Primary hyperoxaluria type 1 in developing countries: novel challenges in a new therapeutic era

ABSTRACT

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inborn error of metabolism characterized by marked hepatic overproduction of oxalate due to deficiency of hepatic peroxisomal alanine-glyoxylate aminotransferase caused by AGXT gene mutation. One major hallmark of PH1 in developed as well as developing countries (DC) is the diagnostic delay. Notably in DC, where the disease is most prevalent and probably underdiagnosed, there are many challenges in PH1 diagnosis and management, with economic constrains and ethical concerns. This has led to the existing gap in the management of PH1 between developed and DC, which is expected to further deepen with the advent of novel therapeutic agents unless appropriate actions are taken. Until recently, treatment possibilities were limited to supportive measures. Thanks to a better understanding of the molecular basis of the disease a number of new therapies are developed, or being developed, leading to profound changes in management strategies. In this review we discuss the current situation of PH1 in DC as well as the accessibility challenges and the advantages of using promising novel therapeutics to bridge the currently existing gap. We also provide an overview of an integrated approach to ensure equitable access of sustainable therapeutics to PH1 patients in DC. This is expected to reduce global PH1 healthcare disparities, improve its standard of care and reduce disability linked to extrarenal complications of PH1 by implementing personalized medicine.

INTRODUCTION

Primary hyperoxaluria type 1 (PH1) is the most frequent and severe form of primary hyperoxalurias, leading to end-stage renal disease (ESRD) and systemic organ damage [1–4]. The estimated disease prevalence ranges from 1–3 per million population [1, 5]. This prevalence is probably higher in inbred populations [1, 5, 6]. Scientific research has led, during the last few years, to major advances in the understanding as well as the management of the disease, with some promising options [7–12]. However, in developing countries (DC), where the disease is most prevalent, and probably underdiagnosed [6, 13–15], physicians as well as patients are still facing lots of challenges in terms of diagnosis, management, and economic and ethical aspects [13–19]. In this article we discuss the current situation in DC highlighting the paradox of the increasing difficulty of management while knowledge is progressing and therapeutic tools are improving. The challenges and opportunities associated with the use of novel therapeutics are also discussed.

Epidemiological perspective

The real burden of PH1 is still unknown; it has an estimated prevalence ranging from 1–3 per million population and an estimated incidence rate of 1:120 000 live births in Europe [1, 5]. In countries with high consanguinity rates, such as North African and Middle Eastern populations, the prevalence of the disease is clearly higher than Europe, the USA and Japan, and its real extent and burden remain largely unknown [13, 15, 20, 21]. The only available data emanate from isolated referral center reports and case series, with small numbers of patients [6, 13, 16, 22–25]. To get a better understanding of genotype–phenotype correlations in such populations, precise epidemiological data are needed. Creating national registries has been extremely useful to this end, and an invaluable tool in monitoring clinical course and outcome of PH1 patients while effectively managing the resources to improve patients’ outcome.

Diagnostic challenges

One major hallmark of PH1 in developed countries as well as DC is the diagnosis delay [3, 14, 26], with an average 5-year time interval from initial symptoms to diagnosis of PH1 [26]. In DC, PH1 is a real public health burden due to diagnosis delay and high rate of ESRD at diagnosis ranging from 27% to 65.4% [6, 22, 23]. Several factors, including the large phenotypic spectrum, the lack of awareness among physicians about the disease and the paucity of diagnostic tools, can explain this diagnosis delay. As a matter of fact, the medical curriculum does not include hyperoxaluria, which remains an unknown disease for many physicians, including pediatricians. Besides, molecular analysis, blood oxalate, urine oxalate, urine glycolate or even urine crystal examination are not easily accessible to all practitioners, as they may be available only in reference centers. To overcome the above hurdles, much effort is deployed to promote a high index of clinical suspicion among pediatricians, urologists, nephrologists and general practitioners. Patients should be screened for PH1: (i) at presentation of a first kidney stone in children, (ii) recurrent or familial stone disease at any age, (iii) nephrocalcinosis and (iv) renal failure of unknown cause, particularly in the presence of nephrocalcinosis and/or urolithiasis burden [2], and subsequently get timely referral to expert centers. Diagnostic strategies should be adapted according to local possibilities, and disease stage and characteristics [8, 24–26] with focus on simple tools such as urine crystal examination and urine oxalate. Also with the technological revolution in next generation sequencing (NGS), cheap and affordable genetic diagnosis and/or screening of PH1 in prevalent communities is now possible.

