Rare Kidney Diseases in Children: Challenges Encountered from a Global Perspective

Rare or orphan kidney diseases are a complex group of disorders characterized by low prevalence, resulting from a genetic or metabolic etiology leading to chronic debilitation, morbidity, or death. A disease is recognized as rare by the World Health Organization if one among 1000 individuals is affected. With more than 150 rare kidney diseases identified, a majority seen in childhood, the burden of 60–80 cases per 100,000 population has been observed in Europe and the United States.1,2 A position statement from Southern Africa reports one in 15 people to have a rare disease and provides policies on health care services for rare diseases.3 A policy call to address the challenges hindering the provision of targeted care for rare kidney diseases has been recently published.4 The European Renal Association-European Dialysis and Transplantation Association registry reveals that every three out of five children undergoing KRT suffer from kidney failure due to a rare kidney disease.5 The burden of rare kidney diseases in low middle-income countries (LMICs), consisting of about 132 countries, is not well reported. In our experience, rare kidney diseases contribute to a similar proportion of children with kidney failure and underscores the fact that rare kidney diseases are not so rare after all (Box 1).

Box 1 Clinical scenarios of rare kidney diseases in under-resourced settings. A 3-year-old boy, symptomatic since infancy, was diagnosed to have cystinosis when corneal crystals were noted on slit-lamp examination. White blood cell cystine level measurement was not available, and the family could not afford genetic testing. Cysteamine in any form was not available, and the child progressed to kidney failure. Transplantation was undertaken with a high risk of long-term morbidity. A 2-year-old girl presented with kidney failure needing urgent dialysis. Evaluation revealed bilateral dense nephrocalcinosis. Genetic analysis confirmed primary hyperoxaluria type 1. The child has remained on dialysis for the last 6 years, with no access to combined liver–kidney transplantation or lumasiran. A 12-year-old girl presented with atypical hemolytic uremic syndrome. Despite plasma exchange, the kidney disease progressed. The family could not access antibody testing, genetic analysis, or eculizumab.

Despite the recent advances in rare kidney disease diagnostic methods, genetic testing, and innovative disease-modifying drug discovery, key challenges like clinical heterogeneity, suboptimal genetic literacy, CKD progression, and lack of integrated patient support exist globally.2 The management of children with rare kidney diseases in high-income countries is fraught with significant challenges in accessing diagnostic testing and expensive treatments. However, the obstacles in LMICs are considerably larger and sometimes unsurmountable. We highlight the unique challenges encountered in managing diseases like nephropathic cystinosis, X-linked hypophosphatemic rickets, primary hyperoxaluria type 1, and atypical hemolytic uremic syndrome in under-resourced settings.

Inequities in Access to Specialized Kidney Care and Diagnostic Testing

A key challenge of rare kidney diseases in LMICs is a delay in diagnosis with few or nonexistent pediatric nephrology centers, requiring patients to travel great distances. Even in large pediatric nephrology centers, definitive diagnostic tests for atypical hemolytic uremic syndrome (aHUS), cystinosis, X linked-hypophosphatemic rickets, and primary hyperoxaluria type 1 are not available, and diagnoses are made on the basis of clinical manifestations, resulting in uncertainty. The accessibility of genetic testing is poor, either unavailable or too expensive to pay for out of pocket.

Inequitable Access to Specific Therapies

The more serious challenge in managing rare kidney diseases in under-resourced settings is the inaccessibility of treatments proven to improve patient outcomes. Managing cystinosis without cysteamine preparations results in early deterioration of kidney function and rapid onset of all its comorbidities. Monoclonal antibodies inhibiting C5 complement protein (eculizumab and ravulizumab) for aHUS, burosumab, a monoclonal antibody recommended for X-linked hypophosphatemic rickets, and lumasiran and nidosiran as double-stranded RNA-mediated interference (RNAi) therapies for primary hyperoxaluria type 1 are promising medications but out of reach to children in LMICs because of the exorbitant cost. A combined liver and kidney transplant in patients with primary hyperoxaluria type 1 requires a well-established transplant program, a rarity in most LMICs. Challenges in procuring therapies for rare kidney diseases in the LMIC context arise at the level of medical fraternity, industry, parents, and regulatory bodies as depicted in Figure 1.

Figure 1:

Challenges in procuring orphan drugs in resource-constrained settings. *When pharmaceutical companies are not licensed to manufacture treatments for rare kidney diseases, the inflated costs of paying for the drug in a foreign currency and the complicated logistics of importing the drug deny patient access to essential therapy. The unwillingness of pharma companies to invest in LMICs where profitability remains uncertain and the poor support from public health care systems to encourage local drug production results in vastly inequitable patient outcomes. LMIC, low middle-income country.

