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Familial Idiopathic Hypercalciuria
Abstract
The frequency of hypercalciuria was determined in the families of nine hypercalciuric patients with idiopathic hypercaliuria who formed recurrent calcium oxalate renal stones. Idiopathic hypercalciuria occurred in 26 of 73 relatives, in three consecutive generations of two families and in two successive generations of four other families. Multiple siblings or children of the probands were affected in three families. Nineteen of 44 first-degree relatives (43 per cent) had idiopathic hypercalciuria, as compared to seven of 29 (29 per cent) other relatives; there was no relation to age or sex. Renal stones were formed by 19 of the 44 first-degree relatives but by none of the others; nine of the 19 were women. We conclude that there is a familial form of hypercalciuria, which appears to be transmitted as an autosomal dominant trait. Stone disease is frequent in first-degree relatives, and affects both sexes equally.
... Hiperkalsiüri ve taş olgularında aile öyküsünde %40 oranında ürolitiyaz öyküsü vardır. 31,[81][82][83][84] İyi bir diyet öyküsü alınmalıdır. Hastanın sıvı ve tuz tüketimi, C vitamini veya D vitamini desteği, özel diyet (ketojenik diyet gibi) alıp almadığı sorgulanmalıdır. ...
... İH'ye neden olan gen ya da genler henüz tanımlanamamıştır, fakat hastalık tam olmayan penetranslı otozomal dominant (OD) kalıtılıyor gibi görünmektedir.10 Nitekim bir çalışmada sağlıklı çocukların %4'ünde İH bulunmuş, bu çocukların %40-50'sinde ise ürolitiyaz açısından pozitif aile öyküsü saptanmıştır.30,31 İH'den sorumlu mekanizmalar; kalsiyumun artmış intestinal absorpsiyonu (absorptif hiperkalsiüri), artmış kemik resorpsiyonu (resorptif hiperkalsiüri) ve/veya azalmış renal kalsiyum reabsorpsiyonudur (renal hiperkalsiüri).32 ...
Renal stones are a major health problem all over the world and endemic in some parts of the world, including Turkey. As in adulthood, renal stone cases are increasing day by day in children today and about 1 in 5 of the stone cases in Turkey are pediatric cases. In this increase, changing food habits and sedanter lyfestyle seems to be responsible. The causes of stone cases in children has also shifted from infectious to metabolic in recent years. The most important metabolic causes are hypercalciuria and hypocitraturia. Anatomical and functional abnormalities of the urinary system causing stasis follows the metabolic causes. The clinical presentation in children is not typical renal colic except during adolescence. As in any disease, anamnesis and physical examination are important in the diagnosis of the cause of renal stone disease. Especially in pediatric cases, it is necessary to question the existence of prematurity, medications used during prematurity period, presence of urinary system abnormality, frequent urinary tract infection history, presence of intestinal malabsorbtion, presence of consanguineous marriage and family history of kidney stones and renal failure. In all renal stone cases, the basis of treatment is the increase in fluid consumption. Other treatment methods are pharmacological agents that can be used according to the type of renal stone. Therefore, the chemical analysis of the reduced or extracted stones are very important both in protecting from the stones and treatment in which pharmacological agents will be given. Here, we have made a brief overview of the causes and medical treatments of childhood renal stones including pathophysiology.
... 33 In a study of adult patients with kidney stones and idiopathic hypercalciuria, hypercalciuria was also found in 43% of first-degree relatives, with a higher incidence of hypercalciuria seen in the second and third generations, strongly suggestive of a genetic basis of idiopathic hypercalciuria. 34 Known rare monogenetic disorders such as Dent disease typically present with familial hypercalciuria and kidney stone disease, and can be distinguished from idiopathic hypercalciuria by their unique disease features ( Table 1). ...
Idiopathic hypercalciuria is defined as excessive urine calcium excretion in the absence of an identifiable cause. It has been strongly associated with the risk of calcium kidney stone formation. Animal and human studies have suggested excessive bone mineral loss or increased gastrointestinal calcium absorption with abnormal renal calcium excretion may contribute to this process. In this article we will review the complex pathophysiology of idiopathic hypercalciuria and discuss clinical management and challenges.
... Overall, the available evidence indicates that urinary calcium excretion has a strong heritable component. In terms of heritability, which reflects how much variation is due to underlying genetic factors, the heritability of primary hypercalciuria was initially reported by Coe et al. [16] to be 43% among first-degree relatives and 36% among all relatives. In a family-based study of metabolic phenotypes, metabolic risk factors and phenotypes were evaluated and compared in families with at least two siblings with a previous history of calcium-component urolithiasis [17]. ...
Objective
Urolithiasis formation has been attributed to environmental and dietary factors. However, evidence is accumulating that genetic background can contribute to urolithiasis formation. Advancements in the identification of monogenic causes using high-throughput sequencing technologies have shown that urolithiasis has a strong heritable component.
Methods
This review describes monogenic factors implicated in a genetic predisposition to urolithiasis. Peer-reviewed journals were evaluated by a PubMed search until July 2023 to summarize disorders associated with monogenic traits, and discuss clinical implications of identification of patients genetically susceptible to urolithiasis formation.
Results
Given that more than 80% of urolithiases cases are associated with calcium accumulation, studies have focused mainly on monogenetic contributors to hypercalciuric urolithiases, leading to the identification of receptors, channels, and transporters involved in the regulation of calcium renal tubular reabsorption. Nevertheless, available candidate genes and linkage methods have a low resolution for evaluation of the effects of genetic components versus those of environmental, dietary, and hormonal factors, and genotypes remain undetermined in the majority of urolithiasis formers.
Conclusion
The pathophysiology underlying urolithiasis formation is complex and multifactorial, but evidence strongly suggests the existence of numerous monogenic causes of urolithiasis in humans.
... Therefore it is important to start effective treatment for correction of underling metabolic abnormalities in such patients. In our study, 60% of the patients had decreased urine 17 output which is comparable to international data. We had higher percentage of hypocitraturia (70%), 18,19 which is compare able to studies from Pakistan. ...
Objective: To determine the frequency of
hypocitraturia in the treated patient of urolithiasis
in Karachi, Pakistan.
Methodology: This is a cross sectional study was
conducted in department of urology at Jinnah
Postgraduate Medical Centre Karachi from
January to December 2018 for a period of one
year. It included 170 patients who had been
treated for stone disease and were stone free at
the time of study. We measured 24 hours urinary
excretion of citrate by enzymatic citrate lyase
analysis (Bergmeyer method).Results: Out of 170 patients, 115 (67.65%) were
male while 55(32.35%) were female. Mean age
was 39.34±11.87 years. Average urinary citrate
level was 262±199 mg/day. Hypocitraturia turned
out to be <320mg/day in 119(70%) patients and 51
(30%) patients had normal urinary citrate levels.
Hypocitraturia was more in patients with stone size
more than 2 cm and disease duration greater than
2 months with significant difference (p=0.001 and
p=0.012, respectively).Conclusion: Hypocitraturia is the most common
metabolic disorder and an important risk factor in
stone formation particularly in calcium stones.
Dietary modifications should also be used in
conjunction with medical therapy. (Rawal Med J
202;45:626-628).
Keywords: Hypocitraturia, urol ithiasis,
pyelolithotomy.
