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Introduction
The management of focal segmental glomerulosclerosis (FSGS) is challenging, and a definitive long-term cure remains elusive. It is associated with poor outcomes due to underlying irreversible glomerular fibrosis, scarring, different degrees of interstitial injury, and a variable rate of chronic kidney disease (CKD) progression [1, 2]. In non-genetic primary FSGS, complete or partial remission (CR or PR) of proteinuria is associated with a better prognosis, with 90% kidney survival at 5 years follow-up. Conversely, approximately 50% of non-responders have kidney failure (KF) by 5 years [1]. Thus, the challenge is to provide optimal therapy to all affected children with the aim of achieving proteinuria remission and thereby improving short-term morbidities and long-term outcomes.
SRNS is a clinical problem for all pediatric nephrologists, with FSGS constituting up to 20% of children presenting with nephrotic syndrome (NS) and 10 to 15% of pediatric KF [3]. There is significant ethnic and geographic variability in the pattern of steroid responsiveness in NS, with higher steroid resistance in African Americans in the USA and in resource-limited regions such as South Africa and Pakistan [4]. An increased prevalence of familial FSGS was reported in a Jordanian cohort with a high rate of progression to KF [5]. Whether the higher steroid resistance reported in many low-resource regions is secondary to a higher prevalence of genetic causes is unclear as there is limited accessibility to genetic studies in most low- and lower-middle-income (LLMIC) countries [6].
Roughly, 1/3 of patients with primary FSGS may have proteinuria remission with steroid courses and renin-angiotensin system inhibitors (RASi), without the addition of other immunosuppressives (IS) [1, 7]. The recent IPNA evidence-based guidelines for steroid-resistant (SR) NS recommend that, if available, genetic testing should be performed in all children diagnosed with primary SRNS, even before a kidney biopsy. In addition, secondary causes should be excluded, and a renal biopsy is indicated, except in known infection or malignancy-associated secondary disease or if a genetic cause is identified. After diagnostic evaluation, it is recommended to initiate RASi therapy and treatment with calcineurin inhibitor (CNI) for at least 6 months. Cyclophosphamide (CP) is suggested as an alternative first-line IS in low-resource settings if CNI is unavailable [8]. Other IS agents used in non-responders include mycophenolate mofetil (MMF) and rituximab (RTX).
Despite multiple trials and guidelines, several challenges in managing primary FSGS remain. At onset, it is difficult to predict response to IS, and the best options for long-term therapy and benefits for kidney survival remain unknown for the individual patient [9]. In addition, many of the drugs used and their monitoring are expensive, associated with adverse effects, and unavailable in many resource-challenged settings.
The setting of the study by Priyanka et al.
This retrospective study [10] was performed in a tertiary care center in India, an LMIC as per World Bank classification [11]. The country has significant diversity in per family income, with a Gini (inequality) coefficient of 34.2 in 2024 [12]. Families from higher socio-economic groups have access to private health care and are often supported by employers or subscribe to health insurance. For patients of lower socio-economic groups, government hospitals, trust-run charitable institutions, and several national and state government schemes are available that subsidize or fund several aspects of management and medications. However, pediatric nephrology facilities usually exist only in tertiary-level institutes based in metro cities. Lack of awareness and inability to avail existing support options, distances and expenses associated with travel to the medical unit, and the loss of caregiver work hours and income for clinic attendance and monitoring requirements, all remain barriers to optimal care.
