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Treatment of the primary hyperoxalurias: A new chapter
Abstract
Despite advances in the enzymology, molecular genetics, and clinical knowledge of the primary hyperoxalurias, few treatments are available. Oxalobacter formigenes is a promising new therapy with potential to induce secretion of oxalate into the intestinal lumen, where it can be degraded by the bacteria.
... Maintenance of sufficient oral or gastric tube fluid intake to maintain high urine volume and use of orally administered inhibitors of calcium oxalate crystal formation are key to minimizing stone formation and preserving kidney function. Both neutral phosphates [111] and citrate [112] reduce calcium oxalate crystal formation in PH. Since kidney outcome in PH has been shown to correlate with the degree of hyperoxaluria [111], reduction in urine oxalate excretion is the most effective treatment strategy. ...
... Both neutral phosphates [111] and citrate [112] reduce calcium oxalate crystal formation in PH. Since kidney outcome in PH has been shown to correlate with the degree of hyperoxaluria [111], reduction in urine oxalate excretion is the most effective treatment strategy. Restriction of dietary oxalate is of limited benefit since the overwhelming majority of oxalate in the urine of PH patients comes from hepatic production. ...
... The role of enteric elimination of oxalate has received considerable attention in recent years. There was optimism based on preliminary studies [111] that treatment with oral Oxalobacter formigenes might reduce oxalate absorption and/or promote its secretion into the intestinal lumen. However, a recent double blind, placebo-controlled clinical trial conducted in the U.S. and Europe failed to show benefit [113]. ...
Genetics plays an important role in establishing susceptibility to nephrolithiasis, although diet and other environmental factors make major contributions. In a small number of patients, the genetic causes of stones are more clearly established. Four of these hereditary diseases include primary hyperoxaluria, Dent disease, cystinuria, and adenine phosphoribosyltransferase deficiency, which results in 2,8-dihydroxyadenine stones. Patients with these disorders often experience recurring stones from early childhood, requiring frequent hospitalizations and procedures. They are at risk of kidney damage and chronic kidney disease. Because of their rarity, these four disorders are difficult to study and recognize. This in turn slows progress toward effective therapies and increases the risk of misdiagnosis or diagnosis late in the course of the disease. Therefore, patients may experience unnecessary and harmful treatments and accelerated loss of kidney function. In this article, we will review the pathogenesis, clinical presentation, diagnosis of and treatments for these four disorders.
... Maintenance of sufficient oral or gastric tube fluid intake to maintain high urine volume and use of orally administered inhibitors of calcium oxalate crystal formation are key to minimizing stone formation and preserving kidney function. Both neutral phosphates [111] and citrate [112] reduce calcium oxalate crystal formation in PH. Since kidney outcome in PH has been shown to correlate with the degree of hyper- oxaluria [111], reduction in urine oxalate excretion is the most effective treatment strategy. ...
... Both neutral phosphates [111] and citrate [112] reduce calcium oxalate crystal formation in PH. Since kidney outcome in PH has been shown to correlate with the degree of hyper- oxaluria [111], reduction in urine oxalate excretion is the most effective treatment strategy. Restriction of dietary oxalate is of limited benefit since the overwhelming majority of oxalate in the urine of PH patients comes from hepatic production. ...
... The role of enteric elimination of oxalate has received considerable attention in recent years. There was optimism based on preliminary studies [111] that treatment with oral Oxalobacter formigenes might reduce oxalate absorption and/or promote its secretion into the intestinal lumen. However, a recent double blind, placebo-controlled clinical trial conducted in the U.S. and Europe failed to show benefit [113]. ...
Adenine phosphoribosyltransferase (APRT) deficiency, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and primary hyperoxaluria (PH) are rare but important causes of severe kidney stone disease and/or chronic kidney disease in children. Recurrent kidney stone disease and nephrocalcinosis, particularly in pre-pubertal children, should alert the physician to the possibility of an inborn error of metabolism as the underlying cause. Unfortunately, the lack of recognition and knowledge of the five disorders has frequently resulted in an unacceptable delay in diagnosis and treatment, sometimes with grave consequences. A high index of suspicion coupled with early diagnosis may reduce or even prevent the serious long-term complications of these diseases. In this paper, we review the epidemiology, clinical features, diagnosis, treatment, and outcome of patients with APRT deficiency, cystinuria, Dent disease, FHHNC, and PH, with an emphasis on childhood manifestations.
... Treatment of primary hyperoxaluria is aimed at decreasing oxalate production and increasing urinary solubility of calcium oxalate. The following therapies have been advocated: Increasing fluid intake, pyridoxine, [77] orthophosphate, [78] magnesium oxide, potassium citrate, [79] and sodium citrate. However, in patients with progressive renal damage leading to failure, combined renal and liver transplantation are recommended. ...
... The role of enteric elimination of oxalate by treatment with oral Oxalobacter formigenes might reduce oxalate absorption and promote its secretion into the intestinal lumen. [78] However, a recent double blind, placebo controlled clinical trial conducted failed to show benefit. [80] 4.8. ...
Urolithiasis is a common multifactorial problem with multi-effect on the patients " quality of life and an economic burden on the individual and the health system of the country. Various intrinsic and extrinsic factors are associated with the risk for stone formation. Among intrinsic factors are race, sex, and genetics. Finding the cause of urolithiasis or establishing it early in life will reduce the consequence and complications of kidney stone disease and hence reduction of the cost in the treatment by establishing preventative measures in addition to patient education. Genetic factors play an important role in the etiology of urolithiasis as a polygenic (common) or monogenic (rare) forms, however its knowledge and early diagnosis is important to achieve the goals of reducing patient suffering and the economic burdens. This chapter entitled " Hereditary Kidney Stones " is devoted to understanding, early recognition, management and prevention of complications of hereditary urolithasis.
... It has been known for some time that 30-50% of patients with type I disease lower their urine oxalate in response to treatment with pyridoxine (vitamin B 6 ). Only in recent years has it become evident that it is the patient's genotype that dictates such response, seen only in those with the commonest mutant allele, G630A [36]. Pyridoxine is effective in individuals both homozygous and heterozygous for these alleles, though the specific mechanism of the vitamin's action under these circumstances is yet unknown. ...
