Inherited monogenic kidney stone diseases: recent diagnostic and therapeutic advances

Hereditary monogenic kidney stone diseases are rare diseases, since they account for nearly 2% of nephrolithiasis cases in adults and 10% in children. Most of them are severe, because they frequently are associated with nephrocalcinosis and lead to progressive impairment of renal function unless an early and appropriate etiologic treatment is instituted. Unfortunately, treatment is often lacking or started too late since they are often misdiagnosed or overlooked. The present review reports the genotypic and phenotypic characteristics of monogenic nephrolithiases, with special emphasis on the recent advances in the field of diagnosis and therapeutics. Monogenic stone diseases will be classified into three groups according to their mechanism: (1) inborn errors of the metabolism of oxalate (primary hyperoxalurias), uric acid (hereditary hyperuricemias) or other purines (2,8-dihydroxyadeninuria), which, in addition to stone formation, result in crystal deposition in the renal parenchyma; (2) congenital tubulopathies affecting the convoluted proximal tubule (such as Dent's disease, Lowe syndrome or hypophosphatemic rickets), the thick ascending limb of Henlé's loop (such as familial hypomagnesemia and Bartter's syndromes) or the distal past of the nephron (congenital distal tubular acidosis with or without hearing loss), which are frequently associated with nephrocalcinosis, phosphatic stones and extensive tubulointerstitial fibrosis; (3) cystinuria, an isolated defect in tubular reabsorption of cystine and dibasic aminoacids, which results only in the formation of stones but requires a cumbersome treatment. Analysis of stones appears of crucial value for the early diagnosis of these diseases, as in several of them the morphology and composition of stones is specific. In other cases, especially if nephrocalcinosis, phosphatic stones or proteinuria are present, the evaluation of blood and urine chemistry, especially with regard to calcium, phosphate and magnesium, is the key of diagnosis. Search for mutations is now increasingly performed in as much as genetic counselling is important for the detection of heterozygotes in autosomic recessive diseases and of carrier women in X-linked diseases. In conclusion, better awareness to the rare monogenic forms of nephrolithiasis and/or nephrocalcinosis should allow early diagnosis and treatment which are needed to prevent or substantially delay progression of end-stage renal disease. Analysis of every first stone both in children and in adults should never be neglected, in order to early detect unusual forms of nephrolithiasis requiring laboratory evaluation and deep etiologic treatment.     

Adenine phosphoribosyltransferase deficiency in children

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder characterized by 2,8-dihydroxyadenine (2,8-DHA) crystalluria that can cause nephrolithiasis and chronic kidney disease. The aim of our study was to assess the clinical presentation, diagnosis, and outcome of APRT deficiency in a large pediatric cohort. All pediatric cases of APRT deficiency confirmed at the same French reference laboratories between 1978 and 2010 were retrospectively reviewed. Twenty-one patients from 18 families were identified. The median age at diagnosis was 3 years. Diagnosis was made after one or more episodes of nephrolithiasis (17 patients), after urinary tract infection (1 patient), and by family screening (3 patients). The diagnosis was based on stone analysis and microscopic examination of urine and/or enzymatic determination of APRT on red blood cells. All children had null APRT enzyme activity in erythrocytes. APRT gene sequencing was performed on 18 patients, revealing six homozygous and 12 compound heterozygous mutations. At diagnosis, half of the patients had decreased kidney function, and two children presented with acute renal failure. Allopurinol treatment was given to all patients at a median dose of 9 mg/kg/day. After a median follow-up of 5 years, all patients showed stabilization or improvement of kidney function, normal growth and development, and six patients had recurrence of nephrolithiasis. Based on these results, we conclude that an excellent outcome can be achieved in children with APRT deficiency who receive the proper treatment.     

