![Pathophysiology of hypercalciuria. Hypercalciuric syndromes all are multisystemic diseases and are arbitrarily divided into three overlapping categories according to the primary or predominant disturbance. In each instance, secondary compensatory changes involve multiple hormones such as parathyroid hormone (PTH) and 1,25-dihydroxy-vitamin D3 [1,25-(OH) 2 vit D]. (A) Renal leak with secondary gut hyperabsorption and increased bone release. (B) Imbalance between bone formation and resorption. (C) Intestinal hyperabsorption. The three primary disturbances can occur simultaneously.](https://www.researchgate.net/profile/Orson-Moe-2/publication/8043920/figure/fig1/AS:394430591848455@1471050989726/Pathophysiology-of-hypercalciuria-Hypercalciuric-syndromes-all-are-multisystemic_Q320.jpg)
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Genetic Hypercalciuria
Abstract and Figures
Hypercalciuria is an important, identifiable, and reversible risk factor in stone formation. The foremost and most fundamental step in dissecting the genetics of hypercalciuria is understanding its pathophysiology. Hypercalciuria is a complex trait. This article outlines the various factors that compromise the attempt to dissect the genetics of hypercalciuria, summarizes the clinical and experimental monogenic causes of hypercalciuria, and outlines the initial results from attempts in studying polygenic hypercalciuria. Finally, the problem is set in perspective of the current database, technologic advances and limitations are highlighted, and prospects of further advances in the field are speculated upon.
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... trait or in association with other metabolic disorders 47 . The causes of hypercalciuria have been described as absorptive (increased gastrointestinal absorption), resorptive (increased bone resorption) or renal (decreased renal reabsorption) losses 59 . However, phenotyping patients in this manner has not proved to be clinically useful. ...
Kidney stones (also known as urinary stones or nephrolithiasis) are highly prevalent, affecting approximately 10% of adults worldwide, and the incidence of stone disease is increasing. Kidney stone formation results from an imbalance of inhibitors and promoters of crystallization, and calcium-containing calculi account for over 80% of stones. In most patients, the underlying aetiology is thought to be multifactorial, with environmental, dietary, hormonal and genetic components. The advent of high-throughput sequencing techniques has enabled a monogenic cause of kidney stones to be identified in up to 30% of children and 10% of adults who form stones, with ~35 different genes implicated. In addition, genome-wide association studies have implicated a series of genes involved in renal tubular handling of lithogenic substrates and of inhibitors of crystallization in stone disease in the general population. Such findings will likely lead to the identification of additional treatment targets involving underlying enzymatic or protein defects, including but not limited to those that alter urinary biochemistry.
... 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.
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.
Stabilization of bone structure and function involves multiple cell-to-cell and molecular interactions, in which the regulatory functions of post-translational modifications such as ubiquitination and deubiquitination shouldn't be underestimated. As the largest family of deubiquitinating enzymes, the ubiquitin-specific proteases (USPs) participate in the development of bone homeostasis and bone-related diseases through multiple classical osteogenic and osteolytic signaling pathways, such as BMP/TGF-β pathway, NF-κB/p65 pathway, EGFR-MAPK pathway and Wnt/β-catenin pathway. Meanwhile, USPs may also broadly regulate regulate hormone expression level, cell proliferation and differentiation, and may further influence bone homeostasis from gene fusion and nuclear translocation of transcription factors. The number of patients with bone-related diseases is currently enormous, making exploration of their pathogenesis and targeted therapy a hot topic. Pathological increases in the levels of inflammatory mediators such as IL-1β and TNF-α lead to inflammatory bone diseases such as osteoarthritis, rheumatoid arthritis and periodontitis. While impaired body metabolism greatly increases the probability of osteoporosis. Abnormal physiological activity of bone-associated cells results in a variety of bone tumors. The regulatory role of USPs in bone-related disease has received particular attention from academics in recent studies. In this review, we focuse on the roles and mechanisms of USPs in bone homeostasis and bone-related diseases, with the expectation of informing targeted therapies in the clinic.