... Pyridoxine is effective in individuals both homozygous and heterozygous for these alleles, though the specific mechanism of the vitamin's action under these circumstances is yet unknown. A novel approach to the treatment of hyperoxaluria might be achieved with oral intestinal colonization with Oxalobacter formigenes, which not only degrades intestinal oxalate but also enhances colonic secretion of endogenously produced oxalate, resulting in decreased blood and urine oxalate levels [36,37]. In patients who develop chronic renal failure and end-stage kidney disease, aggressive dialysis, followed by liver and kidney transplantation, is currently the best available approach. ...
In recent years the incidence of pediatric stone disease has increased several fold, mostly due to hypercalciuria and hypocitraturia. The goal of medical treatment is to protect the patient from formation of new stones and expansion of existing ones. The non-pharmacological means to address stone disease include high fluid intake and, frequently, modification of nutritional habits. The pharmacological treatment is based on the chemical composition of the stone and the biochemical abnormalities causing its formation; hence, chemical analysis of the stone, urine and blood is of paramount importance and should be done when the first stone is detected. This review discusses the current options of medical treatment of pediatric urolithiasis.
... The degradation of intestinal oxalate acts sinergystically with the colonic secretion, reducing blood and urine oxalate levels. [152][153][154] While animal studies have provided compelling evidence that colonization of the intestine with this bacteria reduces urinary oxalate excretion and lowers the risk of forming calcium oxalate kidney stones 155,156 , recent human studies did not acheive the same results. 157,158 As aforementionaded, absorptive hyperoxaluria may be idiopathic or secondary to malabsorptive disorders (small bowel resection, fat malabsorption, chronic diarrhea and pancreatic insufficiency). ...
There is evidence that over the past few decades pediatric urolithiasis has become more common. It affects children of all ages and is the end product of a multifactorial process. In industrialized countries 80-90% of the stones are composed of calcium oxalate, calcium phosphate or a mixture of both. The increased incidence and prevalence of urolithiasis are associated with considerable morbidity and high recurrence rates. The reasons for the
increased prevalence and incidence of urolithiasis are not completely clear, and have been attributed to climate changes, lifestyle changes, nutritional habits, and possibly other environmental factors.This review addresses an update on current management
and future directions of primary urolithiasis in childhood and adolescence. For the purpose of this review primary urolithiasis is defined as stone formation due an abnormality in urine biochemistry resulting from genetic, acquired or yet unknown etiology.
... Initial treatment aims at crystallization inhibition with potassium citrate, orthophosphate, and magnesium [65,68,69]. Since renal functional deterioration correlates with the degree of hyperoxaluria, reduction in urine oxalate excretion is the most effective treatment strategy [70]. Pyridoxine is the only pharmacologic agent that has been shown to reduce oxalate excretion; however, it is only effective in 10-30% of type 1 PH patients [34]. ...
Background
The incidence of nephrolithiasis in children and adolescents is increasing and appears to double every 10 years. The most important role of the pediatric nephrologist is to diagnose and modify various metabolic and non-metabolic risk factors, as well as prevent long-term complications especially in the case of recurrent nephrolithiasis.
Objective
The purpose of this review is to summarize the existing literature on the etiology and management of pediatric nephrolithiasis.
Results
The incidence of kidney stones is increasing; dietary and environmental factors are probably the main causes for this increased incidence. In most pediatric patients, the etiology for the kidney stones can be identified. Metabolic factors, such as hypercalciuria and hypocitraturia, urinary tract infection, and urinary stasis, constitute leading causes. Herein, we review the etiologies, diagnostic work-up, and treatment options for the most prevalent causes of kidney stones. The detrimental effects of excessive dietary sodium, reduced fluid intake, and the benefits of plant-based over animal-based protein consumption on urinary crystal formation are discussed. We also review the long-term complications.
Conclusions
Pediatric nephrologists have an important role in the diagnostic work-up and prevention of recurring nephrolithiasis.
... 13 Several novel molecular approaches to reduce toxic oxalate load have been proposed and are currently under investigation, including oxalate degrading enzyme therapy, correction of AGT mis-targeting and virally mediated AGXT gene therapies. [15][16][17][18][19][20][21][22][23] An alternate approach of substrate reduction, by which the production of glyoxylate is reduced through inhibition of glycolate oxidase (GO), can be a potentially effective therapeutic option. [24][25][26][27] Glycolate is a highly soluble small molecule and can be eliminated in the urine at high concentrations without inducing kidney damage or other toxicity. ...
Primary hyperoxalurias (PHs) are autosomal recessive disorders caused by the overproduction of oxalate leading to calcium oxalate precipitation in the kidney and eventually to end-stage renal disease. One promising strategy to treat PHs is to reduce the hepatic production of oxalate through substrate reduction therapy by inhibiting liver-specific glycolate oxidase (GO), which controls the conversion of glycolate to glyoxylate, the proposed main precursor to oxalate. Alternatively, diminishing the amount of hepatic lactate dehydrogenase (LDH) expression, the proposed key enzyme responsible for converting glyoxylate to oxalate, should directly prevent the accumulation of oxalate in PH patients. Using RNAi, we provide the first in vivo evidence in mammals to support LDH as the key enzyme responsible for converting glyoxylate to oxalate. In addition, we demonstrate that reduction of hepatic LDH achieves efficient oxalate reduction and prevents calcium oxalate crystal deposition in genetically engineered mouse models of PH types 1 (PH1) and 2 (PH2), as well as in chemically induced PH mouse models. Repression of hepatic LDH in mice did not cause any acute elevation of circulating liver enzymes, lactate acidosis, or exertional myopathy, suggesting further evaluation of liver-specific inhibition of LDH as a potential approach for treating PH1 and PH2 is warranted.
... 13 Several novel molecular approaches to reduce toxic oxalate load have been proposed and are currently under investigation, including oxalate degrading enzyme therapy, correction of AGT mis-targeting and virally-mediated AGXT gene therapies. [15][16][17][18][19][20][21][22][23] An alternate approach of substrate reduction, by which the production of glyoxylate is reduced through inhibition of glycolate oxidase (GO), can be a potentially effective therapeutic option. [24][25][26][27] Glycolate is a highly soluble small molecule and can be eliminated in the urine at high concentrations without inducing kidney damage or other toxicity. ...
