Nephrolithiasis-associated bone disease: pathogenesis and treatment options

Nephrolithiasis remains a formidable health problem in the United States and worldwide. A very important but underaddressed area in nephrolithiasis is the accompanying bone disease. Epidemiologic studies have shown that osteoporotic fractures occur more frequently in patients with nephrolithiasis than in the general population. Decreased bone mineral density and defects in bone remodeling are commonly encountered in patients with calcium nephrolithiasis. The pathophysiologic connection of bone defects to kidney stones is unknown. Hypercalciuria and hypocitraturia are two important risk factors for stone disease, and treatments with thiazide diuretics and alkali, respectively, have been shown to be useful in preventing stone recurrence in small prospective trials. However, no studies have examined the efficacy of these agents or other therapies in preventing continued bone loss in calcium stone formers. This manuscript reviews the epidemiology, pathophysiology, and potential treatments of bone disease in patients with nephrolithiasis.

Prevalence and densitometric characteristics of incomplete distal renal tubular acidosis in men with recurrent calcium nephrolithiasis

The aim of this study was to assess the prevalence of incomplete distal renal tubular acidosis (idRTA) in men with recurrent calcium nephrolithiasis and its potential impact on bone mineral density. We conducted a retrospective analysis of 150 consecutive, male idiopathic recurrent calcium stone formers (RCSFs), which had originally been referred to the tertiary care stone center of the University Hospital of Berne for further metabolic evaluation. All RCSFs had been maintained on a free-choice diet while collecting two 24-h urine samples and delivered second morning urine samples after 12 h fasting. Among 12 RCSFs with a fasting urine pH >5.8, a modified 3-day ammonium chloride loading test identified idRTA in 10 patients (urine pH >5.32, idRTA group). We matched to each idRTA subject 5 control subjects from the 150 RCSFs, primary by BMI and then by age, i.e., 50 patients, without any acidification defect (non-RTA group) for comparative biochemistry and dual energy X-ray absorptiometry (DEXA) analyses. The prevalence of primary idRTA among RCSFs was 6.7% (10/150). Patients with idRTA had significantly higher 2-h fasting and 24-h urine pH (2-h urine pH: 6.6 ± 0.4 vs. 5.2 ± 0.1, p = 0.001; 24-h urine pH: 6.1 ± 0.2 vs. 5.3 ± 0.3, p = 0.001), 24-h urinary calcium excretion (7.70 ± 1.75 vs. 5.69 ± 1.73 mmol/d, p = 0.02), but significantly lower 24-h urinary urea excretion (323 ± 53 vs. 399 ± 114 mmol/d, p = 0.01), urinary citrate levels (2.32 ± 0.82 vs. 3.01 ± 0.72 mmol/d, p = 0.04) and renal phosphate threshold normalized for the glomerular filtration rate (TmPO(4)/GFR: 0.66 ± 0.17 vs. 0.82 ± 0.21, p = 0.03) compared to non-RTA patients. No significant difference in bone mineral density (BMD) was found between idRTA and non-RTA patients for the lumbar spine (LS BMD (g/cm(2)): 1.046 ± 0.245 SD vs. 1.005 ± 0.119 SD, p = 0.42) or femoral neck (FN BMD (g/cm(2)): 0.830 ± 0.135 SD vs. 0.852 ± 0.127 SD). Thus, idRTA occurs in 1 in 15 male RCSFs and should be sought in all recurrent calcium nephrolithiasis patients. Bone mineral density, however, does not appear to be significantly affected by idRTA.

An unusual patient with hypercalciuria, recurrent nephrolithiasis, hypomagnesemia and G227R mutation of Paracellin-1. An unusual patient with hypercalciuria and hypomagnesemia unresponsive to thiazide diuretics

A 19-year-old female patient with hypercalciuria and recurrent nephrolithiasis/urinary tract infection unresponsive to thiazide type diuretics is presented. The patient first experienced nephrolithiasis at the age of 4 years. Afterwards, recurrent passages of stones and urinary tract infection occurred. On diagnostic evaluation at the age of 19 years, she also had hypocitraturia and hypomagnesemia. Her serum calcium concentrations were near the lower limit of normal (8.5-8.8 mg/dl; normal range: 8.5-10.5), her serum magnesium concentrations were 1.15-1.24 mg/dl (normal range: 1.4-2.5) and urinary calcium excretion was 900 mg/24 h. PTH concentrations were increased (110-156 pg/ml; normal range: 10-65). We tried to treat the patient with hydrochlorothiazide at a dose of 50 mg/day. During treatment with thiazide diuretics, PTH concentration remained high and the patient had recurrent urinary tract infections and passages of stones. Serum magnesium concentration did not normalize even under the parenteral magnesium infusion. Her mother had a history of nephrolithiasis 20 years ago. Severe hypomagnesemia in association with hypercalciuria/urinary stones is reported as a rare autosomal recessive disorder caused by impaired reabsorption of magnesium and calcium in the thick assending limp of Henle's loop. Recent studies showed that mutations in the CLDN16 gene encoding paracellin-1 cause the disorder. In exon 4, a homozygous nucleotide exchange (G679C) was identified for the patient. This results in a point mutation at position Glycine227, which is replaced by an Arginine residue (G227R). The mother was heterozygous for this mutation. G227 is located in the fourth transmembrane domain and is highly conserved in the claudin gene family. This case indicates the pathogenetic role of paracellin-1 mutation in familial hypomagnesemia with hypercalciuria and nephrocalcinosis and further underlines the risk of stone formation in heterozygous mutation carriers.