Ethical Approach to Rare Kidney Diseases in Children: Principles of Justice and Solidarity

The inaccessibility of rare kidney disease therapies in low-resource settings may be viewed as an injustice to patients, families, and physicians. Inequitable access to efficacious, disease-modifying rare kidney disease treatments based on country of residence and a family's ability to pay results in unfairly different outcomes—greater morbidity, the denial of a childhood, and a greater burden on caregivers. When pediatric nephrologists are certain about the required treatment but cannot pursue it because of systemic inequity on a national or global scale, moral distress occurs. Watching patients with rare kidney diseases suffer greater morbidity and mortality because of the lack of access to effective treatments is demoralizing. Beyond seeking to improve inherent injustices, we must recognize that the burden of society's failures falling predominantly on those considered socially vulnerable (children or the poor) is morally unacceptable.6,7

From a health economics perspective, pharmaceutical companies view investment in rare kidney disease drug manufacturing as risky because of low patient numbers and sales and unlikely profitability. Rare kidney disease registries are nonexistent, and patient numbers cannot be reliably assessed. In LMICs, budgeting large resources for rare kidney diseases is deemed a low priority when viewed from a utilitarian perspective of maximizing public health by achieving cost-effectiveness.8 This dilemma highlights the pressing need for global advocacy among our nephrology community to promote special case status for rare kidney diseases valuing each life, regardless of the prevalence of their disease. The principle of solidarity in biomedical ethics implies a collective commitment to carry costs (financial, social, or emotional burdens) to assist others.9 As nephrologists, we must consider all stakeholders—patients and families, allied health care providers, diagnostic laboratories, the pharmaceutical and biotechnology industry, government regulatory bodies, nonprofit organizations, health insurance providers, and scientists—as a team committed to addressing the inequities in rare kidney disease therapy.

Efforts to Improve Rare Kidney Disease Outcomes in Low-Resource Settings

Efforts from the Indian government include the launch of a national policy for rare disease in 2021 to strengthen tertiary health care facilities for prevention and treatment of rare diseases (https://rarediseases.mohfw.gov.in/uploads/Content/1624967837_Final-NPRD-2021.pdf). The Organization for Rare Diseases India is a not-for-profit organization set up to represent collective voices of all stakeholders in improving health of the patients with rare diseases in India.10 Similar policy recommendations for rare kidney diseases have been laid out for the Southern African and Brazilian regions.3

Further Strategies to Mitigate Inequities in Access to Rare Kidney Disease Therapies Improving awareness of rare kidney diseases by training clinicians to recognize rare kidney diseases, referring to research sites like Online Mendelian Inheritance in Man and initiating open-access patient registries. Enhancing access to diagnostic testing for rare kidney diseases by advocating for low-cost or free genetic testing, training clinicians to interpret genetic analysis reports, and encouraging the development of innovative clinical tests to monitor patients with rare kidney diseases. Joint advocacy efforts by stakeholders to partner with governments and pharmaceutical industries to license rare kidney disease drugs manufacture in LMICs and to regulate drug prices and resource allocation. Professional societies and the medical fraternity need to spearhead and coordinate these efforts. Building strong patient support organizations on a national level in LMICs whose advocacy efforts are supported, nurtured, and advised by well-established patient organizations in high-income countries. Fundraising to pay for rare kidney disease drugs by lobbying insurance to cover rare kidney disease therapies, leveraging community altruism through crowd-funding platforms, corporate social responsibility funds, and fundraising community drives. Research and innovation by supporting scientist research on rare kidney disease focused on innovative solutions for lower-resourced countries with aid from international nephrology societies' grant funds. Negotiating with pharma companies through transnational organizations to ensure that pursuit of profit using the sale of popular medical products is balanced by the sustained production of orphan drugs, at a reasonable price to ensure accessibility in low-resource settings.

Children with rare kidney diseases have serious morbidity and require lifelong treatment. From a global perspective, the most significant challenge in treating these patients is the inequitable access to specific, disease-modifying therapies. It is imperative that children with rare kidney diseases from LMICs do not get left out in the cold.

Disclosures

A. Iyengar reports advisory or leadership roles as a member of the Editorial Boards for Frontiers in Pediatrics and Peritoneal Dialysis International, an Associate Editor for Indian Journal of Nephrology, and Chair of the Mentorship Program of the International Society of Nephrology and reports other interests or relationships as a member of the IPNA, IPTA, ISN, ISRNM, TTS, and WIN. P. Pais reports serving on the following committees of international societies: IPNA—Sister Renal Centre Committee and IPTA—Outreach Committee. These positions are not paid. All remaining authors have nothing to disclose.

Funding

None.

Acknowledgments

The authors would like to acknowledge Valerie Luyckx, MBBCh, MSc, PhD, Department of Nephrology, University Children's Hospital University of Zurich, Zurich, Switzerland, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, Department of Pediatrics and Child Health, University of Cape Town, Cape Town, South Africa; and Aaron Wightman, MD, MA, Associate Professor Paediatrics—Bioethics and Palliative Care, University of Washington School of Medicine Seattle Children's Hospital. Treuman Katz Centre for Paediatric Bioethics and Palliative Care. The content of this article reflects the personal experience and views of the authors and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or CJASN. Responsibility for the information and views expressed herein lies entirely with the authors.

Author Contributions

Conceptualization: Arpana Iyengar, Priya Pais.

Writing – original draft: Arpana Iyengar, Priya Pais.

Writing – review & editing: Ali A. Lanewala, Prasanna B. Shirol.

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