Primary hyperoxaluria type 1 (PH1) is an autosomal recessive, metabolic disorder caused by mutations of alanine-glyoxylate aminotransferase (AGT), a key hepatic enzyme in the detoxification of glyoxylate arising from multiple normal metabolic pathways to glycine. Accumulation of glyoxylate, a precursor of oxalate, leads to the overproduction of oxalate in the liver, which accumulates to high levels in kidneys and urine. Crystalization of calcium oxalate (CaOx) in the kidney ultimately results in renal failure. Currently, the only treatment effective in reduction of oxalate production in patients who do not respond to high-dose vitamin B6 therapy is a combined liver/kidney transplant. We explored an alternative approach to prevent glyoxylate production using Dicer-substrate small interfering RNAs (DsiRNAs) targeting hydroxyacid oxidase 1 (HAO1) mRNA which encodes glycolate oxidase (GO), to reduce the hepatic conversion of glycolate to glyoxylate. This approach efficiently reduces GO mRNA and protein in the livers of mice and non-human primates. Reduction of hepatic GO leads to normalization of urine oxalate levels and reduces CaOx deposition in a preclinical mouse model of PH1. Our results support the use of DsiRNA to reduce liver GO levels as a potential therapeutic approach to treat PH1.Molecular Therapy (2016); doi:10.1038/mt.2016.4.
... 70 In patients with type 1 primary hyperoxaluria, recolonization with O. fomigenes after oral administration reduced urinary oxalate. 71 Hypocitraturia Defined as urinary excretion of less than 320 mg/d for adults, hypocitraturia occurs in 20-60% of patients with nephrolithiasis. 72 Citrate is the dissociated anion of citric acid synthesized in mitochondria and enters into the tricarboxylic acid cycle. ...
The incidence of nephrolithiasis has risen over the last twenty years and continues to rise. Although it is often referred to as a dis-ease, recent advances in the understanding of the pathophysiology suggest that it is a sys-temic disorder. We conducted a PubMed based literature review on the recent advances in the pathophysiology of kidney stone formation. There is a link between diabetes, metabolic syndrome, obesity, insulin resistance and nephrolithiasis. Along with the aging popula-tion and a Western diet, these are the main reasons for the rising incidence and preva-lence of nephrolithiasis. Different theories as to the pathophysiological mechanisms of lith-ogenesis have been proposed, including the free and fixed particle theories, and Randal's plaque hypothesis. Among the different types of kidney stones, those containing calcium are the most common, followed by those contain-ing uric acid, struvite and cystine. Supersaturated urine, acidic urine pH and reductions in kidney stone inhibitors in the urine are the main recognized causes that contribute to the formation of all these stone-types. Nephrolithiasis is considered a sys-temic pathology that may lead to end-stage renal disease. Although much progress has been made, the underlying pathophysiological mechanisms of kidney stone formation are still not fully understood.
... 6 Other treatment options include dialysis, decreasing dietary oxalate consumption, increasing urine output to minimize oxalate deposition using thiazide diuretics due to its calcium retaining properties, and, in some instances, pyridoxine supplementation to promote normal conversion of glyoxylate to glycine. 7 In this case, the patient presented with profound renal failure and its inherent complications. Upon admission, the patient was hyperkalemic, hypocalcemic, hyperphosphatemic, and had pH and HCO3(-) levels of 6.9 and < 5 mEq/L, respectively. ...
... Il a été proposé de traiter l'hyperoxalurie absorptive par probiotique. L'apport per os d'OF pourrait corriger l'hyperoxalurie sans toxicité notable [65,66]. ...
a Service d'urologie, hôpital Bretonneau, 2, boulevard Tonnellé, 37044 Tours cedex 9, France b Service d'urologie, hôpital Tenon, 4, rue de la Chine, 75970 Paris cedex 20, France c Service d'urologie, hôpital Civil, 1, place de l'Hôpital, 67091 Strasbourg cedex, France d Service d'urologie, hôpital de La-Conception, 147, boulevard Baille, 13005 Marseille, France Reçu le 28 juillet 2008 ; accepté le 2 septembre 2008 Disponible sur Internet le 16 octobre 2008 Résumé L'infection urinaire est un facteur de risque de lithogénèse. L'infection urinaire est un facteur de gravité de la lithiase urinaire. Le calcul peut être préexistant et l'infection colo-nise le calcul, calcul infecté. L'infection peut être la cause du calcul, calcul infectieux, struvite par exemple. Mais le calcul infectieux peut aussi être secondaire à un agent infectieux non uri-naire, oxalobacter formigenes (OF) ou nanobactéries. Le traitement de première intention des calculs de struvite est la chirurgie percutanée. L'antiobiothérapie péri-opératoire, la culture des urines rénales et du calcul sont obligatoires. © 2008 Elsevier Masson SAS. Tous droits réservés.
... The severity of the hyperoxaluria correlates with renal outcome in patients with PH [10]. However, the only medical treatment currently available to reduce urine oxalate is pyridoxine, which is effective in fewer than half of the patients with PH type I and ineffective in types II and III [3,11,12]. ...
Primary hyperoxaluria (PH) is a rare genetic disease, in which high urinary oxalate (Uox) cause recurrent kidney stones and/or progressive nephrocalcinosis, often followed by early end-stage renal disease, as well as extremely high plasma oxalate, systemic oxalosis and premature death. Oxalobacter formigenes, an anaerobic oxalate degrading bacterium, naturally colonizes the colon of most humans. Orally administered O. formigenes (Oxabact) was found to significantly reduce urine and plasma oxalate. We aimed to evaluate its effect and safety in a randomized, double-blind, placebo-controlled multicenter study.
Oral Oxabact was given to PH patients (>5 years old, Uox > 1.0 mmol/1.73 m(2)/day, glomerular filtration rate (GFR) > 50 mL/min) at nine PH referral sites worldwide. Primary endpoint was the change from baseline in Uox (mmol/1.73 m(2)/day) after 24 weeks of treatment (>20% reduction).
Of the 43 subjects randomized, 42 patients received either placebo (23 subjects) or Oxabact (19 subjects). The change in Uox was <20% and not different between groups (P = 0.616). Ad hoc analysis was performed in 37 patients compliant with medication and urine processing. Change in Uox was -19% in subjects given Oxabact and -10% in placebo, (P = 0.288), but -21 and -7% with Uox expressed as molar creatinine ratio (Ox:Cr, mmol/mol, P = 0.06). Reduction of Ox:Cr was more obvious for patients with higher baseline values (>160 mmol/mol, Oxabact -28%, placebo -6%; P < 0.082). No serious adverse events were reported.