Late diagnosis of primary hyperoxaluria after failed kidney transplantation

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive inborn error of the glyoxylate metabolism that is based on absence, deficiency or mislocalization of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase. Hyperoxaluria leads to recurrent formation of calculi and/or nephrocalcinosis and often early end-stage renal disease (ESRD) accompanied by systemic calcium oxalate crystal deposition. In this report, we describe an adult female patient with only one stone passage before development of ESRD. With unknown diagnosis of PH, the patient received an isolated kidney graft and developed an early onset of graft failure. Although initially presumed as an acute rejection, the biopsy revealed calcium oxalate crystals, which then raised a suspicion of primary hyperoxaluria. The diagnosis was later confirmed by hyperoxaluria, elevated plasma oxalate levels and mutation of the AGXT gene, showing the patient to be compound heterozygous for the c.33_34InsC and c.508G > A mutations. Plasma oxalate levels did not decrease after high-dose pyridoxine treatment. Based on this case report, we would recommend in all patients even with a minor history of nephrolithiasis but progression to chronic renal failure to exclude primary hyperoxaluria before isolated kidney transplantation is considered.     

Fourteen Monogenic Genes Account for 15% of Nephrolithiasis/Nephrocalcinosis

Nephrolithiasis is a prevalent condition with a high morbidity. Although dozens of monogenic causes have been identified, the fraction of single-gene disease has not been well studied. To determine the percentage of cases that can be molecularly explained by mutations in 1 of 30 known kidney stone genes, we conducted a high-throughput mutation analysis in a cohort of consecutively recruited patients from typical kidney stone clinics. The cohort comprised 272 genetically unresolved individuals (106 children and 166 adults) from 268 families with nephrolithiasis (n=256) or isolated nephrocalcinosis (n=16). We detected 50 likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 14.9% (40 of 268) of all cases; 20 of 50 detected mutations were novel (40%). The cystinuria gene SLC7A9 (n=19) was most frequently mutated. The percentage of monogenic cases was notably high in both the adult (11.4%) and pediatric cohorts (20.8%). Recessive causes were more frequent among children, whereas dominant disease occurred more abundantly in adults. Our study provides an in-depth analysis of monogenic causes of kidney stone disease. We suggest that knowledge of the molecular cause of nephrolithiasis and nephrocalcinosis may have practical implications and might facilitate personalized treatment.     

Néphrocalcinose de l’enfant

Nephrocalcinosis is defined by calcium phosphate or calcium oxalate deposits in the kidney parenchyma, particularly in tubular epithelial cells and interstitial tissue. It should be differentiated from urolithiasis where calcium salts deposits are located in the kidney and urinary tract. The epidemiology of nephrocalcinosis in children is unknown but the condition is not so rare, with an increased incidence in preterm infants. Often detected as an incidental finding, nephrocalcinosis may be classified according to the radiological type: medullary, cortical or diffuse. Nephrocalcinosis in children can be caused by a variety of etiology. The most common causes concern medullary nephrocalcinosis and include hereditary tubular disorders, in particular distal renal tubular acidosis and Dent disease, metabolic disorders such as idiopathic hypercalciuria and hyperoxaluria, and iatrogenic causes such as vitamin D intoxication. In the newborn, the main cause is hypercalciuria of the premature baby, whose multifactorial origin is largely iatrogenic. Primary hyperoxaluria which can lead to early onset nephrocalcinosis and usually to chronic kidney disease should always be considered and further investigated. In order to provide a specific diagnosis, it is essential to take into account the family history, the clinical context and complete laboratory data. Early initiation of an appropriate etiological treatment is recommended and may prevent or delay the progression to chronic kidney disease in some cases.     

Laterality of nephrocalcinosis in kidney stone formers with severe hypocitraturia