Prevalence of nephrolithiasis in patients with ileal bladder substitutes

OBJECTIVES: To assess the effect of ileal bladder substitutes with preservation of the ileocecal valve and distal 25 cm of ileum on nephrolithiasis. METHODS: We reviewed a consecutive series of 518 patients (44 women and 474 men) with ileal orthotopic bladder substitution in whom 55 to 65 cm of ileum was resected but with preservation of the ileocecal valve and distal 25 cm of ileum, to determine prevalence of nephrolithiasis as well as bicarbonate, base excess, creatinine levels, and urinary pH at time of stone diagnosis and 2 years before it. RESULTS: Four male patients with a median age of 66 years (range, 50 to 70 years) developed nephrolithiasis after ileal bladder substitute, for a total of five calculi. The prevalence of nephrolithiasis in this retrospective cohort is thus 1% (5 of 518). They developed the calculi after a median follow-up of 8 years (range, 4 to 17 years). The four patients were diagnosed with calculi at 2.3, 3, 10, 10.3, and 14 years after bladder substitute. Two of the stones were uric acid calculi; the remaining three were calcium oxalate. None of our patients were acidotic or had elevated serum creatinines at time of stone formation. Urinary pH determined once in spontaneously voided urine at the time of stone diagnosis was pH 6.0 for the two uric acid calculi and pH 7.0 for the remaining calculi. CONCLUSIONS: The present study demonstrates a low prevalence of calculi in our cohort.

Lunar tractive forces and renal stone incidence

Background. Several factors are implicated in renal stone formation and peak incidence of renal colic admissions to emergency departments (ED). Little is known about the influence of potential environmental triggers such as lunar gravitational forces. We conducted a retrospective study to test the hypothesis that the incidence of symptomatic renal colics increases at the time of the full and new moon because of increased lunar gravitational forces. Methods. We analysed 1500 patients who attended our ED between 2000 and 2010 because of nephrolithiasis-induced renal colic. The lunar phases were defined as full moon ± 1 day, new moon ± 1 day, and the days in-between as "normal" days. Results. During this 11-year period, 156 cases of acute nephrolithiasis were diagnosed at the time of a full moon and 146 at the time of a new moon (mean of 0.4 per day for both). 1198 cases were diagnosed on "normal" days (mean 0.4 per day). The incidence of nephrolithiasis in peak and other lunar gravitational phases, the circannual variation and the gender-specific analysis showed no statistically significant differences. Conclusion. In this adequate powered longitudinal study, changes in tractive force during the different lunar phases did not influence the incidence of renal colic admissions in emergency department.

Synthesis, maturation, and trafficking of human Na+-dicarboxylate cotransporter NaDC1 requires the chaperone activity of cyclophilin B

Renal excretion of citrate, an inhibitor of calcium stone formation, is controlled mainly by reabsorption via the apical Na(+)-dicarboxylate cotransporter NaDC1 (SLC13A2) in the proximal tubule. Recently, it has been shown that the protein phosphatase calcineurin inhibitors cyclosporin A (CsA) and FK-506 induce hypocitraturia, a risk factor for nephrolithiasis in kidney transplant patients, but apparently through urine acidification. This suggests that these agents up-regulate NaDC1 activity. Using the Xenopus lævis oocyte and HEK293 cell expression systems, we examined first the effect of both anti-calcineurins on NaDC1 activity and expression. While FK-506 had no effect, CsA reduced NaDC1-mediated citrate transport by lowering heterologous carrier expression (as well as endogenous carrier expression in HEK293 cells), indicating that calcineurin is not involved. Given that CsA also binds specifically to cyclophilins, we determined next whether such proteins could account for the observed changes by examining the effect of selected cyclophilin wild types and mutants on NaDC1 activity and cyclophilin-specific siRNA. Interestingly, our data show that the cyclophilin isoform B is likely responsible for down-regulation of carrier expression by CsA and that it does so via its chaperone activity on NaDC1 (by direct interaction) rather than its rotamase activity. We have thus identified for the first time a regulatory partner for NaDC1, and have gained novel mechanistic insight into the effect of CsA on renal citrate transport and kidney stone disease, as well as into the regulation of membrane transporters in general.

