Calcium-containing Kidney Stones Research Articles

MiR-148b-5p regulates hypercalciuria and calcium-containing nephrolithiasis

Calcium-containing stones represent the most common form of kidney calculi, frequently linked to idiopathic hypercalciuria, though their precise pathogenesis remains elusive. This research aimed to elucidate the molecular mechanisms involved by employing urinary exosomal microRNAs as proxies for renal tissue analysis. Elevated miR-148b-5p levels were observed in exosomes derived from patients with kidney stones. Systemic administration of miR-148b-5p in rat models resulted in heightened urinary calcium excretion, whereas its inhibition reduced stone formation. RNA immunoprecipitation combined with deep sequencing identified miR-148b-5p as a suppressor of calcitonin receptor (Calcr) expression, thereby promoting urinary calcium excretion and stone formation. Mice deficient in Calcr in distal epithelial cells demonstrated elevated urinary calcium excretion and renal calcification. Mechanistically, miR-148b-5p regulated Calcr through the circRNA-83536/miR-24-3p signaling pathway. Human kidney tissue samples corroborated these results. In summary, miR-148b-5p regulates the formation of calcium-containing kidney stones via the circRNA-83536/miR-24-3p/Calcr axis, presenting a potential target for novel therapeutic interventions to prevent calcium nephrolithiasis.Graphical abstract

Risk Factors of Asymptomatic Kidney Stone Passage in Adults with Recurrent Kidney Stones.

Kidney stones are a common health problem and are characterized by a high risk of recurrence. A certain number of kidney stones passed asymptomatically. Data regarding the frequency of asymptomatic spontaneous stone passages are limited. To assess the frequency of asymptomatic spontaneous stone passage and its covariates, we conducted a post-hoc analysis of the prospective randomized NOSTONE trial. All asymptomatic spontaneous stone passages were identified by comparing the total number of kidney stones on low-dose non-contrast CT imaging at the beginning and end of the study, considering symptomatic stone passages and surgical stone removal. The statistical analysis focused on the association of independent variables and the number of asymptomatic spontaneous stone passages using linear regression analyses. Of the 416 randomized patients, 383 with both baseline and end-of-study CT were included in this analysis. The median follow-up period was 35 months, the median patient age was 49 years (IQR:40 - 55), and 20% of the patients were female. A total of 442 stone events occurred in 209 out of 383 (55%) patients: 217 out of 442 (49%) were symptomatic spontaneous stone passages, 67 out of 442 (15%) were surgically removed stones, and 158 out of 442 (36%) were asymptomatic spontaneous stone passages. The median size of asymptomatic stones (2.4 mm; IQR:1.95-3.4) and the size of symptomatic stones (2.15 mm; IQR:1.68-2.79) that passed spontaneously were not significantly different (p=0.37). The number of asymptomatic spontaneous stone passages was significantly associated with a higher number of stones on CT at randomization (P=0.001). Limitations include the lack of data on stone size at the time of passage and overrepresentation of White men. Asymptomatic stone passage was common in patients with recurrent calcium-containing kidney stones. The higher the number of stones at presentation, the more likely it was that a kidney stone would spontaneously pass over time without causing any symptoms.

Association of single nucleotide genetic polymorphisms of vitamin D receptor and calcium-sensitive receptor with calcium-containing kidney stones in Chinese Dai populations: a prospective multi-center study.

To evaluate the association between vitamin D receptor (VDRs) and calcium-sensitive receptor (CaSR) gene polymorphisms and calcium-containing kidney stones (CCKS) in Dai populations. A total of 160 CCKS patients and 87 healthy controls were included in this study. CCKS was confirmed using urological computed tomography (CT), plain abdominal radiograph, or surgical lithotomy. Stone samples obtained during surgery were analyzed using infrared spectroscopy. Venous blood and 24-h urine samples were collected and analyzed using Sanger sequencing and high-performance liquid chromatography, respectively. Genetic variants in the VDR gene (rs7975232, rs2228570, rs731236, and rs1544410) and CaSR gene (rs7652589, rs1801725, and rs1042636) were identified through sequence analysis. Analysis of genotype and allele frequencies revealed that the rs7975232 polymorphism in the VDR gene and the rs7652589 allele in the CaSR gene were significantly associated with CCKS. Furthermore, patients carrying the AC and AA genotypes of rs7975232 showed a higher incidence of hypocitraturia compared to those with other genotypes (p < 0.05). The AA and GG genotypes of rs1042636 and the AA genotype of rs7652589 were significantly associated with hypercalciuria (p < 0.05). CCKS in this study population may be closely related to hypocitraturia caused by the VDR locus rs7975232 polymorphism and hypercalciuria caused by the CaSR locus rs1042636 and rs7652589 polymorphism.

