranous nephropathy, but contemporary studies describing predictors of remission and long-term outcomes are lacking. We conducted a retrospective, multicenter cohort study of 328 patients with nephrotic syndrome resulting from idiopathic membranous nephropathy that initially received conservative therapy. Spontaneous remission occurred in 104 (32%) patients: proteinuria progressively declined after diagnosis until remission of disease at 14.7 +/- 11.4 months. Although spontaneous remission was more frequent with lower levels of baseline proteinuria, it also frequently occurred in patients with massive proteinuria: 26% among those with baseline proteinuria 8 to 12 g/24 h and 22% among those with proteinuria >12 g/24 h. Baseline serum creatinine and proteinuria, treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, and a >50% decline of proteinuria from baseline during the first year of follow-up were significant independent predictors for spontaneous remission. Only six patients (5.7%) experienced a relapse of nephrotic syndrome. The incidence of death and ESRD were significantly lower among patients with spontaneous remission. In conclusion, spontaneous remission is common among patients with nephrotic syndrome resulting from membranous nephropathy and carries a favorable long-term outcome with a low incidence of relapse. A decrease in proteinuria >50% from baseline during the first year predicts spontaneous remission.

Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis.

Mutations in the NPHS1 gene cause congenital nephrotic syndrome of the Finnish type presenting before the first 3 months of life. Recently, NPHS1 mutations have also been identified in childhood-onset steroid-resistant nephrotic syndrome and milder courses of disease, but their role in adults with focal segmental glomerulosclerosis remains unknown. Here we developed an in silico scoring matrix to evaluate the pathogenicity of amino-acid substitutions using the biophysical and biochemical difference between wild-type and mutant amino acid, the evolutionary conservation of the amino-acid residue in orthologs, and defined domains, with the addition of contextual information. Mutation analysis was performed in 97 patients from 89 unrelated families, of which 52 presented with steroid-resistant nephrotic syndrome after 18 years of age. Compound heterozygous or homozygous NPHS1 mutations were identified in five familial and seven sporadic cases, including one patient 27 years old at onset of the disease. Substitutions were classified as 'severe' or 'mild' using this in silico approach. Our results suggest an earlier onset of the disease in patients with two 'severe' mutations compared to patients with at least one 'mild' mutation. The finding of mutations in a patient with adult-onset focal segmental glomerulosclerosis indicates that NPHS1 analysis could be considered in patients with later onset of the disease.

TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis.

BACKGROUND: Mutations in the TRPC6 gene have been reported in six families with adult-onset (17-57 years) autosomal dominant focal segmental glomerulosclerosis (FSGS). Electrophysiology studies confirmed augmented calcium influx only in three of these six TRPC6 mutations. To date, the role of TRPC6 in childhood and adulthood non-familial forms is unknown. METHODS: TRPC6 mutation analysis was performed by direct sequencing in 130 Spanish patients from 115 unrelated families with FSGS. An in silico scoring matrix was developed to evaluate the pathogenicity of amino acid substitutions, by using the bio-physical and bio-chemical differences between wild-type and mutant amino acid, the evolutionary conservation of the amino acid residue in orthologues, homologues and defined domains, with the addition of contextual information. RESULTS: Three new missense substitutions were identified in two clinically non-familial cases and in one familial case. The analysis by means of this scoring system allowed us to classify these variants as likely pathogenic mutations. One of them was detected in a female patient with unusual clinical features: mesangial proliferative FSGS in childhood (7 years) and partial response to immunosupressive therapy (CsA + MMF). Asymptomatic carriers of this likely mutation were found within her family. CONCLUSIONS: We describe for the first time TRPC6 mutations in children and adults with non-familial FSGS. It seems that TRPC6 is a gene with a very variable penetrance that may contribute to glomerular diseases in a multi-hit setting.

Hypoalbuminemia is also a marker of fluid excess determined by bioelectrical impedance parameters in dialysis patients.

Hypoalbuminemia may be secondary to volume expansion conditions and an independent risk factor for cardiovascular disease. Bioelectrical impedance analysis (BIA) is an accurate, non-invasive method to measure body composition, especially the water compartments in humans. The aim of this cross-sectional study is to evaluate the relationship between serum albumin concentration (SA) and hydration state measured by whole BIA. The study investigated 108 non-selected patients (73 on hemodialysis, 35 on peritoneal dialysis) with a mean age of 61.4 +/- 15.6 years, 42.7% of whom were female. The patients were allotted to groups according to their SA: Group 1, < or = 3.5 g/dL; Group 2, 3.6-4.0 g/dL; and Group 3, >4.0 g/dL. The BIA parameters used included: total body water, intracellular water (ICW), extracellular water (ECW), phase angle (PA), body cell mass (BCM), ICW/ECW ratio and ICW/ECW ratio patients/controls (fluid index). Seventy-five healthy volunteers formed the control group. A strong positive correlation was found between the PA and fluid index (r (2) = 0.993, P < 0.001), as well as between the PA and SA (r = 0.386, P < 0.001), and the ICW/ECW ratio and SA (r = 0.227, P < 0.001). The ECW was negatively correlated with SA (r = -0.330, P < 0.001). Every 0.1 g/dL decrease in SA was associated with a 0.33 L increase in ECW. Group 1 patients had lower reactance (P = 0.006), PA (P < 0.001), BCM (P = 0.012), fluid index (P < 0.001) and ICW/ECW ratio (P = 0.015), and an increased ECW (NS) than groups 2 and 3. We conclude that hypoalbuminemia is also a marker of fluid excess. The SA is associated to the fluid index and the PA allows assessment of the dry weight and its variations in an individualized manner in dialysis patients.