... Idiopathic hypercalciuria is characterized by normocalcemia in the absence of other diseases that could cause hypercalciuria. Although precise genes that contribute to idiopathic hypercalciuria have not been identified, the condition seems to arise as an interplay between several genes and the environment, and it follows an autosomal dominant pattern of inheritance with incomplete penetrance [73][74][75]. In order to definitively diagnose a patient with idiopathic hypercalciuria, several other conditions that cause normocalcemic hypercalciuria should be excluded such as hereditary hypophosphatemic rickets with hypercalciuria [76]. ...
The prevalence of pediatric nephrolithiasis has increased dramatically in the past two decades for reasons that have yet to be fully elucidated. Workup of pediatric kidney stones should include metabolic assessment to identify and address any risk factors predisposing patients to recurrent stone formation, and treatment should aim to facilitate stone clearance while minimizing complications, radiation and anesthetic exposure, and other risks. Treatment methods include observation and supportive therapy, medical expulsive therapy, and surgical intervention, with choice of treatment method determined by clinicians’ assessments of stone size, location, anatomic factors, comorbidities, other risk factors, and preferences and goals of patients and their families. Much of the current research into nephrolithiasis is restricted to adult populations, and more data are needed to better understand many aspects of the epidemiology and treatment of pediatric kidney stones.
... (21,22) La alta frecuencia de hipercalciuria encontrada coincide con la mayoría de las series, en que se ha mostrado como el factor de riesgo predominante de litiasis. (23,24) Está demostrada la marcada influencia genética que tiene este trastorno, como ha quedado evidenciado por Coe y colaboradores, no obstante, no se ha podido determinar un gen responsable con exactitud, pese a la existencia de múltiples candidatos; (25) en este trabajo se han estudiado individuos aislados en la población, sin recopilación de datos de sus familiares, por lo que no se pueden hacer consideraciones al respecto. ...
Introducción:
La urolitiasis se ha incrementado en las últimas décadas. La enfermedad renal poliquística autosómica dominante (ERPAD), enfermedad renal hereditaria más frecuente, ocupa un lugar preponderante.
Objetivos:
Identificar la frecuencia de presentación de los trastornos metabólicos urinarios en pacientes litiásicos cubanos con ERPAD y sin ella
Métodos:
Estudio descriptivo, transversal. Fueron estudiados 579 pacientes adultos sin ERPAD, seleccionados por muestreo simple aleatorio y los 21 pacientes con ERPAD, del total de pacientes con litiasis urinaria que se realizó estudio metabólico renal en el Laboratorio de Fisiopatología Renal del Instituto de Nefrología, en el periodo 2010-2015. Los datos fueron tomados de la historia clínica y del informe de estudio metabólico renal. La información se procesó de forma automatizada (SPSS 22.0). Se utilizó el promedio, desviación estándar, análisis de distribución de frecuencias y el test de homogeneidad.
Resultados:
En los pacientes con ERPAD predominó el sexo femenino (57,1 %), mientras que en los pacientes sin ERPAD, el masculino (63,4 %). Los trastornos más frecuentes en la población no poliquística fueron hipercalciuria (45,3 %) e hipofosfatemia (17,1 %). En los poliquísticos, aclaramiento aumentado de ácido úrico (38,1 %) e hipercalciuria (23,8 %). Se encontraron diferencias estadísticamente significativas para aumento del aclaramiento de ácido úrico (p = 0,01) e hiperfosfatemia (p = 0,04).
Conclusiones:
Los principales trastornos metabólicos de los pacientes litiásicos, tanto poliquísticos como no poliquísticos, son el aclaramiento de ácido úrico aumentado, hipercalciuria, hiperuricosuria e hipofosfatemia, aunque el orden de presentación es diferente. El aclaramiento de ácido úrico aumentado y la hiperfosfatemia se presentan con mayor frecuencia en los pacientes litiásicos poliquísticos.
... This was independent from dietary confounding factors [27], as no signiicant diference in calcium intake, sodium or urea excretion was observed after PTX. This might be due to underlying idiopathic hypercalciuria, as previously reported [10,[28][29][30][31]. Accordingly, Frøkjaer et al. [10] observed that the decrease of calciuria after PTX was signiicantly less marked in stone former as compared with non-stone formers. ...
Parathyroidectomy (PTX) is routinely performed in hypercalciuric renal stone patients with primary hyperparathyroidism (PHPT). However, some data indicate a persistent stone activity following PTX, raising the issue of the link between PHPT and stone disease. We performed an observational study on 30 renal stone patients diagnosed with PHPT. Patients were selected among 1448 hypercalciuric patients referred in our department for a diagnostic evaluation. Patients with no parathyroid surgery or any biological follow-up were excluded. Clinical and biological data (including 24-h urine collection and a calcium load test) were collected before and within 12 months following surgery. Stone recurrence was evaluated by direct phone contact (median 43 months). Comparison of biological data before and after surgery showed a significant decrease of ionized calcium and serum parathyroid hormone after PTX. All stones contained calcium-dependent species such as carbapatite, brushite or dihydrate calcium oxalate. Urine saturation indexes and calciuria significantly decreased after surgery (from 9.9 to 5.9 mmol/d, p < 0.0001), but a persistent hypercalciuria was detected in 47% of patients. The other stone risk factors including diuresis stayed similar. Stone activity that was increasing (from 0.20–0.30 to 0.50–0.75/year) the 2 years before PTX, significantly decreased after surgery [0.05–0.15/year (p < 0.001)]. PTX in calcium-dependent renal stone formers with PHPT significantly decreases both stone recurrence and urine saturation indexes. However, PTX unmasked an underlying renal stone disease related to idiopathic hypercalciuria in half of patients with a remaining stone activity, testifying the need for patient’s follow-up to prevent stone recurrence.
... En 1979, Coe et al. estudiaron los familiares de 9 pacientes con HI que habían eliminado cálculos de oxalato cálcico y comprobaron la existencia de HI en 26 de los 76 familiares estudiados, sin diferencias en la edad y el sexo; además, el 43% de los familiares en primer grado tenían HI. Los autores sugirieron que se trataba de una herencia autosómica dominante 95 . Posteriormente, varios trabajos insistieron en el carácter genético poligénico de la HI 36,[96][97][98] . ...