Oxabact was safe and well tolerated. However, as no significant change in Uox was seen, further studies to evaluate the efficacy of Oxabact treatment are needed.
A number of inherited metabolic diseases with renal manifestations were previously the remit of paediatric nephrologists, but as medical and scientific advances have improved the quality of life of these children, survival well into adult life is a reality. Therefore, adult nephrologists and their multiprofessional teams will be required to familiarise themselves with these conditions and provide continuing therapy. In some situations such as pregnancy, information is limited, and outcomes are less well known. Prospective data collection from rare disease registries will assist our understanding of the evolution of these conditions. This chapter focuses on two metabolic disorders that have varied presentations and will be seen in adult nephrology practice.KeywordsCystinosis
CTNS
CysteamineCystinePrimary hyperoxaluria
AGXT
GRHPR
HOGA1
OxalateOxalosis
Kidney stone disease is a dreadful pathological condition, and affects 20% of the population worldwide. The majority of renal stones contain calcium oxalate, and oxalate has vital role in the pathogenesis of renal stone. Humans derive oxalate from endogenous production and increased intake of dietary oxalate. Elevated oxalate levels lead to hyperoxaluria, a major risk factor for recurrent nephrolithiasis. Current treatment options in patients with primary and secondary hyperoxaluria are inadequate, and do not always lead to significant reduction in urinary oxalate excretion. Manipulation of gut flora with the potential probiotic bacteria may have a positive impact on gut oxalate levels, and may decrease oxalate absorption. Several reports documented gut microbes capable to degrade luminal oxalate, and reduce the risk of hyperoxaluria. In addition, the oxalate decarboxylase gene from Bacillus subtilis degrades oxalate into CO2 and formate, and studies have proven that administration of recombinant lactic acid bacteria (LAB) expressing oxalate decarboxylase (OxdC) decreased urinary oxalate excretion, and prevented calcium oxalate stone formation. Thus, potential oxalate degrading probiotic recombinant LAB expressing heterologous oxalate decarboxylase could be beneficial to mitigate hyperoxaluria efficiently by intestinal degradation of dietary oxalate.
Introduction and Objective
Our current understanding of the complex spectrum of urolithiasis is quite profound. In this chapter, we will review how we have gotten to our current state-of-the-art knowledge. The scientific method includes the forums where knowledge was propagated, at meetings. In addition, certain basic groups have always found a common ground for generating specific interests by fostering cross-fertilization of ideas.
Methods
Beginning with some of the first organized meetings regarding the science behind urolithiasis, this chapter will present the arenas where the information was disseminated. These are often societies of scientists and clinicians who have a shared interest in stone disease research and clinical management of patients with stone disease. Finally, stone types and the specific scientific historical aspects of each will be reviewed as will be our most up-to-date modern synthesis regarding the origins of stones themselves.
Results
The modern science of stone physiology and pathophysiology has largely been the work of a wide variety of researchers, basic science and clinical that typically presented their data at specific stone symposia that has evolved gradually since the 1970s. That this is a global phenomenon clearly represents the universality of urolithiasis around the planet. Specialty groups interested in urinary stone disease include urologists, nephrologists, endocrinologists, pediatricians, geriatricians, pathologists, chemists, physicists, geneticists, cell biologists, veterinarians, and many others. It has become increasingly apparent that the findings in one arena of science often cross-fertilize the work from others.
Conclusions
The modern synthesis of our understanding of the formation of urolithiasis is the result of the works of thousands of investigators over a truly long period of time.
The primary hyperoxaluria type 1 (PH1) is an autosomal recessive, inherited disease caused by a defect in glyoxylate metabolism. PH1 is characterized by excessive production and urinary excretion of oxalate that lead to renal and systemic damage through the deposition of oxalate crystals into tissues. Although some patients may benefit from aggressive conservative management, the only curative treatment to date is a combined liver-kidney transplantation.
The incidence of stone disease has been rising in recent years and calcium-containing stones (calcium oxalate) are the most prevalent stone types of all. In an attempt to mimic the stone formation process in humans and to understand the mechanisms involved, a number of theoretical, chemical, and animal models have been developed.
In these experimental models, formation of calcium oxalate deposits in the kidney can be demonstrated in a short period of time by enabling the physicians to study the processes involved in stone maturation, as well as for examining the role of inhibitors and promoters of crystal growth. Although rabbits and dogs have also been used, rats are the most commonly used animals for the study of nephrolithiasis.
An accurate and reliable animal model may allow us to develop newer treatment algorithms and medications that may help to better understand the pathogenesis of stone formation and direct improved methods of stone prevention.
There are many similarities between experimental nephrolithiasis-induced rat model and human kidney stone formation where oxalate metabolism is considered to be almost identical between rats and humans. The accumulated data so far have clearly shown that rat models of nephrolithiasis may help us to evaluate the various phases of stone formation including nucleation, aggregation, and retention of crystals.
Last but not least, although the pathogenesis of stone formation can be studied in animal models, the limitations of these models should always be kept in mind.
The primary hyperoxalurias are a group of hereditary disorders characterized by overproduction and accumulation of the metabolic end product oxalate in the body. The heterogeneous nature of these disorders presents diagnostic and therapeutic challenges. While knowledge and understanding of these conditions are continually improving and may in the future yield further therapeutic modalities, at present the only strategy to correct the underlying metabolic defect is by replacement of the macroscopically normal recipient liver. Transplantation has developed to a point where it is accepted as a valuable treatment option for patients with primary hyperoxaluria type 1(PH1), with good long-term results. However, controversies exist over the type and timing of transplantation. Furthermore, the long-term risks of immunosuppression cannot be ignored. This chapter will attempt to outline the different strategies and clinical considerations concerning this topic, illustrated with data collected by the European PH1 transplant registry.
In the past few decades pediatric urolithiasis has become more frequent. The reason for this increase is not completely clear but has been attributed to changes in climate, nutritional habits and possibly other environmental factors. Although less frequent than adult stone disease, urolithiasis in the pediatric age group is also related to significant morbidity, particularly since stones tend to recur, and, thus, should not be underestimated. Most children with idiopathic stone disease have an underlying metabolic abnormality substantiating the importance of metabolic evaluation already following initial diagnosis of urolithiasis. Identification of the metabolic abnormality allows for more specific prescription of non pharmacological and pharmacological interventions aimed at preventing recurrent stone formation. A better understanding of the causes of kidney stone disease will provide better strategies for stone prevention in children.
