Why is diagnosis, investigation, and improved management of kidney stone disease important? Non-pharmacological and pharmacological treatments for nephrolithiasis.

INTRODUCTION: Progress in the medical treatment and management of nephrolithiasis has been limited to date and continues to depend on urinary metabolic screening to assess excretion of the main stone constituents, factors determining stone solubility and precipitation, and on dietary and lifestyle recommendations. AREAS COVERED: In this review, we try to highlight some of the broader aspects of kidney stone disease in relation to recent epidemiological and pathophysiological findings, and emerging new treatments. Specifically, this review will cover recent evidence on the association between metabolic risk factors and kidney stone disease, dietary risk factors, and dietary interventions to prevent kidney stones, and how genomics, metabolomics, and proteomics may improve diagnosis and treatment of this troublesome, if rarely fatal, condition. PubMed was used to identify the most suitable references according to our search strategy; only full manuscripts were included. EXPERT OPINION: What is emerging is that kidney stone disease is not an isolated disorder but is systemic in nature with links to important and common comorbidities such as diabetes, hypertension, cardiovascular disease, and chronic kidney disease. These associations support the need to take nephrolithiasis seriously as a medical condition and to adopt a more holistic approach to its investigation and treatment.

Temporal Trends of Dietary Risk Factors after a Diagnosis of Kidney Stones.

BACKGROUND AND OBJECTIVES: Diet is an important contributor to kidney stone formation, but there are limited data regarding long-term changes in dietary factors after a kidney stone. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: We analyzed data from three longitudinal cohorts, the Health Professionals Follow-Up Study and Nurses' Health Study I and II, comparing changes in dietary factors in participants with and without kidney stones during follow-up. The daily intake of dietary calcium, supplemental calcium, animal protein, caffeine, fructose, potassium, sodium, oxalate, phytate, vitamin D, vitamin C, sugar-sweetened beverages, fluids, net endogenous acid production, and Dietary Approaches to Stop Hypertension score were assessed by repeat food frequency questionnaires and computed as absolute differences; a difference-in-differences approach was used to account for temporal changes using data from participants without kidney stones from the same calendar period. RESULTS: Included were 184,398 participants with no history of kidney stones, 7095 of whom became confirmed stone formers. Several intakes changed significantly over time in stone formers, with some showing a relative increase up to 8 years later, including caffeine (difference in differences, 8.8 mg/d; 95% confidence interval [95% CI], 3.4 to 14.1), potassium (23.4 mg/d; 95% CI, 4.6 to 42.3), phytate (12.1 mg/d; 95% CI, 2.5 to 21.7), sodium (43.1 mg/d; 95% CI, 19.8 to 66.5), and fluids (47.1 ml/d; 95% CI, 22.7 to 71.5). Other dietary factors showed a significant decrease, such as oxalate (-7.3 mg/d; 95% CI, -11.4 to -3.2), vitamin C (-34.2 mg/d; 95% CI, -48.8 to -19.6), and vitamin D (-18.0 IU/d; 95% CI, -27.9 to -8.0). A significant reduction was observed in sugar-sweetened beverages intake of -0.5 (95% CI, -0.8 to -0.3) and -1.4 (95% CI, -1.8 to -1.0) servings per week and supplemental calcium of -105.1 (95% CI, -135.4 to -74.7) and -69.4 (95% CI, -95.4 to -43.4) mg/d for women from Nurses' Health Study I and II, respectively. Animal protein, dietary calcium, fructose intake, Dietary Approaches to Stop Hypertension score, and net endogenous acid production did not change significantly over time. CONCLUSIONS: After the first episode of a kidney stone, mild and inconsistent changes were observed concerning dietary factors associated with kidney stone formation.

Calcium and Vitamin D Supplementation and Their Association with Kidney Stone Disease: A Narrative Review.