In this study, Priyanka et al. report on outcomes in patients with biopsy-proven FSGS, biopsy material being screened by light microscopy (LM), and immunofluorescence (IF). While LM and IF are readily available in Indian pediatric nephrology units, only a few centers nationwide have electron microscopy facilities, and therefore the latter are used sparingly. Genetic tests similarly are available, but due to cost implications, were only performed in selected patients with high risk in this study, i.e., those in whom the disease was familial, associated with extra-renal features, and if there was steroid plus CNI-resistance, as per the Indian SRNS guidelines [13]. Approximately 14% of patients were initially treated with intravenous CP rather than CNI due to its unavailability or financial issues. The clinicians were able to perform and maintain adequate CNI levels in those that did receive them. Drug level monitoring was funded by the institute in this case, and otherwise, is often funded by the drug manufacturers/suppliers. The easy availability of good quality generic agents also reduces costs to some extent [14, 15]. With these limitations, the authors achieved CR/PR rates similar to those from other regions, while CKD rates at 4 years were higher than high-income group countries (HIC).
Relevance and generalizability to other under-resourced regions
The management of FSGS in LLMIC may face several limitations, even exceeding those faced by Priyanka et al. A recent survey revealed that, while 88% of the pediatric nephrology centers in under-resourced areas have kidney pathology services available, the analysis of the biopsy is often restricted to just LM, which significantly limits its value for excluding several primary kidney diseases [6, 16].
In the same survey, genetic studies were available to only 26% of centers [6]. The underlying logic of controlling expense by restricting genetic studies to high-risk patients is that monogenic NS is unlikely to respond to IS [13]. Whether PR may also be considered exempt from need for genetic assessment is unclear since medications like CNIs, RTX, and RASi may act by non-immune mechanisms to reduce proteinuria to some extent [7, 17]. The unavoidable problem here is of potential months of unindicated toxic IS use in undetected monogenic disease. Furthermore, in patients who do not respond and progress to KF, genetic testing provides valuable guidance to the transplant team and the family in the process of decision making [18].
With a gross national income per capita below $4465 USD in LLMICs [11], even medications such as prednisone, generally considered low-cost, may be inaccessible where governmental support is limited or absent. Medications used in SDNS and SRNS, like CNIs, MMF, and RTX, are even more expensive, and guidelines for frequency of monitoring and drug levels may be difficult to follow. Successful strategies that have been used to decrease costs include adding an inexpensive drug like ketoconazole to inhibit the metabolism of cyclosporine. This has been shown to reduce the cost of treatment by more than 50% without increasing adverse events or the need for drug monitoring [19, 20]. Guidelines have suggested the use of CP as an alternative to CNI as the first line in SRNS [8, 13]; however, previous reports as well as the current study show lower rates of response compared to CNI [10, 21, 22]. Delaying or not being able to provide optimum IS may worsen outcomes in regions where the options of effectively managing complications of persistent proteinuria, CKD, and KF are limited.
Future directions
Primary non-genetic FSGS is a heterogeneous disease as is clinically evidenced by different responses to IS and recurrence after kidney transplantation in some patients but not all. Ongoing research may help to differentiate between clinico-pathological entities and allow better tailoring of management, thereby avoiding toxic medications in cases where they are unlikely to be effective, and streamlining resources to target cases where there is a good chance of response [2, 23]. A host of therapies ranging from new IS agents, biological therapies, and extracorporeal treatments to non-specific anti-proteinuric, anti-inflammatory and antifibrotic agents are under investigation and may in the future contribute to improving the long-term kidney survival and effect a cure [23]. In parallel, increased manufacture and availability of quality-controlled generics and biosimilars may reduce costs [24].
Unfortunately, to date, many therapeutic agents and diagnostic tools are not available to children living in non-HIC, or are too expensive, necessitating adaptations in their use which may lead to sub-optimal interventions and outcomes. Access to medications is lowest in non-tertiary community settings where close to 70% report poor access to all medications [25]. Lack of government funding is identified as the major barrier to medication access. Publicly funded treatment for non-dialysis CKD is much lower in LLMIC, with exclusive use of private and out-of-pocket payment methods in 20% of LICs and 9% of LMICs [26]. Moreover, the WHO Model List of Essential Medicines for Children published in 2023 does not have a section on drugs for kidney disease. Of the drugs frequently used to treat FSGS, cyclosporine, and tacrolimus only are included in Sect. 8.1 as immunomodulators for non-malignant disease. Cyclophosphamide and RTX are listed but with cancer as the only indication. The international pediatric nephrology community needs to keep raising awareness of these deficiencies at global, regional, and national levels. FSGS management should be a particular area of interest for advocacy as a response to effective treatment is associated with significantly improved outcomes.