Therapeutic resources

Given the devastating nature of the disease when left untreated or improperly managed, DC are encouraged to act at two main levels to face the medical and societal burden of the disease:

1. Invest in awareness programs for early diagnosis of PH1 patients before renal and extrarenal complications ensue, thereby widening the therapeutic window for PH1 patients with preserved kidney function or moderate chronic kidney disease (CKD) stage while allowing identification of high-risk patients.

2. Explore the therapeutic options for PH1 patients who are diagnosed in an advanced CKD stage.

To date, only very few supportive measures are available for patients suffering from PH1, which, together with the severity of the disorder, renders disease management very challenging [7]. Conservative measures are the cornerstone of PH1 management that can prevent further stone formation and renal function loss [1, 2, 25]. These measures should be initiated as soon as the diagnosis is suspected [1, 2]. Patients should increase their daily water intake, which can be challenging in hot settings, as it requires huge quantities of water, up to 3–5 L/day, including overnight intake. This situation is particularly difficult among infants, which may require the use of nasogastric tube or gastrostomy, and is not easily accepted by the parents. In addition, pyridoxin and crystallization inhibitors may not be available in some countries or medical settings, which limits patients' access to these therapies. In that case, patients should be advised to resort to citrate- and pyridoxine–rich food. Health systems should consider focusing on such therapies, making them accessible to all patients, to prevent the progression to ESRD with subsequent additional costs, morbidity including disability and mortality risk [4].

PH1 accounts for 1–2% cases of pediatric ESRD according to registries from Europe, the USA and Japan [1, 4], however its prevalence is much higher in DC. PH1 is reported to cause 13–15% of pediatric ESRD in Tunisia [13, 27], 10.4% in Kuwait [19] and 16.7% in Jordan [21]. Intensive dialysis regimens with daily hemodialysis associated to peritoneal dialysis, are needed to remove calcium oxalate loads [1, 2, 4, 14]. Dialysis is not available in all resource-limited settings, and intensive strategies are often not possible in DC [28].

Until recently, simultaneous or sequential combined liver and kidney transplantation was considered as the sole therapeutic possibility for PH1 patients having reached advanced stages of CKD [1, 2, 27]. Access to organ transplantation, particularly liver transplantation, depends on the country's possibilities and is often difficult in DC [13, 17, 29, 30].

Interestingly, and despite the fact that PH1 is a rare disease, there has been a growing interest among researchers to develop new therapeutics to treat the devastating metabolic consequences of the disease. Novel treatment options are being developed and tested, including substrate-reduction therapies based on small-molecule inhibitors or the RNA interference (RNAi) technology, gene therapy, enzyme administration approaches, colonization with oxalate-degrading intestinal microorganisms and, in PH1, design of pharmacological chaperones [7, 8, 10, 11, 31]. In addition, some inexpensive molecules such as stiripentol, which targets hepatic lactate dehydrogenase (LDH), is another possibility of extending the PH1 therapeutic arsenal [32–34].

The growing body of novel results has led to the reconsideration of the transplantation strategies, particularly with the recent Food and Drug Administration approval of the first RNAi therapeutic agent for PH1 [12, 35]. With novel therapeutics using RNAi, liver transplantation will no longer be necessary. However, some patients with progressing renal disease or those who will be diagnosed with PH1 at an advanced CKD stage will ultimately need kidney transplantation [12]. Hopefully these therapies, if made available, will profoundly change the outcome of PH1 in DC where both intensive dialysis and complex transplantation procedures may not be possible. Thus, it is of prime importance to focus on early diagnosis and early supportive therapy to prevent ESRD occurrence.

Challenges in limited resource countries

There is an existing gap in the management of PH1 between developed and developing nations, particularly in infants [6, 36]. It is therefore crucial to improve academic knowledge on PH1 and enhance public and medical awareness to identify index PH1 patients. Subsequently, screening of siblings and at-risk families and antenatal screening will aid in early diagnosis of asymptomatic cases.