Background
Nephrolithiasis as a feature of rheumatologic diseases is under recognized. Understanding presenting features, diagnostic testing is crucial to proper management.
Case presentation
A 32 year old woman with a history of recurrent complicated nephrolithiasis presented to a rheumatologist for a several month history of fatigue, dry eyes, dry mouth, arthralgias. She had a positive double-stranded DNA, positive SSA and SSB antibodies. She was diagnosed with Systemic Lupus erythematosus (SLE) and Sjogren's syndrome and was started on mycophenalate mofetil. Of relevance was a visit to her local emergency room 4 years earlier with profound weakness with unexplained marked hypokalemia and a non-anion gap metabolic acidosis. Approximately one year after that episode she developed flank pain and nephrocalcinosis. She had multiple issues over the ensuing years with stones and infections on both sides. Interventions included extracorporeal shockwave lithotripsy as well as open lithotomy and eventual auto-transplantation of left kidney for recurrent ureteric stenosis. 24 h stone profile revealed marked hypocitraturia, normal urine calcium, normal urine oxalate and uric acid. She was treated with potassium citrate. Mycophenolate was eventually stopped due to recurrent urinary tract infections and she was started on Belimumab. Because of recurrent SLE flares, treatment was changed to Rituximab (every 6 months) with clinical and serologic improvement. Her kidney stone frequency gradually improved and no further interventions needed although she continued to require citrate repletion for hypocitraturia.
Conclusions
Nephrolithiasis can be a prominent and even presenting feature in Sjogrens syndrome as well as other rheumatologic diseases. Prompt recognition and understanding disease mechanisms is important for best therapeutic interventions for kidney stone prevention as well as treatment of underlying bone mineral disease.
Résumé
La néphrocalcinose est définie par des dépôts de phosphate de calcium ou d’oxalate de calcium dans le parenchyme rénal, en particulier dans les cellules épithéliales des tubules rénaux et dans le tissu interstitiel. Il faut la différencier des néphrolithiases où les dépôts calciques se situent dans les cavités excrétrices rénales. La néphrocalcinose chez l’enfant n’est pas si rare, avec une augmentation de son incidence chez les enfants nés prématurément. Souvent de découverte fortuite, ses étiologies sont multiples et peuvent être classées en fonction du type radiologique de néphrocalcinose : médullaire, corticale ou mixte (diffuse). Les causes principales retrouvées chez l’enfant concernent la néphrocalcinose médullaire et comportent les tubulopathies héréditaires, en particulier l’acidose tubulaire distale et la maladie de Dent, les anomalies métaboliques telles que l’hypercalciurie idiopathique et les hyperoxaluries, et les formes iatrogènes secondaires, notamment aux surdosages en vitamine D. Chez le nouveau-né, il s’agit principalement de l’hypercalciurie du prématuré dont l’origine, multifactorielle, est en grande partie iatrogène. L’hyperoxalurie primitive, qui entraîne une néphrocalcinose diffuse d’apparition précoce et conduit à une insuffisance rénale chronique, ne doit pas être méconnue et systématiquement être recherchée. Afin de pouvoir établir un diagnostic spécifique, il est essentiel de prendre en compte l’anamnèse familiale, le contexte clinique ainsi que les données biologiques complètes. Instituer précocement un traitement étiologique adapté permettrait de prévenir ou de retarder l’évolution vers une insuffisance rénale chronique.
In this field there has been an explosion of information generated by scientific research. One of the beneficiaries of this has been the study of morphology, where new techniques and analyses have led to insights into a wide range of topics. Advances in genetics, histology, microstructure, biomechanics and morphometrics have allowed researchers to view teeth from alternative perspectives. However, there has been little communication between researchers in the different fields of dental research. This book brings together overviews on a wide range of dental topics linking genes, molecules and developmental mechanisms within an evolutionary framework. Written by the leading experts in the field, this book will stimulate co-operative research in fields as diverse as paleontology, molecular biology, developmental biology and functional morphology.