Idiopathic hypercalciuria (IH) is defined as that clinical situation in which an increase in urinary calcium excretion is observed, in the absence of hypercalcemia and other known causes of hypercalciuria. In recent years, its diagnosis in pediatric age has been more frequent because it has been known that it can debut with very different symptoms, in the absence of kidney stone formation. The discovery of genetic hypercalciuric stone-forming rats has allowed us to glimpse the pathophysiological mechanism of IH since they show many data in common with humans with IH as normal levels of blood calcium, intestinal calcium hyperabsorption, increased bone resorption and a defect in the renal tubular calcium reabsorption. In 1993, it was shown that in these animals there is an increase in the number of vitamin D receptors (VDR) in the intestine, which favors an increase in the functional capacity of calcitriol-VDR complexes that explains the increase in intestinal transport of calcium. The same happens at the bone level producing a greater resorption. In our opinion, IH is a ''metabolic anomaly'' or, better, an inheritable constitutive metabolic characteristic. In this sense, what patients with IH would inherit is the availability of having a greater number of VDRs in their cells than those with normal urinary calcium excretion. IH cannot be considered a sensu stricto disease, so pharmacological treatment must be individualized. Resumen: La hipercalciuria idiopática (HI) se define como aquella situación clínica en la que se comprueba un incremento en la eliminación urinaria de calcio, en ausencia de hipercalcemia y de otras causas conocidas de hipercalciuria. En los últimos años, su diagnóstico en la edad pediátrica ha sido más frecuente debido a que se ha conocido que puede debutar con síntomas muy diversos, en ausencia de formación de cálculos renales. El descubrimiento de las ratas hipercalciuricas ha permitido vislumbrar el mecanismo fisiopatológico de la HI ya que muestran muchos datos en común con los humanos con HI como niveles normales de calcemia, hiperabsorción intestinal de calcio, incremento de la resorción ósea y un defecto en la reabsorción tubular renal de calcio. En 1993, se demostró que en esos animales existe un incremento en el número de receptores de la vitamina D (VDR) del intestino, lo que favorece un aumento de la capacidad funcional de los complejos calcitriol-VDR que explica el incremento en el transporte intestinal de calcio. Lo mismo ocurre a nivel óseo produciéndose una mayor resorción. En nuestra opinión, la HI es una “anomalía metabólica” o, mejor, una característica metabólica constitutiva heredable. En este sentido, lo que los pacientes con HI heredarían es la disponibilidad de tener en sus células un mayor número de VDR que aquellas personas con calciurias normales. La HI no se puede considerar una enfermedad sensu stricto por lo que el tratamiento farmacológico debe ser individualizado. Keywords: Idiopathic hypercalciuria, Vitamin D receptor, Urinary lithiasis, Bone mineral density, Urinary tract infection, Palabras clave: Hipercalciuria idiopática, Receptor de la vitamina D, Litiasis urinaria, Densidad mineral ósea, Infección de vías urinarias
... Six (3.5%) patients in this study had a family history of urolithiasis. A familial occurrence for hypercalciuria, one of the main risk factors for idiopathic urolithiasis has been reported [21]. There is also an autosomal recessive inheritance for cystinuria and primary hyperoxaluria [22,23]. ...
Background: The incidence of upper tract urolithiasis is rising worldwide and treatment options have improved to include extracorporeal shock-wave lithotripsy (ESWL), percutaneous nephrolitothomy (PCNL) and ureterorenoscopy (URS) but sub- Saharan Africa has lagged behind the rest of the world. Open stone surgery was the main surgical treatment for upper tract stones in Kumasi until the introduction of ESWL five years ago. This study was conducted to evaluate ESWL in the management of upper tract urolithiasis in Kumasi, Ghana. Materials and methods: We prospectively analyzed all patients treated for upper tract urolithiasis at the Bomso Specialist Hospital in Kumasi from January 1, 2014, to December 31, 2017. Patients with upper tract stone of 2cm or less underwent ESWL. Data was obtained on patient demographics, stone characteristics, outcome of ESWL and analyzed with PASW Statistics for Windows, Version 18.0. Chicago: SPSS Inc. Results: There were 170 patients with upper tract urinary stones over the study period with a male: female ratio of 2:1. The mean age was 46.5 years. Inadequate fluid intake (<3L/day) was the most common predisposing factor, seen in 45.3% of the patients and the commonest symptom was flank pain, seen in 134 (78.8%) patients. There were 149 (87.6%) patients with solitary stones, mostly in the kidney 115 (67.6%). A total of 142 (83.5%) patients underwent ESWL with successful stone clearance in 120 patients. The most common complication of ESWL was flank pain 36 (25.4%). Conclusions:ESWL is effective for treatment of upper tract urolithiasis and should be available to selected patients in sub- Saharan Africa.
... In 40-50% of patients with recurrent renal stone, there was IH and it is the most common metabolic abnormality (34,35). Moreover, there is IH disease at rates of 35-40% in the first-and seconddegree relatives of patients with IH and renal stone (36). The prevalence is 5-10% in the general population with no stone and among first degree relatives (37,38). ...
Objective:The objective of this study is to assess clinical, laboratory and imaging findings, treatment styles and long-term outcomes of paediatric patients followed with idiopathic hypercalciuria (IH).Materials and Methods:We retrospectively evaluated and reviewed the files of patients aged between 3 months and 18 years with respect to age at the time of diagnosis, gender, admission complaints, follow-up period, laboratory and imaging findings (routine urinary analysis, blood and urinary biochemistry, parathormone, vitamin D level, urinary system ultrasonography and bone mineral density), onset and follow-up anthropometric data and complications.Results:The average ages of male and female patients (total: 52) diagnosed with IH were 30 and 22 years, respectively. The follow-up periods of male and female patients were 44.5±40.8 and 22.5±3.2 (6-96) months. The most frequent admission complaints were abdominal pain and underlying urinary tract infection (UTI) and history of haematuria. The average calcium level at the time of admission was 6.56±2.65 mg/kg/day, and the average calcium/creatinine level was 0.85±0.68 mg/mg. Kidney stones were determined in 41 (79%) patients. In total, 21 (40%) patients had UTI. During follow-up, UTI developed in 6 (11.5%) of them. Following medical treatment and/or nutrition recommendations, there was a reduction in the frequency of UTI rate, haematuria and enuresis (10/11 vs 6/25, p=0.030; 8/8 vs 3/33, p=0.001; and vs 1/46, p
... En 1979, Coe et al. estudiaron los familiares de 9 pacientes con HI que habían eliminado cálculos de oxalato cálcico y comprobaron la existencia de HI en 26 de los 76 familiares estudiados, sin diferencias en la edad y el sexo; además, el 43% de los familiares en primer grado tenían HI. Los autores sugirieron que se trataba de una herencia autosómica dominante 95 . Posteriormente, varios trabajos insistieron en el carácter genético poligénico de la HI 36,[96][97][98] . ...
Resumen: La hipercalciuria idiopática (HI) se define como aquella situación clínica en la que se comprueba un incremento en la eliminación urinaria de calcio, en ausencia de hipercalcemia y de otras causas conocidas de hipercalciuria. En los últimos años, su diagnóstico en la edad pediátrica ha sido más frecuente debido a que se ha conocido que puede comenzar con síntomas muy diversos, en ausencia de formación de cálculos renales. El descubrimiento de las ratas hipercalciúricas ha permitido vislumbrar el mecanismo fisiopatológico de la HI ya que muestran muchos datos en común con los humanos con HI, como niveles normales de calcemia, hiperabsorción intestinal de calcio, incremento de la resorción ósea y un defecto en la reabsorción tubular renal de calcio. En 1993, se demostró que en esos animales existe un incremento en el número de receptores de la vitamina D (VDR) del intestino, lo que favorece un aumento de la capacidad funcional de los complejos calcitriol-VDR que explica el incremento en el transporte intestinal de calcio. Lo mismo ocurre a nivel óseo produciéndose una mayor resorción. En nuestra opinión, la HI es una «anomalía metabólica» o, mejor, una característica metabólica constitutiva heredable. En este sentido, lo que los pacientes con HI heredarían es la disponibilidad de tener en sus células un mayor número de VDR que aquellas personas con calciurias normales. La HI no se puede considerar una enfermedad sensu stricto, por lo que el tratamiento farmacológico debe ser individualizado. Abstract: Idiopathic hypercalciuria (IH) is defined as that clinical situation in which an increase in urinary calcium excretion is observed, in the absence of hypercalcemia and other known causes of hypercalciuria. In recent years, its diagnosis in pediatric age has been more frequent because it has been known that it can debut with very different symptoms, in the absence of kidney stone formation. The discovery of genetic hypercalciuric stone-forming rats has allowed us to glimpse the pathophysiological mechanism of IH since they show many data in common with humans with IH as normal levels of blood calcium, intestinal calcium hyperabsorption, increased bone resorption and a defect in the renal tubular calcium reabsorption. In 1993, it was shown that in these animals there is an increase in the number of vitamin D receptors (VDR) in the intestine, which favors an increase in the functional capacity of calcitriol-VDR complexes that explains the increase in intestinal transport of calcium. The same happens at the bone level producing a greater resorption. In our opinion, IH is a ‘metabolic anomaly’ or, better, an inheritable constitutive metabolic characteristic. In this sense, what patients with IH would inherit is the availability of having a greater number of VDRs in their cells than those with normal urinary calcium excretion. IH cannot be considered a sensu stricto disease, so pharmacological treatment must be individualized. Palabras clave: Hipercalciuria idiopática, Receptor de la vitamina D, Litiasis urinaria, Densidad mineral ósea, Infección de vías urinarias, Keywords: Idiopathic hypercalciuria, Vitamin D receptor, Urinary lithiasis, Bone mineral density, Urinary tract infection
... The development of the next-generation sequencing (NGS) technology, allowing a rapid analysis of multiple genes, is an efficient and cost-effective screening method, increasing our chances to find new genetic mutations. Approximately half of the patients with idiopathic hypercalciuria have a positive family history of kidney stones [53]. Linkage analysis conducted in large families have identified a large number of loci associated with this condition, including the vitamin D receptor, 1-α-hydroxylase, the CaSR and the known crystallization modifiers such as osteopontin, Tamm-Horsfall protein, and osteocalcinrelated gene [1,2,54]. ...