The last decade witnessed a therapeutic revolution as some promising, innovative therapeutic agents are in clinical development with preliminary data of significant efficacy in reducing the hepatic overproduction of oxalate, the real culprit behind the disease. Therefore, DC are experiencing novel challenges sailing into this uncharted territory. Notably, novel therapeutics are less complex than liver or combined liver and kidney transplantation, yet questions regarding accessibility and affordability remain to be answered. It is anticipated that the cost of PH1 novel medications will be unaffordable for resource-constrained health systems in DC, where PH1 is more prevalent (>10% in some North African and Middle Eastern nations). The high cost is expected to constitute a major barrier to access PH1 innovative therapeutic agents and to further deepen the existing management gap unless action is taken. Therefore, an integrated approach including, but not limited to, differential pricing and greater affordability is needed to overcome the key challenge of providing novel therapeutics to PH1 patients in DC. This approach will ensure access to game-changer novel therapeutics in DC, thereby reducing global PH1 healthcare disparities and disability. On the other hand, relatively affordable possible therapeutic options have been reported recently. The use of oral inhibitors to LDH as a potential therapeutic in PH1-afflicted patients remains to be confirmed [32–34]. The challenges and opportunities of using PH1 novel therapeutics in DC are illustrated in Figure 1.

Figure 1:

Challenges and opportunities of using novel therapeutics in DC.

Ethical concerns

Ethical concerns are a major issue related to PH1 in DC. As a matter of fact, infantile PH1 is particularly frequent in some DC, and infants often have ESRD at presentation [6, 30, 37]. The burden of the disease varies among different DC and consequently management plans and clinical outcome. This is mainly determined by the level of index of clinical suspicion of PH1 among health professionals, availability of affordable diagnostic tools as well as access to therapeutic resources including intensive dialysis regimens and transplantation strategies. This situation raises the issue of therapeutic withdrawal in the absence of curative treatment [14, 15]. However, given the new therapeutic advances, this option becomes questionable.

Antenatal diagnosis is another challenging ethical issue, mainly related to cultural convictions. Parental beliefs can be against pregnancy termination in case of a PH1-afflicted fetus [14, 15]. Hopefully, this evolving new era will dramatically change the perspective of PH1 from both the professional and patient/family point of view. The novel NGS technologies allowing cheap and easy genetic screening and antenatal diagnosis would be helpful in diagnosing index cases, at-risk screening and family planning. Moreover the expanding spectrum of potentially effective targeted therapeutics is expected to change the standard of care not only globally, but also in DC, where PH1 is more prevalent.

CONCLUSION

PH1 is an autosomal recessive inborn error of metabolism characterized by marked hepatic overproduction of oxalate. The novel therapeutic era has led to some promising, innovative therapeutic agents capable of reducing the hepatic overproduction of oxalate, the real culprit behind PH1. Therefore, DC are experiencing novel challenges sailing into the uncharted territory of novel therapeutics. Even though novel therapeutics are less complex than liver or combined liver and kidney transplantation, questions regarding accessibility and affordability remain to be answered. The high cost of PH1 novel medications is a major barrier to access these innovative therapeutics in DC. Nevertheless an integrated approach including, but not limited to, differential pricing and greater affordability is greatly needed to overcome this key challenge, thereby reducing global PH1 healthcare disparities. Equitable access to sustainable targeted therapeutics in the current precision medicine era is the cornerstone to favorably change the standard of care for PH1 in DC and to implementing personalized medicine.

FUNDING

This article was published as part of a supplement made possible by Alnylam Pharmaceuticals, Inc. Alnylam selected the Guest Editors for the supplement and agreed the educational objectives with them. The Guest Editors were solely responsible for determining the manuscript topics and the author selection.

CONFLICT OF INTEREST STATEMENT

N.A.S. declares no conflict of interest; S.M. was a coinvestigator of the ePHEX Study designed by OxThera ‘A phase III double-blind, randomised study to evaluate the long-term efficacy and safety of Oxabact’ from June 2019 to July 2021.