Study Type – Aetiology (case series)
Level of Evidence 4 What’s known on the subject? and What does the study add? Systemic urinary stone‐forming conditions such as hypocitraturia or cystinuria should theoretically lead to symmetric and diffuse stone formation. Small studies have shown that some patients with such conditions produce stones primarily on one side. No studies, however, have attempted to quantify the frequency at which such patients form stones asymmetrically. This study demonstrates that despite having a severe systemic condition such as hypocitraturia, patients frequently have asymmetric and focal nephrocalcinosis. This suggests that additional intrinsic local factors such as renal perfusion or vascular injury must also play a role in stone formation. OBJECTIVE To examine the hypothesis that the distribution of nephrocalcinosis in patients with severe hypocitraturia should be symmetric. PATIENTS AND METHODS Patients with profound hypocitraturia defined as a 24‐h urine citrate <50 mg at the time of initial presentation were identified from the metabolic stone clinic database at our academic medical center. Two independent blinded reviewers evaluated all of the abdominal radiographs for the segmental distribution of macroscopic nephrocalcinosis. RESULTS A total of 44 patients met study criteria, with an equal distribution of males and females and a mean age of 55.4 ± 13.7 years. Mean urinary citrate was 28 ± 11 mg/day. Nephrocalcinosis was present in at least one renal segment in 22 patients (50%). Of the 22 patients with nephrocalcinosis, 9 patients (41%) had unilateral nephrocalcinosis and 13 patients (59%) had bilateral nephrocalcinosis. Of the 35 kidneys with nephrocalcinosis, 14 kidneys (40%) had nephrocalcinosis in only one renal segment, 13 kidneys (37%) had nephrocalcinosis in two segments and eight kidneys (23%) had nephrocalcinosis involving all three segments. CONCLUSIONS Despite the systemic nature of severe hypocitraturia, nephrocalcinosis is frequently asymmetric and focal in nature. This suggests that local factors intrinsic to the renal medullary interstitium, such as vascular injury, must play a role in the formation of nephrocalcinosis. Further study to elucidate these intrinsic local factors may further improve the treatment and prevention of urinary stone disease.     

Report of a family with two different hereditary diseases leading to early nephrocalcinosis

The etiologies of early onset nephrocalcinosis in consanguineous families include five major inherited recessive disorders: primary hyperoxaluria (PH), familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), distal renal tubular acidosis (dRTA), hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and antenatal Bartter syndrome. In this paper, we describe two girls from consanguineous parents with early onset nephrocalcinosis. Based on both clinical and biochemical assessment in combination with molecular genetics, we have shown that the etiology of nephrocalcinosis is different in each girl: one had FHHNC and her sister had dRTA.     

Nephrolithiasis related to inborn metabolic diseases

Nephrolithiasis associated with inborn metabolic diseases is a very rare condition with some common characteristics: early onset of symptoms, family history, associated tubular impairment, bilateral, multiple and recurrent stones, and association with nephrocalcinosis. The prognosis of such diseases may lead to life threatening conditions, not only because of unabated kidney damage but also because of progressive extra-renal involvement, either in a systemic form (e.g. primary hyperoxaluria type 1, requiring combined liver and kidney transplantation), or in a neurological form (Lesch–Nyhan syndrome leading to auto-mutilation and disability, phosphoribosyl pyrophosphate synthetase superactivity, which is associated with mental retardation). Patients with other inborn metabolic diseases present only with recurrent stone formation, such as cystinuria, adenine phosphoribosyl-transferase deficiency, xanthine deficiency. Finally, nephrolithiasis may be secondarily part of some other metabolic diseases, such as glycogen storage disease type 1 or inborn errors of metabolism leading to Fanconi syndrome (nephropathic cystinosis, tyrosinaemia type 1, fructose intolerance, Wilson disease, respiratory chain disorders, etc.). The diagnosis is based on highly specific investigations, including crystal identification, biochemical analyses and DNA study. The treatment of nephrolithiasis requires hydration as well as specific measures. Compliance is a major issue regarding the progression of renal damage, but the overall outcome mainly depends on extra-renal involvement in relation to the metabolic defect.     