The Association Between &lt;i&gt;Sodium Citrate Cotransporter (NaDC-1)&lt;/i&gt; Gene Polymorphism and Urinary Citrate Excretion in Patients with Calcium-containing Kidney Stones

The Association Between &lt;i&gt;Sodium Citrate Cotransporter (NaDC-1)&lt;/i&gt; Gene Polymorphism and Urinary Citrate Excretion in Patients with Calcium-containing Kidney Stones

Vitamins as regulators of calcium-containing kidney stones - new perspectives on the role of the gut microbiome.

Calcium-based kidney stonedisease is a highly prevalent and morbid condition, with an often complicated and multifactorial aetiology. An abundance of research on the role of specific vitamins (B6, C and D) in stone formation exists, but no consensus has been reached on how these vitamins influence stone disease. As a consequence of emerging research on the role of the gut microbiota in urolithiasis, previous notions on the contribution of these vitamins to urolithiasis are being reconsidered in the field, and investigation into previously overlooked vitamins (A, E and K) was expanded. Understanding how the microbiota influences host vitamin regulation could help to determine the role of vitamins in stone disease.

Hydrochlorothiazide and Prevention of Kidney-Stone Recurrence

BackgroundNephrolithiasis is one of the most common conditions affecting the kidney and is characterized by a high risk of recurrence. Thiazide diuretic agents are widely used for prevention of the recurrence of kidney stones, but data regarding the efficacy of such agents as compared with placebo are limited. Furthermore, dose–response data are also limited.MethodsIn this double-blind trial, we randomly assigned patients with recurrent calcium-containing kidney stones to receive hydrochlorothiazide at a dose of 12.5 mg, 25 mg, or 50 mg once daily or placebo once daily. The main objective was to investigate the dose–response effect for the primary end point, a composite of symptomatic or radiologic recurrence of kidney stones. Radiologic recurrence was defined as the appearance of new stones on imaging or the enlargement of preexisting stones that had been observed on the baseline image. Safety was also assessed.ResultsIn all, 416 patients underwent randomization and were followed for a median of 2.9 years. A primary end-point event occurred in 60 of 102 patients (59%) in the placebo group, in 62 of 105 patients (59%) in the 12.5-mg hydrochlorothiazide group (rate ratio vs. placebo, 1.33; 95% confidence interval [CI], 0.92 to 1.93), in 61 of 108 patients (56%) in the 25-mg group (rate ratio, 1.24; 95% CI, 0.86 to 1.79), and in 49 of 101 patients (49%) in the 50-mg group (rate ratio, 0.92; 95% CI, 0.63 to 1.36). There was no relation between the hydrochlorothiazide dose and the occurrence of a primary end-point event (P=0.66). Hypokalemia, gout, new-onset diabetes mellitus, skin allergy, and a plasma creatinine level exceeding 150% of the baseline level were more common among patients who received hydrochlorothiazide than among those who received placebo.ConclusionsAmong patients with recurrent kidney stones, the incidence of recurrence did not appear to differ substantially among patients receiving hydrochlorothiazide once daily at a dose of 12.5 mg, 25 mg, or 50 mg or placebo once daily. (Funded by the Swiss National Science Foundation and Inselspital; NOSTONE ClinicalTrials.gov number, NCT03057431.)

