Clinical and Genetic Features of Autosomal Dominant Alport Syndrome: A Cohort Study.

RATIONALE & OBJECTIVE: Alport syndrome is a common genetic kidney disease accounting for approximately 2% of patients receiving kidney replacement therapy (KRT). It is caused by pathogenic variants in the gene COL4A3, COL4A4, or COL4A5. The aim of this study was to evaluate the clinical and genetic spectrum of patients with autosomal dominant Alport syndrome (ADAS). STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 82 families (252 patients) with ADAS were studied. Clinical, genetic, laboratory, and pathology data were collected. OBSERVATIONS: A pathogenic DNA variant in COL4A3 was identified in 107 patients (35 families), whereas 133 harbored a pathogenic variant in COL4A4 (43 families). Digenic/complex inheritance was observed in 12 patients. Overall, the median kidney survival was 67 (95% CI, 58-73) years, without significant differences across sex (P=0.8), causative genes (P=0.6), or type of variant (P=0.9). Microhematuria was the most common kidney manifestation (92.1%), and extrarenal features were rare. Findings on kidney biopsies ranged from normal to focal segmental glomerulosclerosis. The slope of estimated glomerular filtration rate change was-1.46 (-1.66 to-1.26) mL/min/1.73m2 per year for the overall group, with no significant differences between ADAS genes (P=0.2). LIMITATIONS: The relatively small size of this series from a single country, potentially limiting generalizability. CONCLUSIONS: Patients with ADAS have a wide spectrum of clinical presentations, ranging from asymptomatic to kidney failure, a pattern not clearly related to the causative gene or type of variant. The diversity of ADAS phenotypes contributes to its underdiagnosis in clinical practice.

Acute Renal Failure Secondary to an Unusual Familial Metabolic Myopathy.

Rhabdomyolysis is a major cause of acute kidney failure. The etiology is diverse, from full-blown crush syndrome to less frequent causes, such as metabolic myopathy. We describe the case of a 35-year-old male with a history of intermittent myalgias who was admitted to hospital with acute renal failure secondary to rhabdomyolysis. Moderate to intense diffuse uptake of technetium-99m was seen in soft tissues at scintigraphy. The diagnosis of metabolic myopathy was confirmed after careful workup and genetic testing.

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

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.

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.

Sangrado de angiomiolipoma renal en paciente con síndrome de genes contiguos (TSC2/PKD1) tras 17 años de tratamiento renal sustitutivo / Renal angiomyolipoma bleeding in a patient with TSC2/PKD1 contiguous gene syndrome after 17 years of renal replacement therapy

Presentamos el caso de un varón de 32 años, con síndrome de genes contiguos TSC2/PKD1, que le ocasiona esclerosis tuberosa (ET) y poliquistosis renal autosómica dominante simultáneamente. Evolucionó a enfermedad renal terminal y se realizó trasplante renal a los 12 años. Los riñones presentaban angiomiolipomas (AML), que son tumores benignos frecuentes en pacientes con ET. A los 17 años postrasplante, presentó un cuadro de dolor abdominal, anemización y hematoma retroperitoneal. Dicho hematoma se produjo por el sangrado de los AML. Como tratamiento se realizó embolización selectiva. Nuestro paciente podría haberse beneficiado en el momento del trasplante renal del tratamiento con inhibidores de mTOR. Este fármaco actúa como inmunosupresor y reductor tumoral en la ET, al disminuir el riesgo de rotura y hemorragia. En este paciente no se administró porque cuando se trasplantó no se conocía la relación de los inhibidores de mTOR con la ET. Este caso confirma que, a pesar de tratarse de pacientes trasplantados o en diálisis, el riesgo de sangrado por los AML persiste, por lo cual se propone realizar controles periódicos de los riñones propios y valorar la nefrectomía (AU)