The first case of adenine phosphoribosyltransferase deficiency with APRT Q0 (M1V) mutation in Japan

Adenine phosphoribosyltransferase (APRT) deficiency is an enzyme deficiency associated with purine metabolism, a hereditary disease that causes recurrent 2, 8-DHA stone formation due to a complete or partial APRT defect and slowly damages the renal function. Since APRT deficiency can be treated to prevent its progression to renal insufficiency, it is important to detect APRT gene mutations and make a definite diagnosis early. A 3.5-year-old girl presented with painful urination and dysuria, and was admitted to our hospital. The analysis of stones collected after spontaneous passage revealed 2, 8-dihydroxyadenine (DHA) urolithiasis. To make a definite diagnosis, we searched for the APRT gene mutations reported in Japanese. However, no APRT Q0 mutation was identified. Only a heterogeneous mutation, APRT J, was noted. Subsequently, we screened the gene mutation regions reported from Europe and the United States and identified a heterogeneous mutation at the start codon of APRT Q0 from methionine to valine. This is the first report of this mutation in Japan. She was diagnosed with APRT deficiency caused by a compound heterogeneous mutation : APRT Q0/(M1V) APRT J (M136T). We believe that the same gene mutation has been inherited among other Japanese. For the future genetic diagnosis of APRT deficiency, this is a valuable case.     

Rabson-Mendenhall syndrome: medullary sponge kidney, a new component

Rabson-Mendenhall syndrome is a rare genetic disorder characterized by severe insulin resistance, extreme hyperinsulinemia, postprandial hyperglycemia, growth retardation, and dysmorphisms. Enlargement of the kidneys and nephrocalcinosis have been described previously. We report a 10-year-old boy who presented with gross hematuria, unilateral hydronephrosis, and the initial diagnosis of bilateral extensive medullary nephrocalcinosis. Medullary sponge kidney (MSK) was included in the differential diagnosis given the ultrasound findings. Further evaluation by intravenous pyelogram confirmed the suspected bilateral MSK. Given the patient’s history of hydronephrosis due to an obstructing renal stone and MSK, urine calcium excretion was assessed and found to be markedly increased at 9.5 mg/kg per day. To our knowledge, this is the first report of Rabson-Mendenhall syndrome and an association with MSK. We recommend evaluation for nephrocalcinosis, MSK, and hypercalciuria in all children diagnosed with Rabson-Mendenhall syndrome.     

原发性高草酸尿症基因型与表型的研究进展

原发性高草酸尿症是儿童肾结石和慢性肾结石病的重要病因。反复发作的肾结石和肾钙质沉着症提示临床医师应考虑到先天基因缺陷导致的遗传代谢病。不幸的是,由于对原发性高草酸尿症基因型和表型认识上的缺乏,导致诊断和治疗上出现不可接受的延误,甚至造成严重后果。本文就原发性高草酸尿症的基因型与表型的特点、基因型与表型的关系以及原发性高...     

A case of bilateral renal calculi in a 1-year-old female with adenine phosphoribosyl transferase partial deficiency

We report a case of bilateral renal calculi in a 1-year-old female with adenine phosphoribosyl transferase (APRT) partial deficiency. She initially visited another institution with high fever as the major complaint. Computed tomography revealed a bilateral renal stone and left hydro nephrosis. In the urine, there were 2, 8-dihydroxyadenine (DHA) crystals. An analysis of the APRT gene revealed the APRT deficiency and the genotype to be APRT*J/APRT*Q0. We performed extracorporeal shock wave lithotripsy (ESWL) under general anesthesia, and as dissolution therapy we administered Meylon through the nephrostomy and citric acid orally. The stone disappeared from her kidney. The analysis of the stone fragments revealed 2,8- dihydroxyadenine (DHA) urolithiasis.     

Epidemiologic insights into pediatric kidney stone disease

The epidemiology of pediatric kidney stone has not yet been as rigorously defined as that of adult kidney stone disease. Herein, we review our recent epidemiologic works characterizing pediatric stone disease using the Kids’ Inpatient Database (KID). Specifically we investigated the age and gender distribution of pediatric kidney stone disease, changes in disease prevalence over time, and medical comorbidities associated with this disorder. We identified patients by International Classification of Disease 9th Edition (ICD-9) codes for renal and ureteral calculi as the primary diagnosis. Medical comorbidities were identified using specific comorbidity software. Statistical comparisons between children with and without stone disease were performed. In the first decade of life, stone disease was more prevalent among males than females; however, in the second decade of life females were more commonly affected. Of note, there was a significant increase in treated stone disease across both genders between 1997 and 2003. We also found that the risk of kidney stone diagnosis in children younger than 6 years of age was significantly associated with hypertension and diabetes mellitus. The gender distribution among pediatric stone formers varies significantly by age, although overall females have a greater prevalence than males. There is also a strong association of stone disease and both diabetes and hypertension, although this was only observed in children less than 6 years of age. Taken all together, these findings suggest that urolithiasis in the young child is a complex systemic disease process.     