Kidney stone disease is a multifactorial condition influenced by both genetic predisposition and environmental factors such as lifestyle and dietary habits. Although different monogenic polymorphisms have been proposed as playing a causal role for calcium nephrolithiasis, the prevalence of these mutations in the general population and their complete pathogenetic pathway is yet to be determined. General dietary advice for kidney stone formers includes elevated fluid intake, dietary restriction of sodium and animal proteins, avoidance of a low calcium diet, maintenance of a normal body mass index, and elevated intake of vegetables and fibers. Thus, balanced calcium consumption protects against the risk for kidney stones by reducing intestinal oxalate availability and its urinary excretion. However, calcium supplementation given between meals might increase urinary calcium excretion without the beneficial effect on oxalate. In kidney stone formers, circulating active vitamin D has been found to be increased, whereas higher plasma 25-hydroxycholecalciferol seems to be present only in hypercalciuric patients. The association between nutritional vitamin D supplements and the risk for stone formation is currently not completely understood. However, taken together, available evidence might suggest that vitamin D administration worsens the risk for stone formation in patients predisposed to hypercalciuria. In this review, we analyzed and discussed available literature on the effect of calcium and vitamin D supplementation on the risk for kidney stone formation.

[Recurrent Kidney Stones in a patient with Malabsorption Syndrome].

Enteric hyperoxaluria is one of the most frequent complications of bariatric surgery. In this setting the prevalence of kidney stones is increased. Currently the treatment of enteric hyperoxaluria is based not only on the reduction of urinary oxalate but even controlling other lithogenic risk factors, like urinary volume and urinary citrate levels. This case report suggests a possible benefit using magnesium citrate in addition to calcium supplementation, in the treatment of hyperoxaluria caused by enteric malabsorption.

[A young girl with recurrent calculosis and hypercalcemia].

Mutations of the CYP24A1 gene are associated with alterations in the activity of the enzyme 25-OH-D-24-hydroxylase, resulting in dysfunction of the metabolism of vitamin D. This enzymatic deficiency may cause hypercalcemia, low parathyroid hormone levels, hypercalciuria, nephrolithiasis and nephrocalcinosis. The clinical case of a young woman with recurrent renal lithiasis, hypercalcemia and hypercalciuria is described. These features are linked to deficiency of the enzyme 25-OH-D-24-hydroxylase, therefore to a biallelic mutation of the CYP24A1 gene.

Vitamin D Intake and the Risk of Incident Kidney Stones.

PURPOSE: Kidney stones are a common and painful condition. Longitudinal prospective studies on the association between the intake of vitamin D and the risk of incident kidney stones are lacking. MATERIALS AND METHODS: We performed a prospective analysis of 193,551 participants in the Health Professionals Follow-up Study and Nurses' Health Study I and II. Participants were divided into categories of total (less than 100, 100 to 199, 200 to 399, 400 to 599, 600 to 999, 1,000 IU per day or greater) and supplemental (none, less than 400, 400 to 599, 600 to 999, 1,000 IU per day or greater) vitamin D intake. During a followup of 3,316,846 person-years there were 6,576 incident kidney stone events. Cox proportional hazards regression models were adjusted for age, body mass index, comorbidities, use of medications and intake of other nutrients. RESULTS: After multivariate adjustment there was no statistically significant association between vitamin D intake and risk of stones in the HPFS (HR for 1,000 or greater vs less than 100 IU per day 1.08, 95% CI 0.80, 1.47, p for trend = 0.92) and the NHS I (HR 0.99, 95% CI 0.73, 1.35, p for trend = 0.70), whereas there was a suggestion of a higher risk in the NHS II (HR 1.18, 95% CI 0.94, 1.48, p for trend = 0.02). Similar results were found for supplemental vitamin D intake. CONCLUSIONS: Vitamin D intake in typical amounts was not statistically associated with risk of kidney stone formation, although higher risk with higher doses than those studied here cannot be excluded.

Metabolic diagnosis and medical prevention of calcium nephrolithiasis and its systemic manifestations: a consensus statement.

BACKGROUND: Recently published guidelines on the medical management of renal stone disease did not address relevant topics in the field of idiopathic calcium nephrolithiasis, which are important also for clinical research. DESIGN: A steering committee identified 27 questions, which were proposed to a faculty of 44 experts in nephrolithiasis and allied fields. A systematic review of the literature was conducted and 5216 potentially relevant articles were selected; from these, 407 articles were deemed to provide useful scientific information. The Faculty, divided into working groups, analysed the relevant literature. Preliminary statements developed by each group were exhaustively discussed in plenary sessions and approved. RESULTS: Statements were developed to inform clinicians on the identification of secondary forms of calcium nephrolithiasis and systemic complications; on the definition of idiopathic calcium nephrolithiasis; on the use of urinary tests of crystallization and of surgical observations during stone treatment in the management of these patients; on the identification of patients warranting preventive measures; on the role of fluid and nutritional measures and of drugs to prevent recurrent episodes of stones; and finally, on the cooperation between the urologist and nephrologist in the renal stone patients. CONCLUSIONS: This document has addressed idiopathic calcium nephrolithiasis from the perspective of a disease that can associate with systemic disorders, emphasizing the interplay needed between urologists and nephrologists. It is complementary to the American Urological Association and European Association of Urology guidelines. Future areas for research are identified.