Recent advances in molecular biology have characterised a new class of chloride channels that are referred to as voltage-gated chloride channels (CLCs). To date 9 such CLCs (CLC-1 to CLC-7, CLC-Ka and CLC-Kb which are respectively encoded by the genes CLCN1 to CLCN7, CLCNKa and CLCNKb) have been identified in mammals. Mutations in 2 of these, referred to as CLC-5 and CLC-Kb, have been defined in the hypercalciuric nephrolithiasis disorders of Dent's disease and a form of Bartter's syndrome, respectively. In addition, other forms of Bartter's syndrome have been defined with mutations involving the bumetanide-sensitive sodium-potassium-chloride co-transporter (NKCC2) and the potassium channel ROMK. Finally, mutations of the thiazide-sensitive sodium chloride co-transporter (NCCT) are associated with Gitelman's syndrome, in which hypocalciuria and hypomagnesaemia a re notable features, These molecular genetic studies have increased our understanding of the renal tubular mechanisms that regulate mineral homeostasis.
The oculocerebrorenal (Lowe) syndrome is an X-linked recessive disorder characterized by congenital cataracts, hypotonia, developmental delay, poor growth and renal tubular dysfunction. Although the disorder has been mapped to chromosome Xq24-26, the underlying metabolic defect remains unknown. The renal component of the Lowe syndrome comprises tubular dysfunction, that is tubular proteinuria and generalized aminoaciduria progressing to the renal Fanconi syndrome, with later glomerular disease. Clinical problems typically include polyuria, acidosis, hypophosphatemia with rickets and eventually end stage renal disease. Hypercalciuria and its sequelae (nephrocalcinosis and nephrolithiasis) have not been described as cardinal features of the untreated disorder although they reportedly complicate vitamin D and calcium therapy of rickets. We discuss 5 boys with congenital cataracts, hypotonia, developmental delay, failure to thrive and the renal Fanconi syndrome who were diagnosed with the Lowe syndrome and in whom hypercalciuria was documented at diagnosis. We conclude that hypercalciuria and its sequelae may occur commonly in patients with the Lowe syndrome as a component of tubular dysfunction or a complication of therapy.
Very few patients with familial hypomagnesemia, hypercalciuria and nephrocalcinosis have been described. Information about clinical course, familial studies or evolution after renal transplantation is very scant. We have studied eight patients with this syndrome who belong to five different families. The mean age at diagnosis was 15 +/- 7 years (5 to 25 years). The primary clinical data were polyuria-polydipsia (8 cases), ocular abnormalities (5), recurrent urinary tract infections (5) and recurrent renal colics with stone passage (2). Bilateral nephrocalcinosis was observed in all cases. Every patient showed hypomagnesemia (1.1 +/- 0.2 mg/dl) with inappropriately high urinary magnesium (Mg) excretions (70 +/- 17 mg day), Mg clearances (4.4 +/- 1.2 ml/m) and Mg fractional excretions (16.2 +/- 7.1%). Hypercalciuria was present in every case except in those with advanced renal insufficiency. Serum parathormone levels were abnormally high. Serum calcium (Ca), phosphorus and potassium, and urinary excretions of uric acid and oxalate were normal. Neither chronic oral Mg administration nor thiazide diuretics normalized serum Mg levels or urinary Ca excretions, respectively. Follow-up was 6 +/- 4.5 years. Renal function worsened in every case with six patients starting on chronic dialysis after 4.3 +/- 3.8 years. The progression rate of renal insufficiency correlated with the severity of nephrocalcinosis. Five patients have received a kidney graft, and their serum Mg and urinary Ca have always been within normal values after transplantation. Twenty-six members; of four of the affected families were studied: none of them showed hypomagnesemia, renal insufficiency or nephrocalcinosis. However, eleven cases (42%) had hypercalciuria and four of them presented with recurrent renal stones. Two family members had medullary sponge kidneys. In conclusion, progression to renal insufficiency is common in this syndrome; oral Mg and thiazide diuretics are ineffective to correct abnormalities. After kidney graft, tubular handling of Mg and Ca was normal. A striking incidence (42%) of hypercalciuria was found in the familial study.