Conclusions
In the last three decades, the increasing availability of a large number of IS and biological agents has improved the prognosis of patients with primary non-genetic FSGS. Further research into more precise phenotyping to guide therapy, as well as less expensive and less toxic therapeutic agents will hopefully continue to improve outcomes in this difficult condition. However, we cannot ignore the fact many children with primary FSGS living in non-HIC are unable to receive what is considered current optimal therapy. It is our responsibility to develop strategies that will ensure that all children can benefit from recent scientific advances. Although efforts have been made to raise awareness of kidney disease, the fact that most medications used for the treatment of glomerular diseases, including FSGS, are not included in the WHO list of essential medicines is evidence that we need to continue increasing our advocacy efforts [27].
References
Sethna CB, Gipson DS (2014) Treatment of FSGS in children. Adv Chronic Kidney Dis 21:194–199. https://doi.org/10.1053/j.ackd.2014.01.010
VincentiF AA, Ghiggeri GM (2023) State of the art in childhood nephrotic syndrome: concrete discoveries and unmet needs. Front Immunol 14:1167741. https://doi.org/10.3389/fimmu.2023.1167741
Gipson DS, Troost JP, Spino C et al (2022) Comparing kidney health outcomes in children, adolescents, and adults with focal segmental glomerulosclerosis. JAMA Netw Open 5:e2228701. https://doi.org/10.1001/jamanetworkopen.2022.28701
Chanchlani R, Parekh RS (2016) Ethnic differences in childhood nephrotic syndrome. Front Pediatr 4:39. https://doi.org/10.3389/fped.2016.00039
Almardini RI, Albaramki JH, Al-Saliata GM et al (2018) Pediatric focal segmental glomerulosclerosis in Jordan: a tertiary hospital experience. Saudi J Kidney Dis Transpl 29:816–821. https://doi.org/10.4103/1319-2442.239655
Banerjee S, Kamath N, Antwi S, Bonilla-Felix M (2022) Paediatric nephrology in under-resourced areas. Pediatr Nephrol 37:959–972. https://doi.org/10.1007/s00467-021-05059-y
Trautmann A, Seide S, Lipska-Ziętkiewicz BS et al (2023) Outcomes of steroid-resistant nephrotic syndrome in children not treated with intensified immunosuppression. Pediatr Nephrol 38:1499–1511. https://doi.org/10.1007/s00467-022-05762-4
Trautmann A, Vivarelli M, Samuel S et al (2020) IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 35:1529–1561. https://doi.org/10.1007/s00467-020-04519-1
Caster DJ, Magalhaes B, Pennese N et al (2022) Efficacy and safety of immunosuppressive therapy in primary focal segmental glomerulosclerosis: a systematic review and meta-analysis. Kidney Med 4:100501. https://doi.org/10.1016/j.xkme.2022.100501
Priyanka K, Deepthi B, Krishnasamy S et al (2024) Kidney outcomes in children with primary focal segmental glomerulosclerosis from a low- and middle- income country. Pediatr Nephrol. https://doi.org/10.1007/s00467-024-06382-w
World bank country and lending groups (2024) https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groups. Accessed 1 June 2024
Gini coefficient by country (2024) https://worldpopulationreview.com/country-rankings/gini-coefficient-by-country. Accessed 1 June 2024
Vasudevan A, Thergaonkar R, Mantan M et al (2021) Consensus guidelines on management of steroid-resistant nephrotic syndrome. Indian Pediatr 58:650–666
Medeiros M, Lumini J, Stern N et al (2018) Generic immunosuppressants. Pediatr Nephrol 33:1123–1131. https://doi.org/10.1007/s00467-017-3735-z