Urolithiasis is increasingly recognized in pediatric patients and is encountered in a variety of clinical settings: the 8-year-old boy who presents with hematuria, the 14-year old with cystinuria experiencing her fourth episode of renal colic in the past 6 years, the 10-year old with inflammatory bowel disease whose two renal stones were recognized incidentally during imaging for evaluation of abdominal pain, the premature infant with asymptomatic nephrocalcinosis and a stone, the 4-year old in the emergency room with gross hematuria and abdominal pain after recently starting indinavir medication. All have in common particulate material of mineral origin within the urinary tract. An understanding of how and why stones form, along with knowledge of the pathophysiologic states that promote urinary tract calculi, provide the basis for effective clinical management.
A significant increase in the frequency of childhood urolithiasis has been observed during the last 10–15 years. A recent study observed an increase in the incidence of symptomatic kidney stones from 7.9 per 100,000 children in 1996 to 18.5 per 100,000 in 2007. The highest incidence was observed in females aged 14–17 years. These findings have been replicated by others. The reason for this increase is not clear while many hypotheses have been proposed. Most affected children have idiopathic calcium stone disease, while monogenic disorders, which may or may not be associated with chronic kidney disease (CKD), likely account for approximately 10 % of pediatric kidney stone cases. Both environmental and hereditary factors significantly contribute to the risk of stone formation. All children with kidney stone diseases deserve a meticulous evaluation of risk factors which forms the basis for individualized and targeted treatment of the underlying disorders.
The characterization of numerous rare single gene defects associated with nephrolithiasis and/or nephrocalcinosis has advanced our understanding of molecular pathways leading to stone formation. Collectively these monogenic disorders only account for approximately 2% of kidney stones in adults and 10% of childhood stones. Lack of awareness of these rare disorders by physicians or absence of characteristic clinical features that distinguish them from the common type of kidney stones frequently results in unacceptable delays in diagnosis and treatment. A genetic disorder should always be considered during evaluation of kidney stones in children and in unusual adult cases. Important clues that should alert the clinician to a genetic cause of nephrolithiasis will be reviewed along with several of the most common or best characterized single gene disorders, cystinuria, primary hyperoxaluria, Dent's disease, and adenine phosphoribosyltransferase deficiency.
Oxalate is harmful to many organisms by forming insoluble precipitates with some metal cations. In humans, calcium oxalate is a major constituent of kidney stones leading to urolithiasis. Oxalobacter formigenes is a bacterium in most vertebrates and can regulate the homeostasis of oxalate. Replacement therapies of O. formigenes or related-enzymes are new strategies for treating oxalate-related diseases. Oxalyl-CoA decarboxylase (OXC) is an enzyme involved in the oxalate degradation in O. formigenes. In this paper, the catalytic mechanism of OXC was investigated by using the density functional theory (DFT) method. The most likely reaction pathway, detail of elementary steps, and roles of key residues were determined. Our calculation results indicate that the decarboxylation process can proceed rapidly, which agrees well with the experimental observation. In the protonation of the HDC-ThDP intermediate, the 4-NH2 of ThDP is suggested to be the proton donor, which abstracts a proton from the nearby residue E121. The rate-limiting step is calculated to be the proton transfer from 4′-NH2 to the HDC-ThDP intermediate with an energy barrier of 21.8 kcal mol−1. However, if this pathway is blocked by mutating residue E121, the reaction may follow another mechanism, in which Y483 acts as the proton donor and uses a water molecule as a mediator. These findings can explain the experimental observation that replacement of residues Y483 or E121 significantly reduces but does not completely abolish the activity of the enzyme. Our results may provide useful information for exploring the enzymatic mechanism and developing biocatalytic applications for treating the oxalate-related diseases.
Childhood urolithiasis is associated with considerable morbidity and recurrence. Many risk factors--including those metabolic, genetic, anatomic, dietary and environmental in nature--have been identified in children with urinary tract calculi. As pediatric urolithiasis with a metabolic etiology is the most common disease, evaluating the metabolic risk factors in patients is necessary to both effectively treat current stones and prevent recurrence. We discuss causative risk factors of pediatric urolithiasis, as well as the diagnostic and therapeutic approaches.
Kidney transplantation alone in Primary Hyperoxaluria is associated with a high rate of recurrence and in many cases early graft loss. Liver transplantation offers the possibility of correcting the metabolic defect.
A retrospective review of five cases of Primary Hyperoxaluria managed at a major transplant unit was performed.
The 5 patients had a mean age of 32.2 years (range 28-40) at time of first transplantation. 3 patients had kidney only transplants (one live donor, 2 deceased donor) and 2 had segmental liver followed by delayed kidney transplantation. All 3 kidney alone failed and one is now awaiting a live donor transplant, one underwent kidney alone retransplantation (failed 5 years later) and one had a combined deceased donor liver and kidney transplantation (remains well at 4 years). The 2 segmental liver sequential kidney transplant recipients remain well at 1 year and 3 years.
Combined liver-kidney transplantation may be a better choice as the primary transplant procedure. The indication and timing for pre-emptive liver or liver followed by delayed kidney transplantation remains a matter of debate.
The spectrum of primary hyperoxaluria type I is extremely heterogeneous, ranging from singular to recurrent urolithiasis and early end-stage renal disease (ESRD). In infantile oxalosis, the most devastating form, ESRD occurs as early as within the first weeks of life. No kidney replacement therapy sufficiently removes endogenously overproduced oxalate. However, curative combined liver-kidney transplant often is impracticable in small infants. Oxalobacter formigenes (O formigenes), an anaerobic oxalate-degrading bacterium, is a colonizer of the healthy human colon. Oral administration of O formigenes has been shown to significantly decrease urine and plasma oxalate levels in patients with primary hyperoxaluria. We report compassionate use of O formigenes in two 11-month-old girls with infantile oxalosis and ESRD. They received O formigenes twice a day for 4 weeks (or until transplant). Dialysis regimens were unchanged. Plasma oxalate levels decreased from >110 μmol/L before to 71.53 μmol/L under treatment in patient 1 and from >90 to 68.56 μmol/L (first treatment period) and 50.05 μmol/L (second treatment period) in patient 2. O formigenes was well tolerated. No serious side effects were reported. Extremely increased plasma oxalate levels in patients with infantile oxalosis may enable intestinal elimination of endogenous oxalate in the presence of O formigenes. Therefore, O formigenes therapy may be helpful as a bridging procedure until transplant in such patients.