In the last decades, proteomics has been largely applied to the Nephrology field, with the double aim to (1) elucidate the biological processes underlying renal diseases; (2) identify disease-specific biomarkers, predictor factors of therapeutic efficacy and prognostic factors of disease progression. Kidney stone disease, and in particular, inherited nephrolithiasis (INL) are not an exception. Given the multifactorial origin of these disorders, the combination of genomics and proteomics studies may complement each other, with the final objective to give a global and comprehensive mechanistic view. In this review, we summarize the results of recent proteomic studies which have expanded our knowledge about INL, focusing the attention on monogenic forms of nephrolithiasis (cystinuria, Dent’s disease, Bartter syndrome, distal renal tubular acidosis and primary hyperoxaluria), on polygenic hypercalciuria and on medullary sponge kidney disease.
... Hypercalciuria may be a manifestation of systemic diseases such as primary hyperparathyroidism or sarcoidosis, but is considered idiopathic if no underlying cause can be identified. While idiopathic hypercalciuria has been shown to have a genetic predisposition in some cases, it can also be influenced by environmental factors such as diet [40]. Although kidney stone formers have a higher risk of bone fracture than those in the general population [41], it is not clear that hypercalciuria is a cause. ...
The prevalence of nephrolithiasis is increasing worldwide. Understanding and implementing medical therapies for kidney stone prevention are critical to prevent recurrences and decrease the economic burden of this condition. Dietary and pharmacologic therapies require understanding on the part of the patient and the prescribing practitioner in order to promote compliance. Insights into occupational exposures and antibiotic use may help uncover individual risk factors. Follow-up is essential to assess response to treatment and to modify treatment plans to maximize therapeutic benefit.
... More than 50% all the patients with CaOx stones also have idiopathic hypercalciuria. This abnormality affects both sexes with equal frequency and is inherited as an autosomal dominant trait [64,65]. People with idiopathic hypercalciuria absorb more dietary calcium from the gut and excrete more calcium in the urine than do normal people. ...
The formation of urinary stone, urolithiasis, is one the oldest known disease affecting human throughout different civilizations and times. The exact pathophysiological mechanism of urolithiasis is not yet clear, as these calculi are of various types and too complex for simple understanding. A single theory cannot explain its formation; therefore, different theories are presented in various times for its explanation like free particle, fixed particle, Randall's plaque theory. In addition, various factors and components are identified that play an important role in the formation of these urinary calculi. In this review, composition of kidney stones, its prevalence/incidence, explanation of pathophysiological mechanisms and role of various factors; urinary pH, uric acid, parathyroid hormone, citrate, oxalate, calcium and macromolecules; osteopontin, matrix Gla protein, kidney injury molecules, urinary prothrombin fragment-1, Tamm-Horsfall protein, inter-α-inhibitors, have been discussed in detail.
... 3 For the same reason, they are also the most common metabolic anomalies observed in children who, without having eliminated kidney stones yet, have genetic predisposition to develop them. 4,5 This situation, though not specific to the pediatric age, is known as prelithiasis. 6 One of the earliest forms of clinical manifestation in children with prelithiasis is in the form of UTI. ...
Urinary tract infections (UTI) caused by Escherichia coli (E. coli) are common in patients with idiopathic hypercalciuria. As both UTI and hypercalciuria (prelithiasis) have a genetic basis, we wanted to know whether the family history of urolithiasis is more common in children with UTIs caused by E. coli. Secondarily, we wondered if the renal scars are more common in children with prelithiasis.
... Por otra parte, la hipercalciuria idiopática y la hipocitraturia son las causas más comunes de cálculos renales en pacientes tanto adultos como pediátricos 3 . De igual modo, son las anomalías metabólicas observadas más frecuentemente en niños que, sin haber aún eliminado cálculos renales, presentan predisposición genética a su formación 4,5 . Esta situación, que no es exclusiva de la edad pediátrica, se conoce como prelitiasis 6 . ...
Introduction:
Urinary tract infections (UTI) caused by Escherichia coli (E. coli) are common in patients with idiopathic hypercalciuria. As both UTI and hypercalciuria (prelithiasis) have a genetic basis, we wanted to know whether the family history of urolithiasis is more common in children with UTIs caused by E. coli. Secondarily, we wondered if the renal scars are more common in children with prelithiasis.
Material and methods:
Ambispective study with collected data from 104 patients (40 male, 64 female) followed after having been diagnosed of UTI by E. coli at least once. These patients were asked about the existence of urolithiasis in relatives. The calcium and citrate urinary elimination was qunatified in 80 children.
Results:
In the total sample, family history was positive for urolithiasis in a significantly higher frequency in those children (n=71; 68.3%) than in the control population in our area (29.7%; previously published data). Prelithiasis frequency in children with UTI was 47.5% (38/80). An association was observed between the diagnosis of prelithiasis both with family history of urolithiasis (P=.030) and the diagnosis of vesicoureteral reflux (P=.034). Children who developed renal scarring had an increased risk of prelithiasis (OR 5.3; P=.033).
Conclusions:
The frequency of family history of urolithiasis in children with UTI caused by E. coli is very high. Based on our results we hypothesize that the predisposition to lithiasis can involve a constitutively altered defense to E. coli and, therefore, a greater possibility for renal scars.
... Back pain is less common in children and, when present, is often described by the child as a single complaint of abdominal pain. We rst reported that the syndrome of idiopathic hypercalciuria (IH) is more often a cause of non-stone clinical complaints in children rather than a cause of urolithiasis (3,4). We termed this clinical complex as non-calculous symptomatic IH. ...
... Although the genetic component is often considered part of the stone formers' differential diagnosis, people with known genetic causes appear to be few. The familial association of calcium oxalate urolithiasis and primary hypercalciuria, the most common metabolic risk factor, has been corroborated by several familial studies [100][101][102]. The collective estimation for the likelihood of kidney stone formers having affected first-degree or more distant family members is 15-65%; only 5-20% of non-stone formers have relatives with nephrolithiasis [103,104]. ...