Metabolic syndrome and the risk of calcium stones

The metabolic syndrome (MS) is associated with increased prevalence of kidney stones, yet the specific stone type remains largely unknown. This study was conducted to assess whether risk factors associated with calcium nephrolithiasis increase with individual characteristics of the MS.

Alternate or additional findings to stone disease on unenhanced computerized tomography for acute flank pain can impact management

PURPOSE: We evaluated the incidence and clinical relevance of alternate or additional findings on unenhanced CT in patients with acute flank pain and suspected urinary calculi. MATERIALS AND METHODS: A consecutive series of 1,500 patients underwent unenhanced CT due to acute flank pain. The absence or presence of urinary tract calculi and their localization were recorded. Alternate or additional CT findings were classified according to whether they required immediate or deferred treatment, or were of little or no clinical importance. RESULTS: Of the 1,500 patients 1,035 (69%) had urinary tract calculi, including 309 (30%) with nephrolithiasis, 377 (36%) with ureterolithiasis and 349 (34%) with the 2 conditions. Urolithiasis alone was found in 331 of these patients (32%) and additional pathological conditions were noted in 704 (68%). Of all patients 1,064 (71%) had other or additional CT findings. Of all patients 207 (14%) had nonstone related CT findings requiring immediate or deferred treatment, 464 (31%) had pathological conditions of little clinical importance and 393 (26%) had pathological conditions of no clinical relevance. CT was normal in 105 of all patients (7%). CONCLUSIONS: Unenhanced CT in patients with acute flank pain allows the accurate diagnosis of urinary stone disease and it can also provide further important information leading to emergency or deferred treatment in a substantial number of patients.

[Urine analyses for workup of kidney stone disease--interpretation and therapeutic consequences]

Nephrolithiasis is a disease with a high and even rising incidence. It has a high morbidity, generates high costs and has a high recurrence rate. Urinalysis is of importance especially in recurrent stone formers. It allows the identification and quantification of risk factors and the establishment of individual risk profiles. Based on these individual risk profiles, rational therapy for metaphylaxis of kidney stones lowers stone recurrence rates significantly. This review article aims to give a focussed overview of the most important risk factors for kidney stones and reasonable urine tests for evaluation of recurrent kidney stone formers.

[Hypercalcemia in sarcoidosis--case report, prevalence, pathophysiology and therapeutic options]

Hypercalcemia is a highly prevalent complication of sarcoidosis. A medical history of a patient with sarcoidosis is shown as case report. Depending on the population studied about 2-63% of sarcoidosis patients show hypercalcemia. The major difference in the prevalence of hypercalcemia may be in part due to the undulating course of subacute sarcoidosis, so hypercalcemia may be missed when serum calcium is not frequently measured. Hypercalciuria appears to be twice as prevalent then hypercalcemia and should be looked for in every sarcoidosis patient. Hypercalcemia in sarcoidosis is due to the uncontrolled synthesis of 1,25-dihydroxyvitamin D3 by macrophages. 1,25-dihydroxyvitamin D3 leads to an increased absorption of calcium in the intestine and to an increased resorption of calcium in the bone. Immunoregulatory properties have been ascribed to 1,25-dihydroxyvitamin D3. It is an important inhibitor of interleukin-2 and of interferon-gamma-synthesis, two cytokines that are important in granuloma formation in sarcoidosis. It is thought that 1,25-dihydroxyvitamin D3 counterregulates uncontrolled granuloma formation. Treatment of hypercalcemia depends on the serum level of hypercalcemia and its persistence. Generally sarcoidotic patients should be advised to avoid sun exposition to reduce vitamin D3 synthesis in the skin, to omit fish oils that are rich of vitamin D and to produce more than two liters urine a day by adapting fluid intake. Although severe hypercalcemia seems to be rare, glucocorticosteroid treatment should be started if corrected total calcium level rises beyond 3 mmol/l. If hypercalcemia is symptomatic, treatment should be started even at lower levels. Glucocorticosteroids act by inhibition of the overly 1alpha-hydroxylase activity of macrophages. Alternatively, treatment with chloroquine or ketoconazole can be established. If isolated hypercalciuria without hypercalcemia is present with evidence for recurrent nephrolithiasis, patients can be treated with a thiazide diuretic.

Pathophysiology and diagnosis of nephrocalcinosis

Nephrocalcinosis is the result of a myriad of hereditary or acquired diseases in the calcium, phosphate or oxalate metabolism that lead to deposition of calcium containing precipitates within the kidney. Nephrocalcinosis and nephrolithiasis are pathophysiologically tightly related and often co-exist. In the case of recurrent nephrolithiasis, nephrocalcinosis has to be excluded. Stone analysis can yield important clues to the underlying disease process. The best way to diagnose nephrocalcinosis and an accompanying nephrolithiasis is by native computer tomography scans. Untreated, nephrocalcinosis will lead to a progressive decline in renal function and eventually to end stage renal disease. Thus, for each case, the underlying disease process has to be determined and a causative therapy initiated.