For assessment of total oxalic acid (OX) status, reliable quantification of OX in both urine and plasma is important. For urine, but not plasma, a commercial kit is available. We have recently described a LC-MSMS method for OX in plasma. The aim of the present study was to evaluate the usefulness of this assay for urine. We also wanted to evaluate if 24 h urine collection could be substituted by OX/creatinine-ratio (U-OX/crea) in spot-urine, and establish precursory reference intervals for U-OX/crea in children and adults.
Acidified urines were analysed and relevant validation parameters assessed. Diurnal excretion patterns were investigated in nine healthy volunteers on self-chosen diets. For method comparison, 29 urine samples were analysed with both the present method and a commercial urine-oxalate kit. Precursory reference values for U-OX/crea in children and adults (N=103, 1 month-76 years) were calculated.
The within-batch coefficient of variation (CV) was 2.5% and a relative recovery of 97% in urine spiked with 5-200 micromol/L OX was found. The LC-MSMS method gave 7.9% higher OX values compared to the kit. No significant diurnal pattern of U-OX/crea was observed. U-OX/crea in children decreases with age, with no gender dependency. In adults no age variation was found, but females had somewhat higher U-OX/Crea compared to males.
The LC-MSMS method has proven useful for urinary OX quantification. Random spot-urine samples can be used. Age-dependent reference limits for U-OX/crea must be applied in children, in contrast to adults.
Kidney stone disease remains a major health and economic burden on the nation. It has been increasingly recognized that nephrolithiasis can be both a chronic or systemic illness. There have been major limitations in the development of new drugs for the prevention and management of this disease, largely due to our lack of understanding of the complex pathophysiologic mechanisms involving the interaction of three major target organs: the kidney, bone, and intestine. We also do not yet understand the molecular genetic basis of this polygenic disorder. These limitations are coupled with the incorrect perception that kidney stone disease is solely an acute illness, and the lack of reliable tests to assess outcome measures. All of these factors combined have diminished the willingness of the pharmaceutical industry to engage in the development of novel drugs.
Over the past 10 years, major progress has been made in the pathogenesis of uric acid and calcium stones. These advances have led to our further understanding of a pathogenetic link between uric acid nephrolithiasis and the metabolic syndrome, the role of Oxalobacter formigenes in calcium oxalate stone formation, oxalate transport in Slc26a6-null mice, the potential pathogenetic role of Randall's plaque as a precursor for calcium oxalate nephrolithiasis, and the role of renal tubular crystal retention. With these advances, we may target the development of novel drugs including (1) insulin sensitizers; (2) probiotic therapy with O. formigenes, recombinant enzymes, or engineered bacteria; (3) treatments that involve the upregulation of intestinal luminal oxalate secretion by increasing anion transporter activity (Slc26a6), luminally active nonabsorbed agents, or oxalate binders; and (4) drugs that prevent the formation of Randall's plaque and/or renal tubular crystal adhesions.
Lactic acid bacteria (LABs) are being used as a probiotic very often for various enteric problems. Many genetically modified LABs are created by different workers for various novel applications. In this study we examine the expression of heterologous oxalate decarboxylase (oxdc) in Lactobacillus plantarum NC8. Generally, this enzyme is not present in Lactobacillus spp. Oxdc gene from Bacillus subtilis was polymerase chain reaction-amplified and cloned in a shuttle vector pSIP400 series, downstream of the inducible promoter, P(orfx). In the presence of an inducing peptide, Sakacin-P, the expression of OxdC was observed in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The cell-free extract and the purified protein from the recombinant LABs showed the presence of OxdC activity. The above recombinant LABs, with desired modifications, can be used as a possible probiotic for the degradation of intestinal dietary oxalate for preventing enteric hyperoxaluria.
Hyperoxaluria is a major risk factor for recurrent urolithiasis and nephrocalcinosis. We tested an oral therapy with a crystalline, cross-linked formulation of oxalate-decarboxylase (OxDc-CLEC) on the reduction of urinary oxalate and decrease in the severity of kidney injury in two models: AGT1 knockout mice (AGT1KO) in which hyperoxaluria is the result of an Agxt gene deficiency, and in AGT1KO mice challenged with ethylene glycol (EG).
Four different doses of OxDc-CLEC mixed with the food, or placebo were given to AGT1KO mice (200 mg/day, n = 7) for 16 days and to EG-AGT1KO mice (5, 25, and 80 mg, n = 11) for 32 days.
Oral therapy with 200 mg OxDc-CLEC reduced both urinary (44%) and fecal oxalate (72%) in AGT1KO mice when compared to controls. Similarly, in EG-AGT1KO mice, each of the three doses of OxDc-CLEC produced a 30-50% reduction in hyperoxaluria. A sustained urinary oxalate reduction of 40% or more in the 80 mg group led to 100% animal survival and complete prevention of nephrocalcinosis and urolithiasis.
These data suggest that oral therapy with OxDc-CLEC may reduce hyperoxaluria, prevent calcium oxalate nephrocalcinosis and urolithiasis, and can represent a realistic option for the treatment of human hyperoxaluria, independent of cause.
A deficiency of the liver-specific enzyme alanine:glyoxylate aminotransferase (AGT) is responsible for the potentially lethal hereditary kidney stone disease primary hyperoxaluria type 1 (PH1). Many of the mutations in the gene encoding AGT are associated with specific enzymatic phenotypes such as accelerated proteolysis (Ser205Pro), intra-peroxisomal aggregation (Gly41Arg), inhibition of pyridoxal phosphate binding and loss of catalytic activity (Gly82Glu), and peroxisome-to-mitochondrion mistargeting (Gly170Arg). Several mutations, including that responsible for AGT mistargeting, co-segregate and interact synergistically with a Pro11Leu polymorphism found at high frequency in the normal population. In order to gain further insights into the mechanistic link between genotype and enzymatic phenotype in PH1, we have determined the crystal structure of normal human AGT complexed to the competitive inhibitor amino-oxyacetic acid to 2.5A. Analysis of this structure allows the effects of these mutations and polymorphism to be rationalised in terms of AGT tertiary and quaternary conformation, and in particular it provides a possible explanation for the Pro11Leu-Gly170Arg synergism that leads to AGT mistargeting.