Nephrolithiasis is a highly prevalent disease worldwide with rates ranging from 7 to 13% in North America, 5–9% in Europe, and 1–5% in Asia. Due to high rates of new and recurrent stones, management of stones is expensive and the disease has a high level of acute and chronic morbidity. The goal of this study is to review the epidemiology of stone disease in order to improve patient care. A review of the literature was conducted through a search on Pubmed®, Medline®, and Google Scholar®. This review was presented and peer-reviewed at the 3rd International Consultation on Stone Disease during the 2014 Société Internationale d’Urologie Congress in Glasgow. It represents an update of the 2008 consensus document based on expert opinion of the most relevant studies. There has been a rising incidence in stone disease throughout the world with a narrowing of the gender gap. Increased stone prevalence has been attributed to population growth and increases in obesity and diabetes. General dietary recommendations of increased fluid, decreased salt, and moderate intake of protein have not changed. However, specific recommended values have either changed or are more frequently reported. Geography and environment influenced the likelihood of stone disease and more information is needed regarding stone disease in a large portion of the world including Asia and Africa. Randomized controlled studies are lacking but are necessary to improve recommendations regarding diet and fluid intake. Understanding the impact of associated conditions that are rapidly increasing will improve the prevention of stone disease.
... Second, most stones are spontaneously passed without therapeutic intervention, but at great pain and time lost from work. Families segregating an autosomal dominant type of absorptive hypercalciuria have been reported (2,3). There is also a strong genetic contribution to absorptive hypercalciuria in the general population. ...
... Hiperkalsiüri (HC) ÜSTH'lı çocuklarda saptanan en sık metabolik bozukluktur. İki yaşından büyük çocuklarda idrar kalsiyum içeriğinin >4 mg/kg/gün olması veya yaş için belirlenmiş standartlarda >95 persantil değerleri HC olarak adlandırılır (Tablo 2) (28)(29)(30)(31) . Yirmi dört saatlik idrar toplamak özellikle mesane kontrolü olmayan çocuklarda zor olacağından başlangıçta kalsiyum kreatinin oranına bakılması, yüksek çıkan olgularda tedaviye başlanmadan önce 24 saatlik idrar toplayıp HC'nin varlığının doğrulanması gerekir (1) . ...
Purpose of review:
To summarize the latest findings and developments in genomics for kidney stone disease (KSD) that help to understand hereditary pathomechanisms, identify high risk stone formers, provide early treatment and prevent recurrent kidney stone formation.
Recent findings:
Several gene loci associated to KSD have presently been discovered in large Genome-wide association studies. Monogenic causes are rare, but are thought to have higher penetrance, while polygenic causes are more frequent with less penetrance. Although there is a great effort identifying genetic causes of KSD, targeted therapies are scarce.
Summary:
There have been great advancements in genetic research in identifying genetic variants associated with KSD. Identifying these variants and understanding the underlying pathophysiology will not only provide individual risk assessment but open the way for new treatment targets and preventive care strategies.
The pathogenesis of pediatric nephrolithiasis is complex and often multifactorial. However, there are many identifiable underlying diseases and comorbid conditions that predispose children to developing kidney stones. This chapter will detail the many medical disorders that are associated with pediatric kidney stone disease. Both primary and secondary conditions will be examined, with a special focus on genetic causes of stone disease and medications-induced nephrolithiasis reviewed in more detail in separate chapters.KeywordsPediatric kidney stonesComorbid conditionsNephrolithiasis risk
p>There is strong evidence for a familial basis to renal stone disease. However, apart from a number of rare disorders for which the causative genetic mutations are known, our understanding of the heritability of renal stone disease is modest. To explore the familial basis of renal stone disease, the heritabilities of relevant biochemical trait were inspected and the possibility of renal stone linkage to a number of genetic loci was investigated.
Families displaying a clustering of renal stone disease were recruited to the project. Data on the inheritance of renal stone disease within each pedigree was gathered. Biochemical parameters were evaluated in relation to the individual pedigrees in order to dissect traits that might predict risk of renal stone disease. A number of different parameters were discovered to have a strong predictive value for stone disease in individual families.
A microsatellite-based approach to linkage analysis was developed. This approach was used to explore linkage between the renal stone forming trait and a number of candidate genes for renal stone disease. Quantitative biochemical traits that were predictive of renal stone disease were also analysed for linkage to the candidate regions. There was no evidence of linkage of the candidate gene loci with the renal stone phenotype or with the biochemical traits associated with renal stone disease. However the study did provide strong evidence for a quantitative trait locus affecting urinary citrate levels near the sodium-phosphate cotransporter 2 gene (NPT2) on chromosome 5q35 in one of the studied pedigrees.</p
Idiopathic hypercalciuria is characterized by normocalcemia in the absence of known systemic causes of hypercalciuria. Intestinal calcium (Ca) absorption is almost always increased, and serum 1,25(OH)2D levels are elevated in some but not all patients. Idiopathic hypercalciuria (IH) affects 5 to 7% of adults and children and is the single most common cause of Ca oxalate kidney stone formation and also causes low bone mass. All of the metabolic features of IH can be reproduced by the administration of calcitriol to normal adults. There is also evidence of 1,25(OH)2D3 overproduction in some IH subjects. Excess 1,25(OH)2D3 action appears responsible for the intestinal Ca hyperabsorption, increased bone resorption, and decreased renal tubule Ca reabsorption. Serum 1,25(OH)2D3 is elevated in about 60% of patients. Patients with normal serum 1,25(OH)2D3 levels have comparable elevations in intestinal Ca absorption, and the possibility of elevated tissue vitamin D receptor found in GHS rats is suggested by one study in IH subjects which found elevated peripheral blood monocyte levels. Further, GHS rats and IH patients share changes in Ca transport in intestine, bone, and kidney. The GHS model of human IH permits studies of the cellular and molecular mechanisms of hypercalciuria found in humans. In this model, increased levels of VDR protein in duodenum, kidney, and bone may explain the hyperabsorption of Ca, increased bone resorption, and decreased renal tubule Ca reabsorption even in the presence of normal circulating concentrations of 1,25D.
In our study, the mean, min, max, standard deviation, skew and kurtosis
parameters recorded for alpha, beta and delta waves were compared and it
can be seen that they may cause a change in the electrical amplitude values
in the brain. In addition, fast fourier transform (FFT) (FFT max frequency
and FFT maximum value) and power spectral density (PSD) (PSD
maximum frequency and PSD maximum power) were also detected in our
study. Statistical comparison was made between two tasks for alpha, beta
and delta wave. As a result of the statistical analysis, no significant change
was noticed (p> 0.05). Only a significant change in PSD max value was
found for delta wave (p <0.05).
In this study, our aim is to determine what kind of change the two
different responses given to the same numerical calculation on the
electrical activity of the brain EEG alpha, beta and delta waves. For this
reason, our study analyzed the state of EEG activity, especially in case of
a wrong answer to a correct answer. Although there are some increases and
decreases in the amplitudes of the brain waves, a significant statistical
change has not been determined. It is seen that new studies are needed to
support our study, and more detailed studies and more detailed methods
are needed regarding how the neural activity that the brain can change if
the brain responds incorrectly to a correct answer.