Possibilities of multislice computed tomography in assessing the structural and compositional features of calcium-containing urinary stones

The aim: to study the X-ray density index (HU) in calcium-containing urinary stones with different structural and compositional features. The structural and compositional features of 118 samples of calcium-containing urinary stones, which were obtained as a result of extracorporeal shock wave lithotripsy, percutaneous nephrolithotripsy and ureteroscopic lithotripsy in patients with kidney and ureteral stones were studied. The structural features of the stones were evaluated by conducting a crystal-optical analysis, during which the linear dimensions, shape, color and degree of transparency of crystalline elements were estimated, and the volume fractions of the amorphous and crystalline phases in the sample structure were calculated. The compositional features of kidney stones were studied on the basis of a qualitative and quantitative assessment of their mineral composition by infrared spectroscopy. X-ray density of calcium-containing kidney stones was assessed based on the data of computed tomography without contrast, which was performed in all patients in the preoperative period. Structural and compositional features of calcium-containing urinary stones are characterized by the presence in their composition of calcium oxalate compounds in the form of vewellite and weddelite, as well as calcium phosphate in the form of apatite, hydroxylapatite, fluorapatite, carbonate apatite, which, depending on the stage of crystallization, can be in amorphous, amorphous-crystalline or crystalline state. The X-ray density of this type of urinary stones, according to multislice computed tomography, corresponds to the range of 1090-1785 HU. There is a direct correlation between the level of X-ray density of the stone and the volume fraction of the crystalline phase in its structure.

Regional features of actinides deposition in kidney stones of patients with urolithiasis

Uranium is one of the most studied actinoids, widely used in the nuclear industry, and can accumulate in drinking water, soil, plants, and calcium-containing body tissues. The purpose of the work was to investigate the presence of uranium isotopes U-235 and U-238 in the composition of kidney stones of patients with urolithiasis living in the Kharkiv region. The content of U-235 and U-238 was investigated in samples of kidney stones obtained as a result of minimally invasive surgical interventions for urolithiasis in 57 patients, residents of the Kharkiv region, using gamma activation analysis on a linear electron accelerator. According to the results of our research U-235 and U-238 were detected in 13 (27%) samples of calcium-containing kidney stones, the mineral composition of which was represented by calcium oxalate monohydrate (wevellite), calcium oxalate dihydrate (weddellite) and phosphate-calcium compounds (apatite, hydroxyapatite, fluorapatite, carbonateapatite). The content of the above-mentioned isotopes in the composition of kidney stones was equal to ~ 1 ppm (mkg/g). We concluded that timely treatment of urolithiasis will help minimize the toxic effect of uranium on kidney structures. Keywords: uranium, Kharkiv region, uroliths.

Mechanisms Underlying Calcium Nephrolithiasis.

Nephrolithiasis is a worldwide problem with increasing prevalence, enormous costs, and significant morbidity. Calcium-containing kidney stones are by far the most common kidney stones encountered in clinical practice, and thus, hypercalciuria is the greatest risk factor for kidney stone formation. Hypercalciuria can result from enhanced intestinal absorption, increased bone resorption, or altered renal tubular transport. Kidney stone formation is complex and driven by high concentrations of calcium-oxalate or calcium-phosphate in the urine. After discussing the mechanism mediating renal calcium salt precipitation, we review recent discoveries in renal tubular calcium transport from the proximal tubule, thick ascending limb, and distal convolution. Furthermore, we address how calcium is absorbed from the intestine and mobilized from bone. The effect of acidosis on bone calcium resorption and urinary calcium excretion is also considered. Although recent discoveries provide insight into these processes, much remains to be understood in order to provide improved therapies for hypercalciuria and prevent kidney stone formation.

The Activation of ROS/NF-κB/MMP-9 Pathway Promotes Calcium-Induced Kidney Crystal Deposition.