[Urinary specific gravity--comparative measurements using reagent strips and refractometer in 340 morning urine samples]

The specific gravity of urine (SG) indicates the number and weight of solute particles in urine; its measurement is helpful in interpreting proteinuria detected by dipstick tests and in monitoring adequate hydration in patients with nephrolithiasis. Four methods for measuring SG or osmolality of urine are currently available (depression of the freezing-point, urometry, refractometry, cation exchange on a reagent strip). Using a recently developed reagent strip, we have measured SG in morning urines of 340 non-selected outpatients and compared the results with SG measurements by refractometry of the same urines. In 86.2% of all urines, a good positive correlation between SG measured by reagent strip and refractometry was noted (r = 0.913, p = 0.0001). In 13.8% of the urines, however, the SG measured by reagent strip deviated by more than +/- 5 from the value obtained by refractometry; in 90% of these urines, glucosuria (reagent strip values too low or too high), proteinuria (values too high), or bacteriuria/leukocyturia (values too low or too high) could be found. In alkaline urine (pH > 7.0), SG values obtained by reagent strip have to be corrected by +5.

Low bone mass in idiopathic renal stone formers: magnitude and significance

To assess bone mineral density (BMD) in idiopathic calcium nephrolithiasis, dual-energy x-ray absorptiometry was performed at lumbar spine, upper femur (femoral neck, Ward's triangle, and total area), distal tibial diaphysis, and distal tibial epiphysis in 110 male idiopathic calcium stone formers (ICSF); 49 with and 61 without hypercalciuria on free-choice diet). Results were compared with those obtained in 234 healthy male controls, using (1) noncorrected BMD, (2) BMD corrected for age, height, and BMI, and (3) a skeletal score based on a tercile distribution of BMD values at following four sites: lumbar spine, Ward's triangle, tibial diaphysis, and tibial epiphysis. After correction, BMD--and therefore also skeletal score--tended to be lower in the stone formers than in controls at five of the six measurement sites, that is, lumbar spine, upper femur, Ward's triangle, tibial diaphysis, and tibial epiphysis, limit of significance being reached for the last two sites without difference between hypercalciuric (HCSF) and normocalciuric stone formers (NCSF). Estimated current daily calcium intake was significantly lower in patients (616 +/- 499 mg/24 h, mean +/- SEM) than in controls (773 +/- 532, p = 0.02). Of 17 patients who in the past had received a low-calcium diet for at least 1 year, 10 had a low skeletal score (4-6) whereas only 1 had a high score (10-12; p = 0.037). Of the 12 stone formers in the study with skeletal score 4 (i.e., the lowest), 8 had experienced in the past one or more fractures of any kind versus only 19 of the remaining 77 patients with skeletal score 5-12 (p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Incomplete Distal Renal Tubular Acidosis from a Heterozygous Mutation of the V-ATPase B1 Subunit

Congenital distal renal tubular acidosis (dRTA) from mutations of the B1 subunit of the V-ATPase is considered an autosomal recessive disease. We analyzed a dRTA kindred with a truncation-mutation of B1 (p.Phe468fsX487) previously shown to have failure of assembly into the V1 domain of the V-ATPase. All heterozygous carriers in this kindred have normal plasma bicarbonate concentrations, thus evaded the diagnosis of RTA. However, inappropriately high urine pH, hypocitraturia, and hypercalciuria are present either individually or in combination in the heterozygotes at baseline. Two of the heterozygotes studied also have inappropriate urinary acidification with acute ammonium chloride loading and impaired urine-blood pCO2 gradient during bicarbonaturia indicating presence of H+ gradient and flux defects. In normal human renal papillae, wild type B1 is located primarily on the plasma membrane but papilla from one of the heterozygote who had kidney stones had renal tissue secured from surgery showed B1 in both plasma membrane as well as a diffuse intracellular staining. Titrating increasing amounts of the mutant B1 subunit did not exhibit negative dominance over the expression, cellular distribution, or H+-pump activity of the wild type B1 in mammalian HEK293 cells and in V-ATPase-deficient S. cerevisiae. This is the first demonstration of renal acidification defects and nephrolithiasis in heterozygous carriers of mutant B1 subunit; which cannot be attributable to negative dominance. We propose that heterozygosity may lead to mild real acidification defects due to haploinsufficiency. B1 heterozygosity should be considered in patients with calcium nephrolithiasis and urinary abnormalities such as alkalinuria or hypocitraturia.

Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1

Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.