The various forms of Fanconi Renotubular syndromes (FRTS) offer significant challenges for clinicians and present unique opportunities for scientists who study proximal tubule physiology. This review will describe the clinical characteristics, genetic underpinnings, and underlying pathophysiology of the major forms of FRST. Although the classic forms of FRTS will be presented (e.g., Dent disease or Lowe syndrome), particular attention will be paid to five of the most recently discovered FRTS subtypes caused by mutations in the genes encoding for GATM, SLC34A1, EHHADH, HNF4A or NDUFAF6. We will explore how mutations in these genes revealed unexpected mechanisms that lead to compromised proximal tubule functions. We will also describe the inherent challenges associated with gene discovery studies based on findings derived from small, single-family studies by focusing the story of FRTS type 2 (SLC34A1). Finally, we will explain how extensive alternative splicing of HNF4A has resulted in confusion with mutation nomenclature for FRTS type 4.
Nephrolithiasis (kidney stones, urolithiasis) is the formation of stone-like concretions in the urinary system caused by the precipitation of calcium, phosphate, urate, and other molecules. The incidence and prevalence of nephrolithiasis among adults in the USA have been increasing for 30 years. According to the National Health and Nutrition Examination Survey (NHANES 2007–2010), current prevalence is estimated at 8.8% among adults as compared to a prevalence of 5.2% in 1994. More than $5.3billion is spent directly and indirectly on treatment for nephrolithiasis annually in the USA. Kidney stones are more prevalent in men than women with a lifetime risk of 12% in men and 6% in women. As many as 20% of patients present with renal colic and require urological intervention.
SURGICAL PROCEDURES IN COVID-19 PATIENTS
Kidney stone formation is common, and most stone formers have no known systemic disease as the cause of their stone formation but may have one or more metabolic abnormalities that result from a combination of genetic predisposition and environmental factors. Calcium stones are by far the most common, accounting for 80% of all stones; uric acid stones are found in about 10% of stone formers, struvite in about 5%, and other types of stones are considered rare. Stones form because urine becomes supersaturated with the stone material, allowing crystals to form in the kidney. All stone formers have at least modest crystal deposits in papillary tissue, which often serve as anchor sites for stone formation and growth. Idiopathic calcium oxalate stones are the most commonly seen in practice and affect people of all ages, increasingly including children. Many idiopathic stone formers have one or more metabolic abnormalities that provoke supersaturation, including hypercalciuria, hyperoxaluria, or hypocitraturia. The physiologic processes that lead to abnormal excretion of these solutes are currently under investigation.
Kidney stones affect 11% of men and 6% of women and incidence is on the rise. When stones pass through urinary tract, the symptoms can be debilitating, resulting in significant morbidity and cost to the medical system. Almost half of first-time stone formers have a recurrent episode. Thus, prevention of recurrence is important. Evaluation of the patient for stone-forming risk factors includes history, imaging, stone analysis, and metabolic workup. The evaluation begins with patient history focused on medications, diseases, diet, and work habits that increase the risk. Imaging with computed tomography and ultrasound helps determine the burden, size, and location of the stone(s) in the urinary tract. Stone analysis when available is important in determining the type of stone. Metabolic workup consists of targeted blood work and urinalysis as well as a 24-hour urine collection. The cornerstone of the stone evaluation is the 24-hour urine collection especially in recurrent stone formers as its components determine the risk of stone formation. The 24-hour urine values guide medical management and dietary modifications for prevention of recurrence, and follow-up collections determine the effectiveness of the therapy.
The incidence of nephrolithiasis in pediatrics is increasing. All children with nephrolithiasis should have a complete metabolic evaluation on initial presentation, as a metabolic risk factor may be found in the majority of children. Careful consideration in pediatric nephrolithiasis of rare genetic causes of kidney stones disease should be at the forefront of the evaluation, as many of these disorders present in childhood and are associated with a lifetime of morbidities related to nephrolithiasis as well as the risk for development of chronic kidney disease. Treatment of the underlying metabolic risk factors helps prevent further stone formation and the morbidities associated with stone formation, such as pain, surgery, and chronic kidney disease.
Calcium kidney stones are common worldwide. Most are idiopathic and composed of calcium oxalate. Calcium phosphate is present in around 80% and may initiate stone formation. Stone production is multifactorial with a polygenic genetic contribution. Phosphaturia is found frequently among stone formers but until recently received scant attention. This review examines possible mechanisms for the phosphaturia and its relevance to stone formation from a wide angle. There is a striking lack of clinical data. Phosphaturia is associated, but not correlated, with hypercalciuria, increased 1,25 dihydroxy-vitamin D [1,25 (OH) 2 D], and sometimes evidence of disturbances in proximal renal tubular function. Phosphate reabsorption in the proximal renal tubules requires tightly regulated interaction of many proteins. Paracellular flow through intercellular tight junctions is the major route of phosphate absorption from the intestine and can be reduced therapeutically in hyperphosphatemic patients. In monogenic defects stones develop when phosphaturia is associated with hypercalciuria, generally explained by increased 1,25 (OH) 2 D production in response to hypophosphatemia. Calcification does not occur in disorders with increased FGF23 when phosphaturia occurs in isolation and 1,25 (OH) 2 D is suppressed. Candidate gene studies have identified mutations in the phosphate transporters, but in few individuals. One genome-wide study identified a polymorphism of the phosphate transporter gene SLC34A4 associated with stones. Others did not find mutations obviously linked to phosphate reabsorption. Future genetic studies should have a wide trawl and should focus initially on groups of patients with clearly defined phenotypes. The global data should be pooled.
The Ca²⁺-sensing receptor (CaSR) is a dimeric family C G protein-coupled receptor that is expressed in calcitropic tissues such as the parathyroid glands and the kidneys and signals via G proteins and β-arrestin. The CaSR has a pivotal role in bone and mineral metabolism, as it regulates parathyroid hormone secretion, urinary Ca²⁺ excretion, skeletal development and lactation. The importance of the CaSR for these calcitropic processes is highlighted by loss-of-function and gain-of-function CaSR mutations that cause familial hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, respectively, and also by the fact that alterations in parathyroid CaSR expression contribute to the pathogenesis of primary and secondary hyperparathyroidism. Moreover, the CaSR is an established therapeutic target for hyperparathyroid disorders. The CaSR is also expressed in organs not involved in Ca²⁺ homeostasis: it has noncalcitropic roles in lung and neuronal development, vascular tone, gastrointestinal nutrient sensing, wound healing and secretion of insulin and enteroendocrine hormones. Furthermore, the abnormal expression or function of the CaSR is implicated in cardiovascular and neurological diseases, as well as in asthma, and the CaSR is reported to protect against colorectal cancer and neuroblastoma but increase the malignant potential of prostate and breast cancers.
Five to ten percent of adults and children express the idiopathic hypercalciuria (IH) phenotype, which is the single most common cause of Ca oxalate kidney stone formation and is often accompanied by low bone mass. All of the metabolic features of IH can be reproduced in healthy volunteers by administration of small doses of 1,25(OH)2D3. 1,25(OH)2D3 overproduction with elevated serum levels occurs in about 60% of IH subjects, whereas the remainder has normal serum 1,25(OH)2D3 levels. Excess 1,25(OH)2D3 appears responsible for the intestinal Ca hyperabsorption, increased bone resorption, and decreased renal tubule Ca reabsorption. Patients with normal serum 1,25(OH)2D3 levels have comparable elevations in intestinal Ca absorption and bone resorption and decreased renal tubule Ca reabsorption, which may be due to amplification of circulating 1,25(OH)2D3 biologic activity through elevated tissue vitamin D receptor (VDR). The latter has been demonstrated in genetic hypercalciuric stone-forming rats and in peripheral blood monocytes from IH kidney stone formers. The animal homolog of human IH shares the changes in Ca metabolism with IH patients, and the model permits studies of the cellular and molecular mechanisms of hypercalciuria found in humans. Insights into the genetic and pathophysiologic changes associated with increased activity of the VDR are needed to develop more targeted therapies to reduce comorbidities including nephrolithiasis and prevent bone loss.
