#2316 Towards the new era of nephrology. What implications do genetic studies have on individuals with kidney disease?
Authors: Cintra Melissa , Peña María Ramírez , Heres Salia Virxinia Pol , De la Prada Francisco José , León Juan María Borregero , Lazo Mercedes Salgueira 
Published: May 2024

Abstract

Background and Aims
The study of kidney disease (KD), including genetics, may involve a significant change in the management, treatment, and prognosis of the patient.

Method
Retrospective study assessing the impact of genetic studies (GS) requested by the nephrology department at Virgen Macarena Hospital over 43 months (June/2019 to December/2022). We analyze diagnoses before and after GS, as well as their impact. The sequencing platforms used include Illumina HiSeq-MiSeq-NovaSeq and Ion Torrent. Common databases consulted include ClinVar, RefSeq, Ensembl, NCBI, ExAC, aHUS, and BIER.

Results
A total of 118 patients with genetic studies (GS) were analyzed. The mean age was 45.2 ± 16, with 51% being male and 49% female. 78% had first and/or second-degree relatives with kidney disease, and in 43 cases (36%), no family history was known. The mean creatinine (Cr) was 1.9±2 mg/dl, glomerular filtration rate (GFR) was 67 ± 40 ml/min, and urine albumin/creatinine ratio (UAC) was 770 ± 1700 mg/g, with hematuria present in 57.6% of patients. A renal biopsy (RB) was performed in 32 patients (27%).
The indications for genetic testing were as follows: extension of studies in biopsied nephropathy (20%), cystic kidney disease (29%), non-biopsiable or chronic kidney disease (21%), family history (33%), and for research or trial purposes (1%). In 22%, a study of a known familial mutation was conducted, while the remaining cases involved gene panel analysis.
The pre-genetic diagnoses were as follows: 39% glomerular disease, 22% other conditions (suspected Alport and Fabry), 16% autosomal dominant polycystic kidney disease (ADPKD), 8% complement-associated pathology (CAP), 5% other cystic diseases, 4% tubulointerstitial nephropathies (TIN), 3% nephropathy of unknown origin, 2% diabetic nephropathy, and 2% nephroangiosclerosis. GS was positive in 76 patients (N = 76; 64%).
Variants were detected in 76 patients, with 14 patients exhibiting two concurrent variants in the same or different genes, and 4 patients having up to 3 variants. The most frequent variants were identified in the genes: COL4A, PKD1, C3, MCP, and CFH. Of these, 37% were pathogenic mutations, 26.6% were likely pathogenic, 33% were variants of uncertain significance (VUS) possibly related to the pathology, and 3.2% were unrelated VUS. In cases with negative GS results (42; 35%), we considered that the pre-genetic diagnosis was excluded in 17% of the overall patient cohort. Post-GS diagnoses included Alport (30; 25%), ADPKD (16, 14%), CAP (13; 11%), focal segmental glomerulosclerosis (6; 5%), TIN (4; 3%), autosomal recessive polycystic kidney disease (ARPKD) (1; 1%), congenital anomalies of the kidney and urinary tract (CAKUT) (1; 1%), and other conditions (5; 4%).
The concordance between the pre-genetic diagnosis and GS result was 52% (N = 61). It led to a change in diagnosis in 48% of patients (N = 56); both positive and exclusionary results had an impact on clinical management in 83% (N = 98), and it resulted in a change in treatment in 20% (N = 24).

Conclusion
Genetic studies allow us to trace the origin of the kidney disease, providing a fundamental diagnostic tool. According to the literature, the most frequently diagnosed variants were those related to Alport syndrome, renal polycystic disease (with PKD1 being the most common), and mutations associated with complement pathway pathology. The implications and diagnostic changes brought about by genetic studies justify their implementation. In some cases, they also reclassify the kidney disease in our patients, enabling access to specific treatments.