Calcium oxalate (CaOx), calcium phosphate (CaP), and uric acid or urate are the most common crystals seen in the kidneys. Most of the crystals evoke an inflammatory response leading to fibrosis, loss of nephrons, and eventually to chronic renal failure. Of the three, CaOx monohydrate is the most reactive, whereas some forms of CaP do not evoke any discernible response. Reactive oxygen species are produced during the interactions between the crystals and renal cells and are responsible for the various cellular responses. CaOx crystals generally form in the renal tubules. Exposure of renal epithelial cells to CaOx crystals results in the increased synthesis of osteopontin, bikunin, heparan sulfate, monocyte chemoattractant protein 1 (MCP-1), and prostaglandin (PG) E2, which are known to participate in inflammatory processes and in extracellular matrix production. CaOx crystal deposition in rat kidneys also activates the renin-angiotensin system. Both Ox and CaOx crystals selectively activate p38 mitogen-activated protein kinase (MAPK) in exposed tubular cells. CaP crystals can form in the tubular lumen, tubular cells, or tubular basement membrane. Renal epithelial cells exposed to brushite crystals produce MCP-1. Basic CaP and calcium pyrophosphate dihydrate induce mitogenesis in fibroblasts, stimulate production of PGE2, and up-regulate the synthesis of metalloproteinases (MMP) while down-regulating the production of inhibitors of MMPs through activation of p42/44 MAPK. Deposition of urate crystals in the kidneys becomes associated with renal tubular atrophy, interstitial fibrosis, and development of inflammatory infiltrate. Renal epithelial cells exposed to uric acid crystals synthesize MCP-1 as well as PGE2. Monocytes or neutrophils exposed to urate crystals produce tumor necrosis factor alpha, interleukin-1 (IL-1), IL-6, and IL-8. Expression of IL-8 is mediated through extracellular signal-regulated kinase 1 (ERK-1)/ERK-2 and nuclear transcription factors activated protein 1 and nuclear factor kappabeta. Urate crystals also stimulate the macrophages to produce MMPs.
The primary goal of this study was to test the hypothesis that Oxalobacter colonization alters colonic oxalate transport thereby reducing urinary oxalate excretion. In addition, we examined the effects of intraluminal calcium on Oxalobacter colonization and tested the hypothesis that endogenously derived colonic oxalate could be degraded by lyophilized Oxalobacter enzymes targeted to this segment of the alimentary tract. Oxalate fluxes were measured across short-circuited, in vitro preparations of proximal and distal colon removed from Sprague-Dawley rats and placed in Ussing chambers. For these studies, rats were colonized with Oxalobacter either artificially or naturally, and urinary oxalate, creatinine and calcium excretions were determined. Colonized rats placed on various dietary treatment regimens were used to evaluate the impact of calcium on Oxalobacter colonization and whether exogenous or endogenous oxalate influenced colonization. Hyperoxaluric rats with some degree of renal insufficiency were also used to determine the effects of administering encapsulated Oxalobacter lysate on colonic oxalate transport and urinary oxalate excretion. We conclude that in addition to its intraluminal oxalate-degrading capacity, Oxalobacter interacts physiologically with colonic mucosa by inducing enteric oxalate secretion/excretion leading to reduced urinary excretion. Whether Oxalobacter, or products of Oxalobacter, can therapeutically reduce urinary oxalate excretion and influence stone disease warrants further investigation in long-term studies in various patient populations.
Urolithiasis is one of the most common urologic diseases in industrialized societies. Calcium oxalate is the predominant component in 70-80% of kidney stones, and small changes in urinary oxalate concentration affect the risk of stone formation. SLC26A6 is an anion exchanger expressed on the apical membrane in many epithelial tissues, including kidney and intestine. Among its transport activities, SLC26A6 mediates Cl(-)-oxalate exchange. Here we show that mutant mice lacking Slc26a6 develop a high incidence of calcium oxalate urolithiasis. Slc26a6-null mice have significant hyperoxaluria and elevation in plasma oxalate concentration that is greatly attenuated by dietary oxalate restriction. In vitro flux studies indicated that mice lacking Slc26a6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate. We conclude that the anion exchanger SLC26A6 has a major constitutive role in limiting net intestinal absorption of oxalate, thereby preventing hyperoxaluria and calcium oxalate urolithiasis.
Primary hyperoxaluria is characterized by severe urolithiasis, nephrocalcinosis, and early renal failure. As treatment options are scarce, we aimed for a new therapeutic tool using colonic degradation of endogenous oxalate by Oxalobactor formigenes. Oxalobacter was orally administered for 4 weeks as frozen paste (IxOC-2) or as enteric-coated capsules (IxOC-3). Nine patients (five with normal renal function, one after liver-kidney transplantation, and three with renal failure) completed the IxOC-2 study. Seven patients (six with normal renal function and one after liver-kidney transplantation) completed the IxOC-3 study. Urinary oxalate or plasma oxalate in renal failure was determined at baseline, weekly during treatment and for a 2-week follow-up. The patients who showed >20% reduction both at the end of weeks 3 and 4 were considered as responders. Under IxOC-2, three out of five patients with normal renal function showed a 22-48% reduction of urinary oxalate. In addition, two renal failure patients experienced a significant reduction in plasma oxalate and amelioration of clinical symptoms. Under IxOC-3 treatment, four out of six patients with normal renal function responded with a reduction of urinary oxalate ranging from 38.5 to 92%. Although all subjects under IxOC-2 and 4 patients under IxOC-3 showed detectable levels of O. formigenes in stool during treatment, fecal recovery dropped directly at follow up, indicating only transient gastrointestinal-tract colonization. The preliminary data indicate that O. formigenes is safe, leads to a significant reduction of either urinary or plasma oxalate, and is a potential new treatment option for primary hyperoxaluria.