Kidney stones are prevalent, cause considerable morbidity though little mortality. The most common metabolic abnormality in patients with kidney stones is hypercalciuria, which is a complex metabolic trait that is dependent on three major organs: the amount of dietary calcium absorbed, any net calcium released from bone resorption in excess of formation, and the extent to which filtered calcium is reabsorbed in the renal tubule. Each of these calcium fluxes is under control of number of factors and hormones, including parathyroid hormone and 1,25-dihydroxy-vitamin D. Whether a patient forms a kidney stone is dependent not only on the magnitude of the hypercalciuria but also on urinary volume, excretion of other ions, including oxalate, citrate, and phosphate, and on local factors in the urinary tract. Hypercalciuria, and resultant stone formation, is a partially inherited trait. Given the many determinants of not only urine calcium excretion, but also the other factors that determine whether a patient will form a kidney stone, it is clear that multiple genetic loci are involved. In this chapter, we will describe the progress made in understanding the genetic basis for hypercalciuria and stone formation in both experimental models and in man.
Renal tubular acidosis is a term applied to several conditions in which metabolic acidosis is caused by specific defects in renal tubular hydrogen ion secretion. Three types of renal tubular acidosis generally are recognized based on the nature of the tubular defect. Nephrolithiasis occurs only in type I renal tubular acidosis, a condition marked by an abnormality in the generation and maintenance of a hydrogen ion gradient by the distal tubule. A forme fruste of type I renal tubular acidosis has been described in which the characteristic defect in distal hydrogen ion secretion occurs in the absence of metabolic acidosis (incomplete renal tubular acidosis). Type I renal tubular acidosis is a heterogeneous disorder that may be hereditary, idiopathic or secondary to a variety of conditions. Secondary type I renal tubular acidosis in sporadic cases is associated most commonly with autoimmune diseases, such as Sjögren’s syndrome and systemic lupus erythematosus, and it occurs more frequently in women than men.
This chapter focuses on the genetics of renal stones and in particular those associated with hypercalciuric renal stone disease (nephrolithiasis) in man. The greatest risk factor for nephrolithiasis, after controlling for known dietary determinants, is having an affected family member. Families with idiopathic hypercalciuria (IH) and recurrent calcium oxalate stones usually reveal an autosomal dominant mode of inheritance. Patients with autosomal dominant hypocalcaemia with hypercalciuria (ADHH) usually have mild hypocalcaemia that is generally asymptomatic but may in some patients be associated with carpopedal spasm and seizures. Studies of monogenic forms of hypercalciuric nephrolithiasis, e.g., Bartter syndrome, Dent's disease, autosomal dominant hypocalcemic hypercalciuria, hypercalciuric nephrolithiasis with hypophosphatemia, and familial hypomagnesemia with hypercalciuria have helped to identify a number of transporters, channels, and receptors that are involved in regulating the renal tubular reabsorption of calcium.
The elucidation of the metabolism of vitamin D has increased our understanding of mineral homeostasis. Vitamin D is produced in the skin as cholecalciferol (vitamin D3) and is absorbed in the small bowel as both vitamin D3 and D2 (ergocalciferol). Since the parent compound cannot be readily measured, estimates of vitamin D stores are made from assays of the circulating 25-hydroxy metabolites. In normal individuals, dermal synthesis seems to be much more important than the diet as a source of vitamin D. Circulating 25(OH)D3 is more abundant than 25(OH)D2 even in the winter and despite vitamin D2 dietary supplementation (Poskitt et al., 1979). Since vitamin D2 and D3 are hydroxylated at a comparable rate (Whyte et al., 1979), this implies that dermal synthesis is more important than diet in normal circumstances. Similarly, 25(OH)D levels correlate, not with dietary intake, but rather with recorded sunlight and season of the year (Stryd et al., 1979). Conversion to 25(OH)D occurs mainly in the microsomal fraction of the liver. This conversion is inhibited mainly by the liver and plasma pool of vitamin D and 25(OH)D, rather than by calcium and phosphate (Bhattacharya and DeLuca, 1973; Mawer, 1977). Control is not rigorous, however, and 25(OH)D levels do reflect provision of parent vitamin D to the liver. By contrast, the circulating levels of the 1,25(OH)2D metabolites do not correlate well with nutritional vitamin D status and are normal or low with vitamin D loading (Hughes et al., 1976). Circulating levels of 25(OH)D are 10–40 ng/ml in the United States, depending on season and latitude, and lower in Great Britain. 25(OH)D undergoes enterohepatic circulation (Arnaud et al., 1975), but the significance of this observation remains unclear; possibly, enhanced delivery to the intestine facilitates 24-hydroxylation (see below).
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.
Renal stone disease is a frequent condition, causing a huge burden on health care systems globally. Calcium-based calculi account for around 75% of renal stone disease and the incidence of these calculi is increasing, suggesting environmental and dietary factors are acting upon a preexisting genetic background. The familial nature and significant heritability of stone disease is known, and recent genetic studies have successfully identified genes that may be involved in renal stone formation. The detection of monogenic causes of renal stone disease has been made more feasible by the use of high-throughput sequencing technologies and has also facilitated the discovery of novel monogenic causes of stone disease. However, the majority of calcium stone formers remain of undetermined genotype. Genome-wide association studies and candidate gene studies implicate a series of genes involved in renal tubular handling of lithogenic substrates, such as calcium, oxalate, and phosphate, and of inhibitors of crystallization, such as citrate and magnesium. Additionally, expression profiling of renal tissues from stone formers provides a novel way to explore disease pathways. New animal models to explore these recently-identified mechanisms and therapeutic interventions are being tested, which hopefully will provide translational insights to stop the growing incidence of nephrolithiasis.
The most common presentation of nephrolithiasis is idiopathic calcium stones in patients without systemic disease. Most stones are primarily composed of calcium oxalate and form on a base of interstitial apatite deposits, known as Randall's plaque. By contrast some stones are composed largely of calcium phosphate, as either hydroxyapatite or brushite (calcium monohydrogen phosphate), and are usually accompanied by deposits of calcium phosphate in the Bellini ducts. These deposits result in local tissue damage and might serve as a site of mineral overgrowth. Stone formation is driven by supersaturation of urine with calcium oxalate and brushite. The level of supersaturation is related to fluid intake as well as to the levels of urinary citrate and calcium. Risk of stone formation is increased when urine citrate excretion is <400 mg per day, and treatment with potassium citrate has been used to prevent stones. Urine calcium levels >200 mg per day also increase stone risk and often result in negative calcium balance. Reduced renal calcium reabsorption has a role in idiopathic hypercalciuria. Low sodium diets and thiazide-type diuretics lower urine calcium levels and potentially reduce the risk of stone recurrence and bone disease.
The term idiopathic hypercalciuria (IH) has been assigned to normocalcemic hypercalciuria of unknown etiology. The syndrome is characterized by an abnormally high renal excretion of calcium; normocalcemia, normo- or hypo-phosphatemia and high frequency of renal calcium stones (1). The mechanism underlying the hypercalciuria in IH is not known with certainty and two different abnormalities have been proposed as the primary cause: intestinal hyperabsorption or decreased tubular reabsorption of calcium (2, 3). Elevated serum levels of parathyroid hormone have been observed in IH by several investigators and considered by some to reflect secondary hyperparathyroidism as a response to renal calcium loss (4), and by others “normocalcemic” primary hyperparathyroidism (5,6).