Idiopathic hypercalciuria is an important risk factor for the formation of calcium-containing kidney stones. Matrix metalloproteinase-9 (MMP-9) is closely related to cell and tissue remodeling and is involved in ectopic tissue calcification. However, little is known about its role in kidney stone formation. In this study, we found that the expression of MMP-9 and that of osteoblastic-related proteins was increased in normal rat kidney epithelial-like (NRK-52E) cells following treatment with a high concentration of calcium, while the knockout or overexpression of MMP-9 could, respectively, significantly inhibit or upregulate the expression of osteoblastic-related proteins and calcium crystal deposition. In addition, apoptosis and calcium crystal deposition were significantly reduced in Sprague–Dawley rats with 1,25(OH)2D3-induced hypercalciuria following MMP-9 inhibitor I treatment. Furthermore, inhibiting reactive oxygen species (ROS) production or the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway significantly reduced calcium-induced MMP-9 expression and calcium crystal deposition. In summary, our results suggested that a high calcium concentration promotes epithelial–osteoblastic transformation and calcium crystal deposition in renal tubule cells by regulating the ROS/NF-κB/MMP-9 axis and identified a novel role for MMP-9 in regulating calcium-induced calcium crystal deposition in renal tubules.

Challenges in the management of chronic hypoparathyroidism.

The first adjunctive hormone therapy for chronic hypoparathyroidism, recombinant human parathyroid hormone (1–84) (rhPTH(1–84)) was approved by the FDA in January 2015. Since the approval of rhPTH(1–84), growing interest has developed in other agents to treat this disorder in both the scientific community and among pharmaceutical companies. For several reasons, conventional therapy with calcium and activated vitamin D supplementation, magnesium supplementation as needed, and occasionally thiazide-type diuretic therapy remains the mainstay of treatment, while endocrinologists and patients are constantly challenged by limitations of conventional treatment. Serum calcium fluctuations, increased urinary calcium, hyperphosphatemia, and a constellation of symptoms that limit mental and physical functioning are frequently associated with conventional therapy. Understanding how conventional treatment and hormone therapy work in terms of pharmacokinetics and pharmacodynamics is key to effectively managing chronic hypoparathyroidism. Multiple questions remain regarding the effectiveness of PTH adjunctive therapy in preventing or slowing the onset and progression of the classical complications of hypoparathyroidism, such as chronic kidney disease, calcium-containing kidney stones, cataracts, or basal ganglia calcification. Several studies point toward an improvement in the quality of life during replacement therapy. This review will discuss current clinical and research challenges posed by treatment of chronic hypoparathyroidism.Key points:Conventional therapy with calcium and activated forms of vitamin D are currently the mainstays of treatment for most patients with chronic hypoparathyroidism.Hormone therapy can be administered through FDA-approved once-daily rhPTH(1–84), or off-label multiple-daily injections of teriparatide. The former is the only FDA-approved drug, with safety and efficacy supported by a randomized placebo-controlled trial and open-label long-term extension trial data.Twice-daily teriparatide has been used in children safely for up to 10 years.New pharmacological options that replace the deficient hormone wi ll likely be available within the next few years.

Changes in urinary risk profile after short-term low sodium and low calcium diet in recurrent Swiss kidney stone formers

BackgroundKidney stone disease is common in industrialized countries. Recently, it has attracted growing attention, because of its significant association with adverse renal outcomes, including end stage renal disease. Calcium-containing kidney stones are frequent with high recurrence rates. While hypercalciuria is a well-known risk factor, restricted intake of animal protein and sodium, combined with normal dietary calcium, has been shown to be more effective in stone prevention compared with a low-calcium diet. Notably, the average sodium intake in Switzerland is twice as high as the WHO recommendation, while the intake of milk and dairy products is low.MethodsWe retrospectively analyzed Swiss recurrent kidney stone formers (rKSF) to test the impact of a low-sodium in combination with a low-calcium diet on the urinary risk profile. In patients with recurrent calcium oxalate containing stones, we investigated both, the consequence of a low-sodium diet on urinary volume and calcium excretion, and the influence of a low-sodium low-calcium diet on urinary oxalate excretion.ResultsOf the 169 patients with CaOx stones, 49 presented with hypercalciuria at baseline. The diet resulted in a highly significant reduction in 24-h urinary sodium and calcium excretion: from 201 ± 89 at baseline to 128 ± 88 mmol/d for sodium (p < 0.0001), and from 5.67 ± 3.01 to 4.06 ± 2.46 mmol/d (p < 0.0001) for calcium, respectively. Urine volume remained unchanged. Notably, no increase in oxalate excretion occurred on the restricted diet (0.39 ± 0.26 vs 0.39 ± 0.19 mmol/d, p = 0.277). Calculated Psf (probability of stone formation) values were only predictive for the risk of calcium phosphate stones.ConclusionA diet low in sodium and calcium in recurrent calcium oxalate stone formers resulted in a significant reduction of urinary calcium excretion, but no change in urine volume. In this population with apparently low intake of dairy products, calcium restriction does not necessarily result in increased urinary oxalate excretion. However, based on previous studies, we recommend a normal dietary calcium intake to avoid a potential increase in urinary oxalate excretion and unfavorable effects on bone metabolism in hypercalciuric KSFs.

