Genetic testing to the rescue: a case-based call to establish genetic units in nephrology centers across a medium-low income country. Lesson for the clinical nephrologist

A 30-year-old woman, mother of three children, with an unremarkable medical history, presented to our Nephrology department in Mansoura, Egypt, with acute-onset nephrotic syndrome. The initial workup revealed negative serology for the main immunologic and infectious causes, and a percutaneous kidney biopsy revealed focal segmental glomerulosclerosis (FSGS). Genetic testing was not available. She was initially managed with conservative antiproteinuric therapy and high-dose oral corticosteroids for 16 weeks without achieving remission. Steroids were gradually tapered, and cyclosporine was initiated with therapeutic trough level monitoring. Despite 6 months of therapy, she experienced recurrent hospitalizations for cyclosporin-associated acute kidney injury, and proteinuria persisted. Cyclosporine was therefore withdrawn, and she was started on mycophenolate mofetil (MMF), titrated up to 2 g/day for 8 months. Once more, remission was not achieved, and her clinical course was complicated by severe pneumonia requiring hospitalization. Following recovery from pneumonia, she received two doses of rituximab, yet proteinuria persisted and progressive kidney dysfunction developed. Over three years of immunosuppression and after multiple complications, she eventually developed kidney failure and is currently maintained on chronic hemodialysis. Table 1 illustrates a comparison of the 3-year cumulative cost of sequential immunosuppressive therapy versus early genetic testing (if it had been performed) in the index patient. Comparison of 3-year cumulative cost of sequential immunosuppressive therapy versus early genetic testing in the index patient. Abbreviations: AKI, acute kidney injury; ICU, intensive care unit; N/A, not applicable. a This value represents the estimated cumulative total cost over a 3-year follow-up period, combining direct drug costs and major complication-related healthcare expenditures (hospital admissions, ICU stay, and management of drug-related adverse events). Costs are presented as approximate estimates in USD/EGP, based on local pricing and institutional billing data at the time of treatment. Comparison of 3-year cumulative cost of sequential immunosuppressive therapy versus early genetic testing in the index patient. Abbreviations: AKI, acute kidney injury; ICU, intensive care unit; N/A, not applicable. a This value represents the estimated cumulative total cost over a 3-year follow-up period, combining direct drug costs and major complication-related healthcare expenditures (hospital admissions, ICU stay, and management of drug-related adverse events). Costs are presented as approximate estimates in USD/EGP, based on local pricing and institutional billing data at the time of treatment. Genetic assessment has emerged as the fundamental blueprint for many kidney disorders. Several glomerular, tubular, and cystic diseases are now acknowledged to have a hereditary basis, yet they may present with variable or atypical phenotypes that delay or complicate definitive diagnosis and, genetic testing is increasingly used as an essential tool to establish an accurate diagnosis and guide management.1 Genetic testing has a significant diagnostic yield, in particular in nephrotic syndrome, nephrolithiasis, congenital, and cystic kidney diseases.2 Comprehensive panels analyzing kidney-related genes are now widely available for prices from less than $500 US Dollars, often including genetic counseling, making them increasingly accessible in diverse clinical settings.3 Given its low cost, high sensitivity, and ability to sequence multiple genes in parallel, next-generation sequencing (NGS) has become the preferred approach. Kidney gene panels may be phenotype-specific (eg, nephrotic syndrome) or fixed, covering a broad range of kidney-related disorders.4 Currently, over 3900 genes have been linked to monogenic disorders, with more than 600 being specifically associated with kidney or urologic diseases.5 In low- and middle-income countries (LMICs), implementation of genetic testing is hindered by insufficient infrastructure and technological capacity. In an African survey, 81% of respondents identified lack of infrastructure as the greatest barrier, followed by limited data on disease susceptibility in local populations, and inadequate genetics-focused education for the health care teams. Other barriers include low prioritization of genetic testing and concerns regarding cost-effectiveness and equitable access.6 Through this case