2,8-Dihydroxyadeninuria: laboratory diagnosis and therapy control

This report is concerned with the experience gained with two 2,8-dihydroxyadenine (2,8-DHA) stone patients. When adenine phosphoribosyltransferase (APRT) deficiency is suspected, the risk of stone formation can be detected at an early stage from the crystalline urinary sediment. Infrared spectroscopic analysis of the crystals or of a urinary stone, if present, will confirm the diagnosis. Determination of the APRT activity will facilitate quantification of the enzyme deficiency and elucidation of the hereditary history. 2,8-DHA excretion in the 24-hour urine and its circadian rhythm were determined at 3-hour intervals using a new method of high performance liquid chromatography determination. This method also provides a means of monitoring the effectiveness of allopurinol therapy.     

Two heterozygous mutations of CLDN16 in a Japanese patient with FHHNC

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC, MIN 248250) is a rare autosomal recessive tubular disorder that eventually progresses to renal failure. However, the progression to end-stage renal failure can vary from patient to patient. A primary defect is related to impaired tubular resorption of magnesium and calcium in the thick ascending limb of Henles loop. Recently, paracellin-1 was identified as a renal tight junction protein predominantly expressed in TAL. Mutations of its gene (CLDN16) have been shown to cause FHHNC. We describe a sporadic Japanese case of FHHNC. The male patient showed hematuria, hypercalciuria, and nephrocalcinosis at 5 years of age. Hypomagnesemia was also noticed at this time. As renal function gradually deteriorated, further evaluation was performed at 14 years of age and a diagnosis of FHHNC was made. Despite several medications (magnesium supplementation, citrate, and hydrochlorothiazide), he eventually progressed to renal insufficiency at 19 years of age. Analysis of the CLDN16 gene demonstrated two heterozygous mutations (R149Q and R216C). Mutations of the same amino acids have already been described in FHHNC and thus these mutations might be the cause of the disease in our patient. Hence, we confirm the genetic impairment of the CLDN16 gene in a Japanese patient with FHHNC.     

Cystine urolithiasis in Finland

Cystine stone material was collected from 27 patients treated in various hospitals in Finland. The prevalence of cystine stones was found to be one/year/1,000,000 inhabitants. A total of 49 operations were performed on 20 patients, with five nephrectomies carried out as the first stage of treatment in the patients with stones. Extracorporeal shock wave lithotripsy (ESWL) failed to fragment cystine stones in one patient and percutaneous stone removal was necessary. The delay in the diagnosis of cystinuria averaged 5.1 years. Most patients with cystine stones had homozygous cystinuria. Anuria due to recurrent stone formation occurred in three patients. Chronic urinary tract infection was seen in nine out of 15 (60%) women patients and four of these nine had inflammatory changes in the kidneys diagnosed by urography. Early diagnosis of cystinuria is important to avoid kidney injury and recurrence of cystine stones.     

Follow-up of five patients with FHHNC due to mutations in the Paracellin-1 gene

Familial hypomagnesemia, hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive inherited disorder that has recently been attributed to a defect in the paracellin-1 ( PCLN-1)gene, encoding for a protein responsible for the tubular reabsorption of magnesium and calcium. Limited information is available on clinical course, therapy and prognosis. We provide information on five patients with FHHNC and their follow-up at our institution. Polyuria, nephrocalcinosis and hyperuricemia were the main clinical findings of a diagnosis at a median age of 4.4 years. The clinical course of PCLN-1 mutations as presented in this study is highly variable, ranging from compensated renal failure to end-stage renal failure - as happened in two of our patients. The progression to renal failure cannot be deduced from the initial presentation. Medical treatment does not appear to influence the progression of the disease. Despite calcium and magnesium substitution, normal values could not be achieved in these patients. Early treatment with vitamin D and calcium was essential to maintain growth. Adequate treatment allows for a normal height and pubertal development.     

