Background and Aims Hereditary factors represent an important cause of nephrolithiasis which will generate stone disease in adult. Molecular analysis in patients with nephrolithiasis (NL) and/or nephrocalcinosis (NC) for a genetic mutation has become more accessible and the benefits are highlighted by an increasing number of publications. The aim of the paper was to study genetic screening for 36 NL and/or NC patients in order to identify the cases that can be confirmed by mutations in known kidney stone genes. Method Between 2020–2022 we included 35 adult patients with NL/NC with onset on pediatric age or in young adults, plus one of the following criteria: family history for NL/NC, indicative phenotype, recurrent NL. All the patients were diagnosed with NL and/or NC by ultrasound or computed tomography scan. Inform consent was signed and dated before blood samples and we performed genetic testing using nephrolithiasis panel (that include 45 genes) from 2 laboratories. In addition, we performed clinical assessment in a multidisciplinary team, underwent metabolic assessment, and caring out the genealogical tree. Results The study included 18 females and 17 males. The mean age of studied patients was 34.9 ± 10.3 years (range 18 – 54 years), although mean age of NL/NC diagnosis was 19.4 ± 12.0 years (range 0.5 – 34 years). 29 patients presented NL of any type, 12 patients presented both NL and NC, and 3 patients isolated NC. All the patients presented positive family history of NL/NC, 17 (48.5%) patients had pediatric age of onset, 17 (48.5%) patients presented indicative phenotype and 19 (54.2%) recurrent stone disease. Causative monogenic mutations were detected in 25 of 35 NL/NC. We identified 20 deleterious variants in 12 out of 45 analyzed genes. Genetic testing was positive with a definite diagnosis (had pathogenic variant) in 17 (48.6%) of cases, while 3 (8.6%) patients presented likely pathogenic variants, and 5 (14.3%) patients had variants of uncertain significance (VUS). In our cohort, the most common cause of kidney stone disease was cystine nephrolithiasis in 8 (22.8%) patients, followed by hereditary distal renal tubular acidosis in 4 patients, Dent disease in 3 patients, primary hyperoxaluria type 1 in 2 patients, familial hypomagnesaemia with hypercalciuria and nephrocalcinosis in 2 patients. Other causes of kidney stone disease included: renal hypouricemia type 1, hereditary hypophosphatemic rickets with hypercalciuria, primary mitochondrial disorders, autosomal dominant familial idiopathic hypercalciuria, Bartter syndrome type 3, and autosomal dominant tubulo-interstitial disease with hyperuricemia. Pathogenic mutations were detected in the following 5 dominant disease genes: SLC7A9 (4 patients), SLC4A1 (3 patients), ADCY10 (1 patient), HNF1B (2 patients), POLG (1 patient). Also, we identified pathogenic mutations in the following 7 recessive disease genes: CLCN5 (3 patients), AGXT (2 patients), CLDN16 (2 patients), SLC3A1 (3 patients), SLC34A3 (1 patient), WDR72 (1 patient), CLCNKB (1 patient). The mean eGFR for the study group was 71.2 ± 37.6 ml/min/1.72 m2. Seventeen patients presented eGFR < 60 ml/min/1.73 m2: seven patients CKD stage 3, four patients CKD stage 4, two patients CKD stage 5, and two patients were with renal replacement therapy. Conclusion Genetic kidney stone disease is an underdiagnosed condition. Although 48.5% of the patients had NL/NC onset on pediatric age, the molecular diagnosis was performed in adulthood, and, for some of them, when they suffer of advanced kidney disease. In our cohort, genetic testing had a high rate of positive molecular diagnosis of NL/NC due to selection criteria. Five of our patients presented VUS, but with disease-specific phenotype. We emphasize the importance of reporting these cases to generate additional evidence that could allow the reclassification of these variants. We conclude that the molecular diagnosis improves patient management, prevent or delay chronic kidney disease, offer possibility of genetic counseling and an extended screening to the family. Thus, our study showed the potential benefits of genetic testing, especially in high-risk groups for stone disease.
BACKGROUND AND AIMS Fabry disease (FD) is a rare lysosomal storage disease causing progressive kidney, nervous system and heart disorders. Specific therapy may stop or mitigate disease progression, but is very expensive and results depend significantly on early initiation of treatment. Thus, clear criteria for treatment options are necessary. Kidney biopsy in FD has important diagnostic, prognostic and therapeutically implications. Some countries already decided to include as a criterion for reimbursement of FD-specific therapy in presence of renal biopsy evidence related to FD. National criteria for starting FD specific therapy according to renal involvement include eGFR <80 mL/min/1.73 m2 and/or proteinuria >300 mg/day. METHOD The aim of our retrospective study is to evaluate clinical and histological aspects of renal involvement in untreated female patients diagnosed with FD by genetic test between 2015 and 2021 in our center. Biological renal manifestations using serum creatinine, albumin creatinine ratio and proteinuria. Also, presence of neurological involvement was assessed by clinical exam, electroneurographic exam and brain magnetic resonance, and heart manifestations were assessed by echocardiography, electrocardiogram (ECG), ECG Holter and cardiac magnetic resonance. Kidney biopsy specimens were analyzed by light and electron microscopy. Specific renal FD lesions, as well as general lesions of progression, were evaluated according to the International Study Group of Fabry Nephropathy Score Sheet. RESULTS From a total of 25 female patients, we enrolled 11 female patients in which kidney biopsy was performed. The mean age at diagnosis was 47.7 ± 12 years (range 30–65 years), although mean age of symptoms onset was 36.1 years. The mean eGFR was 72.7 ± 19.8 mL/min/1.72 m2 while mean proteinuria was 0.72 ± 1.3 mg/day. Average Mainz score was 16.6 ± 11.5. Heart involvement was found in five patients (45.5%), and neurological manifestations were present in five patients. Co-morbidities were as follows: arterial hypertension in six patients, diabetes mellitus in one patient and obesity in two patients. All kidney biopsies showed lysosomal accumulation in the podocytes, in the parietal cells of the Bowman capsule and in the tubules, while vascular inclusions were found in nine cases. Also, we observed segmental glomerular sclerosis in four cases and global glomerular sclerosis in three cases, interstitial fibrosis in six cases, tubular atrophy in five cases, arteriosclerosis in four cases and arteriolar hyalinosis in five cases. Considering national criteria for initiation of FD therapy, five patients (54.6%) fulfilled the renal criteria, three patients (27.3%) presented criteria for other organs involvement, while three patients (mean age 37.7 years) did not fulfill any criteria. We emphasize that, even in our six patients without renal criteria for FD therapy, kidney biopsy showed FD-specific lesions (lysosomal accumulation) in all cases, associated with segmental glomerular sclerosis in one case, interstitial fibrosis in four cases, tubular atrophy in three cases, arteriosclerosis in one case and arteriolar hyalinosis in three cases. Thus, in our three patients without clinical, biological and imaging criteria for FD therapy, evidence of specific FD lesions in kidney biopsy supported our recommendation to initiate FD treatment. CONCLUSION The data from our small cohort of females with Fabry disease underline the importance of kidney biopsy for detection of early kidney involvement and provide additional support to the consideration of early initiation of FD-specific therapy, potentially improving long-term outcome. Thus, proof of specific FD renal lesions as revealed by kidney biopsy could become a distinct criterion for initiation of FD therapy, in the absence of other criteria according to current guidelines. Future studies are necessary in order to specify the role of renal histology in the establishment of the proper timing to start the FD treatment, especially in young patients.
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