Do "inhibitors of crystallisation" play any role in the prevention of kidney stones? A critique.

A critical examination of data in the literature and in as yet unpublished laboratory records on the possible role of so-called inhibitors of crystallisation in preventing the formation of calcium-containing kidney stones leads to the followingconclusions. So-called inhibitors of spontaneous "self-nucleation" are unlikely to play any role in the initiation of the crystallisation of CaOx or CaP in urine because excessive urinary supersaturation of urine with respect to these salts dominates the onset of "self-nucleation" within the normal time frame of the transit of tubular fluid through the nephron (3-4min). Inhibitors of the crystal growth of CaOx crystals may or may not play a significant role in the prevention of CaOx stone-formation since once again excessive supersaturation of urine can overwhelm any potential effect of the inhibitors on the growth process. However, they may play a role as inhibitors of crystal growth at lower levels of metastable supersaturation when the balance between supersaturation and inhibitors is more equal. Inhibitors of CaOx crystal aggregation may play a significant role in the prevention of stones, since they do not appear to be strongly affected by excessive supersaturation, either in vitro or in vivo. Inhibitors of CaOx crystal binding to renal tubular epithelium may exist but further studies are necessary to elucidate their importance in reducing the risk of initiating stones in the renal tubules. Inhibitors of CaOx crystal binding to Randall's Plaques and Randall's Plugs may exist but further studies are necessary to elucidate their importance in reducing the risk of initiating stones on renal papillae. There may be an alternative explanation other than a deficiency in the excretion of inhibitors for the observations that there is a difference between CaOx crystal size and degree of aggregation in the fresh, warm urines of normal subjects compared those in urine from patients with recurrent CaOx stones. This difference may depend more on the site of "self-nucleation" of CaOx crystals in the renal tubule rather than on a deficiency in the excretion of so-called inhibitors of crystallisation by patients with CaOx stones. The claim that administration of potassium citrate, potassium magnesium citrate or magnesium hydroxide reduces the rate of stone recurrence may be due to the effect of these forms of medication on the supersaturation of urine with respect to CaOx and CaP rather than to any increase in "inhibitory activity" attributed to these forms of treatment. In summary, there is a competition between supersaturation and so-called inhibitors of crystallisation which ultimately determines the pattern of crystalluria in stone-formers and normals. If the supersaturation of urine with respect to CaOx reaches or exceeds the 3-4min formation product of that salt, then it dominates the crystallisation process both in terms of "self-nucleation" and crystal growth but appears to have little or no effect on the degree of aggregation of the crystals produced. At supersaturation levels of urine with respect to CaOx well below the 3-4min formation product of that salt, the influence of inhibitors increases and some may affect not only the degree of aggregation but also the crystal growth of any pre-formed crystals of CaOx at these lower levels of metastability.

Factors associated with patient recall of individualized dietary recommendations for kidney stone prevention.

Dietary approaches to preventing the recurrence of idiopathic calcium-containing kidney stones are effective. However, a lifelong commitment to prevention is challenging for many patients. Multiple patient factors likely account for compliance and adherence with dietary recommendations. We examined patients' recall and compliance with dietary recommendations provided during clinical evaluation. Of 275 patients who received dietary recommendations from a dietitian, 112 completed an investigator-designed survey querying their recollection of dietary recommendations. Patients' responses were compared with the recommendations actually provided as entered in patients' medical records. Patients (62% male, 56±13 years; 38% female, 52±14 years) were provided 3.4±1.1 recommendations (min-max, 1-6) and recalled 67% of recommendations. Highest recalls were for (i) lower meat/fish/poultry intake, (ii) higher fluid intake and (iii) lower sodium (⩾68% for all). Lowest recalls were for weight loss, using citrus juices and increasing fruits/vegetables (⩽61% for all). Forty-seven percent of patients given 1-3 recommendations recalled 100%, whereas only 23% of patients provided >3 recommendations did so (P=0.011). Even though 38% of patients reported some difficulty following dietary recommendations, nearly all (91%) said that they were willing to continue following them. Higher patient recall is associated with ⩽3 dietary recommendations. Patient recall of recommendations that were not actually provided ('false recall') may contribute to reduced recall and confusion about the most important dietary strategies to reduce their stone risk. Accordingly, providers should prioritize the most important dietary recommendations, reserving those less important for follow-up, and address any confusion patients have from information received prior to evaluation.