Combined liver-kidney transplantation for primary hyperoxaluria type 1 in young children.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare condition in which deficiency of the liver enzyme alanine:glyoxylate aminotransferase leads to renal failure and systemic oxalosis. Combined liver-kidney transplantation (LKT) is recommended for end-stage renal failure (ESRF) in adults, but management of infants and young children is controversial. We retrospectively reviewed six children who underwent LKT for PH1. METHODS: The median age at diagnosis was 1.8 years (range 3 weeks to 7 years). Two children presented with severe infantile oxalosis at 3 and 9 weeks, five patients had ESRF with nephrocalcinosis and systemic oxalosis, (median duration of dialysis 1.3 years), and one had progressive chronic renal failure. Four children underwent combined LKT, one child staged liver then kidney, and one infant had an isolated liver transplant. The median age at transplantation was 8.9 years (range 1.7-15 years). RESULTS: Overall patient survival was four out of six. The two infants with PH1 and severe systemic oxalosis died (2 and 3 weeks post-transplant) due to cardiovascular oxalosis and sepsis. The other four children are well at median follow-up of 10 months (range 6 months to 7.4 years). No child developed hepatic rejection and all have normal liver function. Renal rejection occurred in three patients. Despite maximal medical management, oxalate deposits recurred in all renal grafts, contributing to graft loss in one (one of the infants who died), and significant dysfunction requiring haemodialysis post-transplant for 6 months. CONCLUSIONS: LKT is effective therapy for primary oxalosis with ESRF but has a high morbidity and mortality rate in children who present in infancy with nephrocalcinosis and systemic oxalosis. We feel that earlier LKT, or pre-emptive liver transplantation, may be a better therapeutic strategy to improve the outlook for these patients.     

Nephrocalcinosis and urolithiasis in children

The incidence of adult urolithiasis has increased significantly in industrialized countries over the past decades. Sound incidence rates are not available for children, nor are they known for nephrocalcinosis, which can appear as a single entity or together with urolithiasis. In contrast to the adult kidney stone patient, where environmental factors are the main cause, genetic and/or metabolic disorders are the main reason for childhood nephrocalcinosis and urolithiasis. While hypercalciuria is considered to be the most frequent risk factor, several other metabolic disorders such as hypocitraturia or hyperoxaluria, as well as a variety of renal tubular diseases, e.g., Dent's disease or renal tubular acidosis, have to be ruled out by urine and/or blood analysis. Associated symptoms such as growth retardation, intestinal absorption, or bone demineralization should be evaluated for diagnostic and therapeutic purposes. Preterm infants are a special risk population with a high incidence of nephrocalcinosis arising from immature kidney, medication, and hypocitraturia. In children, concise evaluation will reveal an underlying pathomechanism in >75% of patients. Early treatment reducing urinary saturation of the soluble by increasing fluid intake and by providing crystallization inhibitors, as well as disease-specific medication, are mandatory to prevent recurrent kidney stones and/or progressive nephrocalcinosis, and consequently deterioration of renal function.     

小儿上尿路结石伴肾功能不全的保留肾脏手术(附118例报告)

目的　探讨小儿上尿路结石所致肾功能不全保留肾脏手术的适应证及疗效。　方法　对 118例上尿路结石伴肾功能不全患儿的病理及临床资料进行回顾性分析。　结果　 118例患儿 88个肾及 30根输尿管切开取石术及肾造瘘术 ,痊愈 115例 ,治愈率 97.5 % ,死亡 3例 ,死亡率 2 .5 % ,术后无发生上尿路狭窄者。　结论　小儿上尿路结石所致急慢性肾功能不全 ,早期诊断 ,尽早解除梗阻是保护及改善肾功能的关键 ,根据病史、体征、患侧肾皮质厚度及肾功能情况 ,有无感染等综合判断是保留肾脏手术成功的重要条件。