Socal MP, Cordeiro T, Anderson GF, Bai G (2022) Estimating savings opportunities from therapeutic substitutions of high-cost generic medications. JAMA Netw Open 5:e2239868. https://doi.org/10.1001/jamanetworkopen.2022.39868
Davis J, Tjipto A, Hegerty K, Mallett A (2019) The use of electron microscopy in the diagnosis of focal segmental glomerulosclerosis: are current pathological techniques missing important abnormalities in the glomerular basement membrane? F1000Res 8:1204. https://doi.org/10.12688/f1000research.19997.2
Büscher A, Beck BB, Melk A et al (2016) Rapid response to cyclosporin A and favorable renal outcome in nongenetic versus genetic steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 11:245–253. https://doi.org/10.2215/CJN.07370715
Sinha R, Sarkar S, Mandal K, Tse Y (2021) Uptake of next-generation sequencing in children with end-stage renal disease secondary to focal segmental glomerulosclerosis and parental decision for kidney transplantation-experience from a low resource setting: a retrospective cohort study. Pediatr Transplant 25:e13960. https://doi.org/10.1111/petr.13960
Iyengar A, Kamath N, Phadke KD, Bitzan M (2013) Cyclosporine/ketoconazole reduces treatment costs for nephrotic syndrome. Indian J Nephrol 23:419–423. https://doi.org/10.4103/0971-4065.120338
El-Husseini A, El-Basuony F, Mahmoud I et al (2006) Impact of the cyclosporine-ketoconazole interaction in children with steroid-dependent idiopathic nephrotic syndrome. Eur J Clin Pharmacol 62:3–8. https://doi.org/10.1007/s00228-005-0064-0
Liu ID, Willis NS, Craig JC (2019) Hodson EM (2019) Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev 11:CD003594. https://doi.org/10.1002/14651858.CD003594.pub6
Trautmann A, Bodria M, Ozaltin F et al (2015) Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort. Clin J Am Soc Nephrol 10:592–600. https://doi.org/10.2215/CJN.06260614
de Cos M, Meliambro K, Campbell KN (2022) Novel treatment paradigms: focal segmental glomerulosclerosis [published correction appears in Kidney Int Rep. 2023 8:949]. Kidney Int Rep 8:30–35. https://doi.org/10.1016/j.ekir.2022.10.004
Becker C (2022) Decreasing drug costs through generics and biosimilars. https://www.ncsl.org/health/decreasing-drug-costs-through-generics-and-biosimilars. Accessed 2 June 2024
Francis A, Abdul Hafidz MI, Ekrikpo UE et al (2022) Barriers to accessing essential medicines for kidney disease in low- and lower middle-income countries. Kidney Int 102:969–973. https://doi.org/10.1016/j.kint.2022.07.029
Bello AK, Okpechi IG, Levin A et al (2023) ISN–Global Kidney Health Atlas: a report by the International Society of Nephrology: an Assessment of Global Kidney Health Care Status focussing on capacity, availability, accessibility, affordability and outcomes of kidney disease. International Society of Nephrology, Brussels, Belgium. https://www.theisn.org/initiatives/global-kidney-health-atlas/. Accessed May 2024
Web Annex B. World Health Organization Model List of Essential Medicines for Children – 9th List (2023) In: The selection and use of essential medicines 2023: Executive summary of the report of the 24th WHO Expert Committee on the Selection and Use of Essential Medicines 24 – 28 April 2023. Geneva: World Health Organization; 2023 (WHO/MHP/HPS/EML/2023.03) https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2023.03/. Accessed May 2024
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Banerjee, S., Bonilla-Felix, M. Management of focal segmental glomerulosclerosis in resource-limited regions. Pediatr Nephrol (2024). https://doi.org/10.1007/s00467-024-06430-5
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DOI: https://doi.org/10.1007/s00467-024-06430-5