we argue that the upfront investment in establishing genetic laboratories, or at least finding pathways for early genetic analysis, is not a luxury but a cost-saving necessity. Early and accurate genetic diagnosis allows for precision medicine, avoids years of futile treatment, and reduces healthcare expenditures, making the case for urgent implementation of genomic medicine in LMICs like Egypt. Our patient presented with steroid-resistant FSGS. Despite sequential therapy with high-dose corticosteroids, calcineurin inhibitors, mycophenolate mofetil, and rituximab, she failed to achieve remission and suffered multiple drug-related complications. The clinical course, characterized by persistent proteinuria and multi-drug resistance, strongly suggested an underlying genetic form of FSGS. Early access to genetic testing could have established this diagnosis promptly, sparing the patient years of futile immunosuppression, avoiding preventable adverse effects, and substantially reducing healthcare costs. It is important to emphasize that identifying a genetic form of FSGS does not imply that patients should remain untreated. Genetic FSGS is primarily managed with conservative measures aimed at reducing proteinuria and controlling the complications of nephrotic syndrome. A brief initial trial of immunosuppression may be considered while awaiting genetic results, and low dose calcineurin inhibitors may be used for their antiproteinuric effect. However, once a genetic etiology is confirmed, there may be no justification for escalating immunosuppressive regimens, as these are unlikely to induce remission while exposing patients to avoidable toxicity and financial burden. Steroid-resistant FSGS is a prototypical example of monogenic kidney disorders. Recent advances revealed that histopathological lesions such as FSGS, minimal change disease, or collapsing glomerulopathy are not distinct diseases per se, but rather nonspecific patterns of podocyte injury. Pathogenic variants causing podocytopathies are currently identified in approximately 30% of patients with steroid-resistant nephrotic syndrome (SRNS).7 In a recent Egyptian cohort, genome sequencing revealed 24 variants in SRNS-related genes, including nine novel mutations in NPHS1, NPHS2, COL4A3, MYO1E, NUP93, PLCE1, PODXL, SMARCAL1, and WT1. Overall, disease-causing variants were detected in 56% of families, with NPHS2 being the most frequently affected gene, followed by NPHS1, WT1, and SMARCAL1.8 Genetic confirmation also informs kidney transplant planning by guiding donor selection, predicting recurrence risk, and facilitating preemptive transplantation. By shortening the diagnostic odyssey and enabling precision treatment, genetic testing ultimately improves patient outcomes and optimizes healthcare resource utilization.9 Table 1 highlights the stark contrast between the cumulative costs of prolonged empirical immunosuppressive therapy and early implementation of genetic testing. Over 3 years, our patient incurred more than $2000 US (≈96 000 EGP) in direct medication costs, in addition to over $1600 US (≈80 000 EGP) in expenses related to treatment complications, including hospitalizations and ICU admission. In comparison, an early comprehensive genetic panel would have cost approximately $410 US (≈20 000 EGP), providing a definitive diagnosis and potentially eliminating the need for years of ineffective and toxic therapy. This case, still unsolved from the point of view of genetic testing, represents a strong call to action for establishing dedicated pathways for genetic testing and ideally genetic units linked to every nephrology center, ensuring timely access to genetic testing, counseling, and precision management, and ultimately transforming the care of hereditary kidney disease in Egypt as well as in other LMICs. None. Shimaa A. Shabaka: Conceptualization, Methodology, Literature search, Data curation, Formal analysis, Writing original draft, Review & editing, Visualization, and Final approval of the manuscript. This research received no specific grant from any funding agency in the public, commercial, or not for profit sectors. All data generated or analyzed are included in this published article. Not applicable, as this is a single case-based review and did not involve experimental protocols. All methods were carried out in accordance with relevant guidelines and regulations (Declaration of Helsinki). Written informed consent was obtained from the patient to participate with these data. Written informed consent was obtained from the patient for publication of this information. All identifying information has been removed to ensure anonymity.