Multidisciplinary management improves the genetic diagnosis of hereditary kidney diseases in the next generation sequencing (NGS) era.

BACKGROUND AND OBJECTIVE: Hereditary kidney diseases (HKD) are a frequent cause of chronic kidney disease, and their diagnosis has increased since the introduction of next generation sequencing (NGS). In 2018, the Multidisciplinary Unit for Hereditary Kidney Diseases of the Region of Murcia (UMERH-RM) was founded based on the genetic study of HKD. The objective of this study is to analyze the results obtained in the first 3 years of operation, and to analyze the clinical factors associated to a final genetic diagnosis. MATERIALS AND METHODS: All the patients studied with the HKD gene panel were included. The characteristics between those who obtained a final genetic diagnosis and those who did not were compared. RESULTS: A total of 360 patients were studied, detecting genetic variants in 164 not related patients (45.6%). 45 of these were variants of uncertain significance requiring a family co-segregation study, which was facilitated by the multidisciplinary unit. Overall, considering the results obtained with the NGS panel and the extended genomic studies, a final diagnostic yield of HRD of 33.3% (120/360) was achieved, and including incidental findings 35.6% (128/360). Two hundred and twenty-three patients with suspected Alport syndrome were studied. Diagnosis was confirmed in 28.5% (COL4A4 most frequent gene), more frequently women with an obvious compatible family history. They also had frequently microhematuria, although 5 patients without microhematuria confirmed the diagnosis. There were no differences in age, proteinuria, renal function, hearing loss, or ophthalmologic abnormalities. The most frequent finding in the renal biopsy was mesangial proliferation. We estimate that 39 patients avoided renal biopsy. A total of 101 patients with suspected PKD were also studied, 49.5% had a conclusive genetic result (most frequent gene PKD1), more frequently women, with larger kidney sizes (although 9 patients with normal kidney size confirmed diagnosis). Again, the most predictive characteristic of genetic outcome was family history. CONCLUSIONS: The implementation of an NGS panel for HKD, together with the multidisciplinary approach to cases, has improved the diagnostic performance of HKD. In our sample, autosomal dominant Alport syndrome is of highest incidence. Ophthalmological and auditory examinations did not contribute to the diagnosis. We have seen a significant decrease in the indication of renal biopsies thanks to molecular diagnosis. The multidisciplinary approach, with the active participation of nephrologists, paediatricians, clinical and molecular geneticists, with insistence on adequate patient phenotyping and review of their family history, offers a better interpretation of genetic variants, allowing reclassification of the diagnosis of some nephropathies, thus improving their management and genetic advice.

El manejo multidisciplinar mejora el diagnóstico genético de las enfermedades renales hereditarias en la era de next generation sequencing (NGS) / Multidisciplinary management improves the genetic diagnosis of hereditary kidney diseases in the next generation sequencing (NGS) era

Antecedentes y objetivo Las enfermedades renales hereditarias (ERH) son una causa frecuente de enfermedad renal crónica, habiéndose incrementado su diagnóstico desde la introducción de la secuenciación masiva (NGS). En 2018 se fundó la Unidad multidisciplinar de Enfermedades Renales Hereditarias de la Región de Murcia basándose en el estudio genético de las ERH mediante panel de genes. El objetivo de este estudio es analizar los resultados obtenidos en los primeros tres años de funcionamiento, así como analizar los factores clínicos que se asocian a la obtención de un diagnóstico genético final. Materiales y métodos Se incluyeron los pacientes estudiados mediante panel de genes de ERH y se compararon las características entre los que obtuvieron un diagnóstico genético final y los que no. Resultados Se estudiaron un total de 360 pacientes, detectándose variantes genéticas en 164 pacientes (45,6%) no relacionados familiarmente. Cuarenta y cinco de estas variantes eran de significado clínico incierto precisando estudio de cosegregación familiar, facilitado por la unidad multidisciplinar. Globalmente, considerando los resultados obtenidos con el panel de NGS realizado en el CBGC y los estudios genómicos ampliados, se consiguió un rendimiento diagnóstico final de ERH del 33,3% (120/360), contando hallazgos incidentales, del 35,6% (128/360). Se estudiaron 223 pacientes con sospecha de síndrome de Alport, confirmándose el diagnóstico en un 28,5% (gen más frecuente COL4A4), los cuales eran con más frecuencia mujeres, y con clara historia familiar compatible. También tenían con más frecuencia microhematuria, aunque 5 pacientes sin microhematuria confirmaron diagnóstico. No hubo diferencias en la edad, proteinuria, función renal, hipoacusia o alteraciones oftalmológicas (AU)