Normokalzämische Hyperkalziurie und normourikämische Hyperurikosurie sind jene Stoffwechselstörungen, welche am häufigsten bei Harnsteinpatienten nachgewiesen werden können und welche in kausalem Zusammenhang mit der Harnsteindiathese gebracht werden. Nun ist bis zum jetzigen Zeitpunkt nicht bekannt, ob es sich bei diesen metabolischen Störungen um angeborene Zustandsbilder handelt, oder ob sie im Laufe des Lebens auftreten, bzw. ob ihr Erscheinen zeitlich limitiert ist und sie plötzlich wieder verschwinden. Während die normourikämische Hyperurikosurie zweifellos mit der Purinaufnahme in der Nahrung zusammenhängt, wenngleich sie nicht ausschließlich durch sie erklärt werden kann, berichtete PAK kürzlich über eine Langzeitbeobachtung von einigen Patienten mit renaler bzw. intestinaler Hyperkalziurie, bei welchen keine Änderung der Stoffwechselsituation über Jahre zu verzeichnen war (1). Dies veranlaßte ihn zu der Vermutung, daß es sich um ein zeitlich nicht limitiertes Krankheitsbild handelt, und er empfahl demzufolge eine lebenslange medika - mentöse Therapie.
Epidemiologic studies regarding renal lithiasis have been published since the 1940s. These studies were primarily based on hospital survey analyses, thus, excluding stone disease not requiring hospitalization. In general, stones occur in 9 to 20 persons per 10,000 population.1,2 Roughly 12% of the population is expected to have a urinary stone at some time in their lives.3 The annual patient cost in the United States was at least $47.3 million during 1974.4 Approximately 80% of stones consist of calcium oxalate, 10% struvite, and 7% uric acid.5
The causes for the hypercalciuria and diagnostic criteria for the various forms of hypercalciuria were sought in 56 patients with hypercalcemia or nephrolithiasis (Ca stones), by a careful assessment of parathyroid function and calcium metabolism. A study protocol for the evaluation of hypercalciuria, based on a constant liquid synthetic diet, was developed. In 26 cases of primary hyperparathyroidism, characteristic features were: hypercalcemia, high urinary cyclic AMP (cAMP, 8.58+/-3.63 SD mumol/g creatinine; normal, 4.02+/-0.70 mumol/g creatinine), high immunoreactive serum parathyroid hormone (PTH), hypercalciuria, the urinary Ca exceeding absorbed Ca from intestinal tract (Ca(A)), high fasting urinary Ca (0.2 mg/mg creatinine or greater), and low bone density by (125)I photon absorption. The results suggest that hypercalciuria is partly secondary to an excessive skeletal resorption (resorptive hypercalciuria). The 22 cases with renal stones had normocalcemia, hypercalciuria, intestinal hyperabsorption of calcium, normal or low serum PTH and urinary cAMP, normal fasting urinary Ca, and normal bone density. Since their Ca(A) exceeded urinary Ca, the hypercalciuria probably resulted from an intestinal hyperabsorption of Ca (absorptive hypercalciuria). The primacy of intestinal Ca hyperabsorption was confirmed by responses to Ca load and deprivation under a metabolic dietary regimen. During a Ca load of 1,700 mg/day, there was an exaggerated increase in the renal excretion of Ca and a suppression of cAMP excretion. The urinary Ca of 453+/-154 SD mg/day was significantly higher than the control group's 211+/-42 mg/day. The urinary cAMP of 2.26+/-0.56 mumol/g creatinine was significantly lower than in the control group. In contrast, when the intestinal absorption of calcium was limited by cellulose phosphate, the hypercalciuria was corrected and the suppressed renal excretion of cAMP returned towards normal. Two cases with renal stones had normocalcemia, hypercalciuria, and high urinary cAMP or serum PTH. Since Ca(A) was less than urinary Ca, the hypercalciuria may have been secondary to an impaired renal tubular reabsorption of Ca (renal hypercalciuria). Six cases with renal stones had normal values of serum Ca, urinary Ca, urinary cAMP, and serum PTH (normocalciuric nephrolithiasis). Their Ca(A) exceeded urinary Ca, and fasting urinary Ca and bone density were normal. The results support the proposed mechanisms for the hypercalciuria and provide reliable diagnostic criteria for the various forms of hypercalciuria.
Circulating levels of immunoreactive parathyroid hormone (PTH) were measured in 40 patients with idiopathic hypercalciuria (IH) before and during reversal of hypercalciuria with thiazide, and in four normal subjects before and during induction of hypercalciuria with furosemide. 26 patients with IH had elevated serum PTH levels. The remaining patients had normal levels. Although the correlation was not complete, high PTH levels were generally found in patients who had more severe average urinary calcium losses. When initially elevated. PTH levels fell to normal or nearly normal values during periods of thiazide administration lasting up to 22 months. When initially normal, PTH levels were not altered by thiazide. Reversal of hyperparathyroidism by thiazide could not be ascribed to the induction of hypercalcemia, since serum calcium concentration failed to rise in a majority of patients. Renal hypercalciuria produced by furosemide administration elevated serum PTH to levels equivalent to those observed in patients with IH. The findings in this study help to distinguish between several current alternative views of IH and its relationship to hyperparathyroidism. Alimentary calcium hyperabsorption cannot be the major cause of IH with high PTH levels, because this mechanism could not elevate PTH. Idiopathic hypercalciuria cannot be a variety of primary hyperparathyroidism, as this disease is usually defined, because PTH levels are not elevated in all patients and, when high, are lowered by reversal of hypercalciuria. Primary renal loss of calcium could explain the variable occurrence of reversible hyperparathyroidism in IH, since renal hypercalciuria from furosemide elevates serum PTH in normal subjects. Consequently, a reasonable working hypothesis is that IH is often due to a primary renal defect of calcium handling that leads, by unknown pathways, to secondary hyperparathyroidism.
A group of 273 children with minor complaints was screened for idiopathic hypercalciuria by measurement of the urine Ca/Cr. Borderline or definitely high levels were noted in 17 of these children, 11 of whom were boys. More intensive metabolic studies were completed on four of these children and on three children who were noted to have symptomatic renal stones associated with idiopathic hypercalciuria. These studies suggest that IH, well recognized in adults, may have its origins in childhood and that appropriate management, if initiated in childhood, may have significant long-term benefits.
The 24-h urinary excretion of calcium was measured in a group of male idiopathic stone-formers and in their age-, weight-, and sex-matched controls. The mean 24-h urinary excretion of calcium was significantly higher in the stone-formers than in their controls (P < 0.001) but there was considerable overlap between the two groups.An examination of the frequency distributions using probit transformation analysis showed that the two distributions were of the same form and were super-imposable when the urinary excretion of calcium of every stone-former was reduced by 75 mg/day. Both distributions were non-Gaussian with significant positive coefficients of skewness. This asymmetry was due to a distortion only at the lower end of each frequency distribution since the probit transformations showed that the upper 70% of values in each population belonged to a Gaussian distribution.It is suggested that the distortion at the lower end of each distribution is due to a build-up of values over a range of limits below which urinary calcium excretions in a given population do not normally fall. The shape of the probit transformation curve is consistent with a build-up of values over a range of limits in which the frequency of each limit belongs to a Gaussian distribution. This “distribution of limits” extends over the range 50–250 mg calcium/day for normal men and 125–325 mg/day for stoneformers.