Dietary recommendations and treatment of patients with recurrent idiopathic calcium stone disease.

This review describes the various dietary regimens that have been used to advise patients on how to prevent the recurrence of their calcium-containing kidney stones. The conclusion is that although there is some general advice that may be useful to many patients, it is more efficacious to screen each patient individually to identify his/her main urinary, metabolic, nutritional, environmental, and lifestyle risk factors for stone-formation and then tailor specific advice for that particular patient based on the findings from these investigations. If the patient can be motivated to adhere strictly to this conservative approach to the prophylactic management of their stone problem over a long time period, then it is possible to prevent them from forming further stones. This approach to stone management is considerably less expensive than any of the procedures currently available for stone removal or disintegration. In the UK, for each new stone episode prevented by this conservative approach to prophylaxis it is calculated to save the Health Authority concerned around £2000 for every patient treated successfully. In the long term, this accumulates to a major saving within each hospital budget if most stone patients can be prevented from forming further stones and when the savings are totalled up country-wide saves the National Exchequer considerable sums in unclaimed Sick Pay and industry a significant number of manpower days which would otherwise be lost from work. It is also of immense relief and benefit to the patients not to have to suffer the discomfort and inconvenience of further stone episodes.

Uromodulin upregulates TRPV5 by impairing caveolin-mediated endocytosis

Uromodulin (UMOD) is synthesized in the thick ascending limb and secreted into urine as the most abundant protein. Association studies in humans suggest protective effects of UMOD against calcium-containing kidney stones. Mice carrying mutations of Umod found in human uromodulin-associated kidney disease (UAKD) and Umod deficient mice exhibit hypercalciuria. The mechanism for UMOD regulation of urinary Ca2+ excretion is incompletely understood. We examined if UMOD regulates TRPV5 and TRPV6, channels critical for renal transcellular Ca2+ reabsorption. Coexpression with UMOD increased whole-cell TRPV5 current density in HEK293 cells. In biotinylation studies UMOD increased TRPV5 cell-surface abundance. Extracellular application of purified UMOD upregulated TRPV5 current density within physiological relevant concentration ranges. UMOD exerted a similar effect on TRPV6. TRPV5 undergoes constitutive caveolin-mediated endocytosis. UMOD had no effect on TRPV5 in a caveolin-1 deficient cell line. Expression of recombinant caveolin-1 in these cells restored the ability of UMOD to upregulate TRPV5. Secretion of UAKD-mutant UMOD was markedly reduced and coexpression of mutant UMOD with TRPV5 failed to increase its current. Immunofluorescent studies demonstrated lower TRPV5 expression in Umod−/− mice compared to wild-type. UMOD upregulates TRPV5 by acting from extracellular and by decreasing endocytosis of TRPV5. The stimulation of Ca2+ reabsorption via TRPV5 by UMOD may contribute to protection against kidney stone formation.