In this review, we focus on the role of gastrointestinal transport of oxalate primarily from a contemporary physiological standpoint with an emphasis on those aspects that we believe may be most important in efforts to mitigate the untoward effects of oxalate. Included in this review is a general discussion of intestinal solute transport as it relates to oxalate, considering cellular and paracellular avenues, the transport mechanisms, and the molecular identities of oxalate transporters. In addition, we review the role of the intestine in oxalate disease states and various factors affecting oxalate absorption.
Pyridoxine (VB6) response in type I primary hyperoxaluria (PHI) is variable, with nearly equal numbers of patients showing partial to complete reductions in oxaluria, and resistance. Because high urine oxalate concentrations cause stones and renal injury, reduction in urine oxalate excretion is deemed favorable. Mechanisms of VB6 action on hepatic alanine:glyoxylate aminotransferase (AGT), the deficient enzyme in PHI, and VB6 dose response have not been well-characterized.
Sequencing or restriction site-generating polymerase chain reaction (PCR) was used for c.508 genotyping in 23 PHI patients. Pre- and post-VB6 24-hour urine oxalate excretion and VB6 dose were ascertained by retrospective chart review.
There were six c.508 G>A homozygotes (AA), eight heterozygotes (GA), and nine patients lacking this change (GG). Pre-VB6 urine oxalate excretion was 152 +/- 39, 203 +/- 68 and 206 +/- 74 mg/1.73 m(2)/24 hours, respectively, and did not differ [AA vs. GA (P= 0.07); AA vs. GG (P= 0.07); GA vs. GG, (P= 0.47)]. Post-VB6 urine oxalate excretion was normal in AA (pre- vs. post-VB6) (P < 0.001), partially reduced in GA (P < 0.001), and unchanged in GG (P= 0.06). Urine oxalate excretion attenuation was similar for VB6 doses (mg/kg/day) of 1 to 4.9, 5 to 9.9, and 10 to 14.9 in AA (P= 0.41, P= 0.28, and P= 0.11, respectively) and GA (P= 0.42, P= 0.39, and P= 0.30, respectively) during follow-up.
Presence of the c.508 G>A allele confers VB6 response in PHI and VB6 doses of 5 mg/kg/day appear sufficient. c.508 genotyping can be used to predict VB6 response and guide treatment in PHI. [c represents cDNA sequence where nucleotide position +1 corresponds to the adenine (A) of the translation start codon ATG. Equivalent positions based on 5' UTR nucleotide numbering are as follows: c.508 G>A = G630A (Gly170Arg), c.32 C>T = C154T (Pro11Leu), and c.454 T>A = T576A (Phe152Ile)], yields highest residual AGT activity. To test whether VB6 response might be attributable to this allele, we performed c.508 genotyping.
Primary hyperoxaluria (PH) is an inherited disorder that causes calcium urolithiasis and renal failure. Due to its rarity, experience at most centers with this disease is limited.
A secure, web-based, institutional review board/ethics committee and American Health Insurance Portability and Accountability Act (HIPAA)-compliant registry was developed to facilitate international contributions to a data base. To date 95 PH patients have been entered.
PH type was confirmed in 84/95 (PH1 79%, PH2 9%). Mean age +/- SD at symptom onset was 9.5 +/- 10.2 (median 5.5) years whereas age at diagnosis was 15.0 +/- 15.2 (median 10.0) years. Urolithiasis was present at diagnosis in 90% (mean 7, median 1, stones prior to diagnosis) and nephrocalcinosis in 48%. Surprisingly 15% of the patients were asymptomatic at the time of diagnosis. Nineteen of the 95 patients were first recognized to have PH after they had reached end-stage renal disease, with the diagnosis made only after kidney transplantation in 7 patients. Patients were followed for 12.1 +/- 10.6 (median 9.4) years. Thirty-four of 95 progressed to end-stage renal failure, before (19 patients) or after (15 patients) diagnosis. In the PH1 cohort actuarial renal survival was 64% at 30 years of age, 47% at 40 years, and 29% at 50 years.
We have developed a PH registry, and demonstrated the feasibility of this secure, web-based approach for data entry. By facilitating accumulation of an increasing cohort of patients, this registry should allow more complete characterization of clinical expression of PH, an appreciation of geographic variability, and identification of treatment outcomes.
Intestinal oxalate transport, mediated by anion exchange proteins, is important to oxalate homeostasis and consequently to calcium oxalate stone diseases. To assess the contribution of the putative anion transporter (PAT)1 (Slc26a6) to transepithelial oxalate transport, we compared the unidirectional and net fluxes of oxalate across isolated, short-circuited segments of the distal ileum of wild-type (WT) mice and Slc26a6 null mice [knockout (KO)]. Additionally, urinary oxalate excretion was measured in both groups. In WT mouse ileum, there was a small net secretion of oxalate (J(net)(Ox) = -5.0 +/-5.0 pmol.cm(-2).h(-1)), whereas in KO mice J(net)(Ox) was significantly absorptive (75 +/- 10 pmol.cm(-2)h.h(-1)), which was the result of a smaller serosal-to-mucosal oxalate flux (J(sm)(Ox)) and a larger mucosal-to-serosal oxalate flux (J(ms)(Ox)). Mucosal DIDS (200 microM) reduced J(sm)(Ox) in WT mice, leading to reversal of the direction of net oxalate transport from secretion to absorption (J(net)(Ox) = 15.0 +/- 5.0 pmol.cm(-2).h(-1)) , but DIDS had no significant effect on KO ileum. In WT mice in the absence of mucosal Cl(-), there were small increases in J(ms)(Ox) and decreases in J(sm)(Ox) that led to a small net oxalate absorption. In KO mice, J(net)(Ox) was 1.5-fold greater in the absence of mucosal Cl(-), due solely to an increase in J(ms)(Ox). Urinary oxalate excretion was about fourfold greater in KO mice compared with WT littermates. We conclude that PAT1 is DIDS sensitive and mediates a significant fraction of oxalate efflux across the apical membrane in exchange for Cl(-); as such, PAT1 represents a major apical membrane pathway mediating J(sm)(Ox).
The Metabolic and Molecular Bases of Inherited Disease
- Cj Danpure
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- Cr Scriver
- Al Beaudet
- Ws Sly
Danpure CJ. Primary hyperoxaluria. In: Scriver
CR, Beaudet AL, Sly WS et al. (eds). The Metabolic
and Molecular Bases of Inherited Disease.
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Primary hyperoxaluria
- Danpure