Background and objective Hereditary kidney diseases (HKD) are a frequent cause of chronic kidney disease, and their diagnosis has increased since the introduction of next generation sequencing (NGS). In 2018, the Multidisciplinary Unit for Hereditary Kidney Diseases of the Region of Murcia (UMERH-RM) was founded based on the genetic study of HKD. The objective of this study is to analyze the results obtained in the first 3 years of operation, and to analyze the clinical factors associated to a final genetic diagnosis. Materials and methods All the patients studied with the HKD gene panel were included. The characteristics between those who obtained a final genetic diagnosis and those who did not were compared. Results A total of 360 patients were studied, detecting genetic variants in 164 not related patients (45.6%). 45 of these were variants of uncertain significance requiring a family co-segregation study, which was facilitated by the multidisciplinary unit. Overall, considering the results obtained with the NGS panel and the extended genomic studies, a final diagnostic yield of HRD of 33.3% (120/360) was achieved, and including incidental findings 35.6% (128/360). Two hundred and twenty-three patients with suspected Alport syndrome were studied. Diagnosis was confirmed in 28.5% (COL4A4 most frequent gene), more frequently women with an obvious compatible family history. They also had frequently microhematuria, although 5 patients without microhematuria confirmed the diagnosis. There were no differences in age, proteinuria, renal function, hearing loss, or ophthalmologic abnormalities. The most frequent finding in the renal biopsy was mesangial proliferation. We estimate that 39 patients avoided renal biopsy (AU)

Impact of Serum Magnesium Levels on Kidney and Cardiovascular Prognosis and Mortality in CKD Patients.

INTRODUCTION: In the general population, hypomagnesemia has been associated with cardiovascular events and hypermagnesemia with overall mortality. In chronic kidney disease (CKD) the evidence is not so strong. The objective of our study was to investigate the relationship between serum magnesium (SMg) concentration and cardiovascular morbidity and mortality, all-cause mortality, and the progression to kidney failure in a population with CKD. METHODS: Observational study of a cohort of 746 patients with CKD. Baseline characteristics and analytical profile were collected at the first visit, and patients were followed for a mean of 42.6 months. RESULTS: A cohort of 746 patients were analyzed, age 70 ± 13 years, 62.9% were male, 45.2% had CKD grade 3, and 35.9% grade 4. The mean SMg concentration was 2.09 ± 0.33 mg/dL, with a close correlation between SMg concentration and serum creatinine, phosphorus, and intact parathyroid hormone (iPTH) values. Use of calcitriol was associated with higher SMg (SMgH) concentration, while calcium supplements and proton pump inhibitors (PPIs) were associated with lower SMg concentration. For risk of cardiovascular events, patients with hypermagnesemia had an overall higher risk on a crude analysis (Log Rank 4.83, P = .28) and adjusted analysis (HR = 1.34, CI 1.02-1.77, P = .037). For risk of all-cause mortality, patients with hypermagnesemia had an overall higher risk on crude analysis (Log Rank 13.11, P > .001) and adjusted analysis (HR = 1.5424, IC = 1.002-2.319, P = .049). After performing a propensity score matching for SMg concentration, we achieved two comparable groups of 287 patients, finding again higher all-cause mortality in the hypermagnesemia group (LogRank 15.147, P < .001), that persisted in the Cox model adjusted for calcium, phosphorus, and iPTH. No association was found between SMg concentration and initiation of kidney replacement therapy (KRT). CONCLUSIONS: Magnesium concentration increases with decreasing kidney function. Hypermagnesemia predicts cardiovascular events and all-cause mortality in this same population. Thus, magnesium supplementation should be used with caution in these patients.

Double filtration plasmapheresis in the treatment of pancreatitis due to severe hypertriglyceridemia.

BACKGROUND: Severe hypertriglyceridemia (HTG) leads to major complications such as acute pancreatitis. Lipoprotein apheresis has been proposed as a therapeutic tool for decreasing triglyceride levels, although experience is limited. OBJECTIVE: To describe our experience with double filtration plasmapheresis (DFPP) in patients with severe HTG and pancreatitis in the plasmapheresis unit of a tertiary hospital in Spain. METHODS: We recruited 4 patients with severe HTG (triglycerides [TGs] >1000 mg/dL) and acute pancreatitis. All the patients underwent DFPP as part of their treatment. Epidemiologic and laboratory data were collected before and after each plasmapheresis session. RESULTS: The average TG level before plasmapheresis was 3136 mg/dL (35.44 mmol/L; range, 1306-6693 mg/dL, 14.76-75.63 mmol/L), and the average Acute Physiology And Chronic Health Evaluation (APACHE) II level before the first session was 6 (range, 3-8). All patients made a full recovery, with a significant improvement in TG levels after plasmapheresis. The mean number of sessions was 2.1 (range, 1-3), and mean TG level after plasmapheresis was 428 mg/dL (4.84 mmol/L; range, 169-515 mg/dL; 1.91-5.82 mmol/L). After the first session, the mean decrease in TG levels was 69.16% (2169 mg/dL, range, 945-5925 mg/dL; 24.51 mmol/L, range, 10.78-66.95 mmol/L), and after the last session, TG levels fell by 89.09% (2794 mg/dL, range, 945-6198 mg/dL; 31.57 mmol/L, range, 10.68-70.04 mmol/L). None of the patients developed complications related to plasmapheresis. CONCLUSIONS: According to available evidence and our own experience, DFPP can be an effective and rapid treatment option in patients with severe HTG and complications. However, further research, including randomized controlled studies, is necessary.