The Relation Between Bone and Stone Formation

Hypercalciuria is the most common metabolic abnormality found in patients with calcium-containing kidney stones. Patients with hypercalciuria often excrete more calcium than they absorb, indicating a net loss of total-body calcium. The source of this additional urinary calcium is almost certainly the skeleton, the largest repository of calcium in the body. Hypercalciuric stone formers exhibit decreased bone mineral density (BMD), which is correlated with the increase in urine calcium excretion. The decreased BMD also correlates with an increase in markers of bone turnover as well as increased fractures. In humans, it is difficult to determine the cause of the decreased BMD in hypercalciuric stone formers. To study the effect of hypercalciuria on bone, we utilized our genetic hypercalciuric stone-forming (GHS) rats, which were developed through successive inbreeding of the most hypercalciuric Sprague-Dawley rats. GHS rats excrete significantly more urinary calcium than similarly fed controls, and all the GHS rats form kidney stones while control rats do not. The hypercalciuria is due to a systemic dysregulation of calcium homeostasis, with increased intestinal calcium absorption, enhanced bone mineral resorption, and decreased renal tubule calcium reabsorption associated with an increase in vitamin D receptors in all these target tissues. We recently found that GHS rats fed an ample calcium diet have reduced BMD and that their bones are more fracture-prone, indicating an intrinsic disorder of bone not secondary to diet. Using this model, we should better understand the pathogenesis of hypercalciuria and stone formation in humans to ultimately improve the bone health of patients with kidney stones.

The mechanism of hypocalciuria with NaCl cotransporter inhibition

Thiazide diuretics are used to prevent the recurrence of calcium-containing kidney stones. The ability of these drugs to reduce urinary calcium excretion has a key role in this process. Although studies have shown a reduction in the recurrence rate of calcium-containing stones in patients treated with thiazides, whether hypocalciuria results from increased calcium reabsorption in the proximal or distal nephron is still unclear. When extracellular fluid volume is considerably reduced, the proximal tubule is likely to have a major role in thiazide-induced hypocalciuria. This process frequently occurs when high doses of thiazides and sodium restriction are prescribed for the treatment of kidney stone disease. The distal tubule is predominantly involved in NaCl cotransporter inhibition-induced hypocalciuria when the extracellular fluid volume is not reduced, a clinical scenario observed in patients with Gitelman syndrome. In this Perspectives article, we discuss the evidence supporting the hypocalciuric effects of NaCl cotransporter inhibition in the proximal and distal nephron.

Thiazides diuretics in the treatment of nephrolithiasis: are we using them in an evidence-based fashion?

In the 1980s a change occurred in hydrochlorothiazide prescribing practices for hypertension from high-dose (50 mg/day) to low-dose (12.5-25 mg/day) therapy. However, randomized controlled trials (RCT) for prevention of calcium-containing kidney stones (CCKS) employed only high doses (≥ 50 mg/day). We hypothesized that these practices have resulted in underdosing of hydrochlorothiazide for prevention of CCKS. Patients with a filled prescription for thiazide diuretics that underwent a 24-h urine stone risk factor analysis were eligible. Those with evidence that thiazide was prescribed for CCKS were further analyzed. Of 107 patients, 102 were treated with hydrochlorothiazide, 4 with indapamide, and one with chlorthalidone. Only 35% of hydrochlorothiazide-treated patients received 50 mg/day; a dose previously shown to reduce stone recurrence. Fifty-two percent were prescribed 25 mg and 13% 12.5 mg daily, doses that were not studied in RCT. Evidence-based hydrochlorothiazide use was suboptimal regardless of where the patient received care (Nephrology or Endocrinology clinic). In a small subset of patients (n = 6) with 24-h urinary calcium excretion measured at baseline and after 2 hydrochlorothiazide doses (25 and ≥ 50 mg), there was a trend toward decreased urinary calcium excretion as the dose was increased from 25 to ≥ 50 mg/day (p = 0.051). Low-dose hydrochlorothiazide was often used for prevention of CCKS despite the fact that there is no evidence that it is effective in this setting. This may have resulted from a practice pattern of using lower doses for hypertension therapy or a lack of knowledge of RCT results in treatment of CCKS.

Dietary salt, urinary calcium, and kidney stone risk.

Both salt-loading studies and reports of free-living populations find that urinary calcium excretion increases approximately 1 mmol (40 mg) for each 100 mmol (2300 mg) increase in dietary sodium in normal adults. Renal calcium stone-formers with hypercalciuria appear to have greater proportional increases in urinary calcium (approximately 2 mmol) per 100 mmol increase in salt intake. Thus, reduction of dietary NaCl may be a useful strategy to decrease the risk of forming calcium-containing kidney stones.