We report the case of a 32-year-old male diagnosed with TSC2/PKD1 contiguous gene syndrome, presenting with tuberous sclerosis (TS) and autosomal dominant polycystic kidney disease simultaneously. He progressed to end-stage renal disease and received a kidney transplant at the age of 12. The native kidneys presented angiomyolipomas (AML), which are common benign tumours in patients with TS. Seventeen years after transplantation, he presented with abdominal pain, anaemia and a retroperitoneal haematoma, the latter caused by renal AML bleeding. Selective embolisation was performed. Our patient could have benefited from the administration of mTOR inhibitors at transplant. This therapy is immunosuppressive and reduces the size of benign tumours in TS as well as the risk of rupture and bleeding. This patient did not receive mTOR inhibitors at the time of the transplant because the relationship between mTOR inhibitors and TS was unknown at that time. This case confirms the persistent risk of renal AML bleeding for both transplanted patients and patients on dialysis. As a result, we would recommend routine check-ups of native kidneys and nephrectomy assessment (AU)

Renal angiomyolipoma bleeding in a patient with TSC2/PKD1 contiguous gene syndrome after 17 years of renal replacement therapy. / Sangrado de angiomiolipoma renal en paciente con síndrome de genes contiguos (TSC2/PKD1) tras 17 años de tratamiento renal sustitutivo.

We report the case of a 32-year-old male diagnosed with TSC2/PKD1 contiguous gene syndrome, presenting with tuberous sclerosis (TS) and autosomal dominant polycystic kidney disease simultaneously. He progressed to end-stage renal disease and received a kidney transplant at the age of 12. The native kidneys presented angiomyolipomas (AML), which are common benign tumours in patients with TS. Seventeen years after transplantation, he presented with abdominal pain, anaemia and a retroperitoneal haematoma, the latter caused by renal AML bleeding. Selective embolisation was performed. Our patient could have benefited from the administration of mTOR inhibitors at transplant. This therapy is immunosuppressive and reduces the size of benign tumours in TS as well as the risk of rupture and bleeding. This patient did not receive mTOR inhibitors at the time of the transplant because the relationship between mTOR inhibitors and TS was unknown at that time. This case confirms the persistent risk of renal AML bleeding for both transplanted patients and patients on dialysis. As a result, we would recommend routine check-ups of native kidneys and nephrectomy assessment.

HLA-DQA1 and PLA2R1 polymorphisms and risk of idiopathic membranous nephropathy.

BACKGROUND AND OBJECTIVES: Single nucleotide polymorphisms (SNPs) within HLA complex class II HLA-DQ α-chain 1 (HLA-DQA1) and M-type phospholipase A2 receptor (PLA2R1) genes were identified as strong risk factors for idiopathic membranous nephropathy (IMN) development in a recent genome-wide association study. Copy number variants (CNVs) within the Fc gamma receptor III (FCGR3) locus have been associated with several autoimmune diseases, but their role in IMN has not been studied. This study aimed to validate the association of HLA-DQA1 and PLA2R1 risk alleles with IMN in a Spanish cohort, test the putative association of FCGR3A and FCGR3B CNVs with IMN, and assess the use of these genetic factors to predict the clinical outcome of the disease. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: A Spanish cohort of 89 IMN patients and 286 matched controls without nephropathy was recruited between October of 2009 and July of 2012. Case-control studies for SNPs within HLA-DQA1 (rs2187668) and PLA2R1 (rs4664308) genes and CNVs for FCGR3A and FCGR3B genes were performed. The contribution of these polymorphisms to predict clinical outcome and renal function decline was analyzed. RESULTS: This study validated the association of these HLA-DQA1 and PLA2R1 SNPs with IMN in a Spanish cohort and its increased risk when combining both risk genotypes. No significant association was found between FCGR3 CNVs and IMN. These results revealed that HLA-DQA1 and PLA2R1 genotype combination adjusted for baseline proteinuria strongly predicted response to immunosuppressive therapy. HLA-DQA1 genotype adjusted for proteinuria was also linked with renal function decline. CONCLUSION: This study confirms that HLA-DQA1 and PLA2R1 genotypes are risk factors for IMN, whereas no association was identified for FCGR3 CNVs. This study provides, for the first time, evidence of the contribution of these HLA-DQA1 and PLA2R1 polymorphisms in predicting IMN response to immunosuppressors and disease progression. Future studies are needed to validate and identify prognostic markers.