Total, Dietary, and Supplemental Vitamin C Intake and Risk of Incident Kidney Stones.

BACKGROUND: Previous studies of vitamin C and kidney stones were conducted mostly in men and either reported disparate results for supplemental and dietary vitamin C or did not examine dietary vitamin C. STUDY DESIGN: Prospective cohort analysis. SETTING & PARTICIPANTS: 156,735 women in the Nurses' Health Study (NHS) I and II and 40,536 men in the Health Professionals Follow-up Study (HPFS). PREDICTOR: Total, dietary, and supplemental vitamin C intake, adjusted for age, body mass index, thiazide use, and dietary factors. OUTCOMES: Incident kidney stones. RESULTS: During a median follow-up of 11.3 to 11.7 years, 6,245 incident kidney stones were identified. After multivariable adjustment, total vitamin C intake (<90 [reference], 90-249, 250-499, 500-999, and ≥1,000mg/d) was not significantly associated with risk for kidney stones among women, but was among men (HRs of 1.00 [reference], 1.19 [95% CI, 0.99-1.46], 1.15 [95% CI, 0.93-1.42], 1.29 [95% CI, 1.04-1.60], and 1.43 [95% CI, 1.15-1.79], respectively; P for trend = 0.005). Median total vitamin C intake for the 500- to 999-mg/d category was ∼700mg/d. Supplemental vitamin C intake (no use [reference], <500, 500-999, and ≥1,000mg/d) was not significantly associated with risk for kidney stones among women, but was among men (HR, 1.19 [95% CI, 1.01-1.40] for ≥1,000mg/d; P for trend = 0.001). Dietary vitamin C intake was not associated with stones among men or women, although few participants had dietary intakes > 700mg/d. LIMITATIONS: Nutrient intakes derived from food-frequency questionnaires, lack of data on stone composition for all cases. CONCLUSIONS: Total and supplemental vitamin C intake was significantly associated with higher risk for incident kidney stones in men, but not in women.

Physical activity, energy intake and the risk of incident kidney stones.

PURPOSE: Recent data suggest that higher physical activity and lower energy intake may be associated with a lower risk of kidney stones. To our knowledge whether these associations could be reproduced in other study populations after accounting for life-style and dietary factors is not known. MATERIALS AND METHODS: We analyzed data on 3 large prospective cohorts, including HPFS, and NHS I and II. Information was collected by validated biennial questionnaires. The HR of incident stones in participants in different categories of physical activity and energy intake was assessed by Cox proportion hazards regression adjusted for age, body mass index, race, comorbidity, medication, calcium supplement use, fluid and nutrient intake. RESULTS: Analysis included 215,133 participants. After up to 20 years of followup 5,355 incident cases of kidney stones occurred. On age adjusted analysis higher levels of physical activity were associated with a lower risk of incident kidney stones in women (NHS I and II) but not in men. However, after multivariate adjustment there was no significant association between physical activity and kidney stone risk in HPFS, and NHS I and II (highest vs lowest category HR 1.00, 95% CI 0.87-1.14, p for trend = 0.94, HR 1.01, 95% CI 0.85-1.19, p for trend = 0.88 and HR 1.03, 95% CI 0.90-1.18, p for trend = 0.64, respectively). Energy intake was not associated with stone risk (multivariate adjusted p for trend ≥0.49). CONCLUSIONS: In 3 large prospective cohorts there was no independent association between physical activity and energy intake, and the incidence of symptomatic kidney stones.

Effects of prednisone on biomarkers of tubular damage induced by radiocontrast in interventional cardiology.

BACKGROUND: Contrast-induced nephropathy (CI-AKI) is a complication of diagnostic/therapeutic hemodynamic procedures in cardiology, which may also cause renal cholesterolinic atheroembolism. Despite the severe clinical impact of these complications, there is no optimal therapy for preventing and treating them. We suggest a short course of high-dose steroids as an effective preventive measure. METHODS: Patients at risk of CI-AKI (n = 38) undergoing cardiovascular procedures were assigned 1:1 to 1 of 2 experimental arms (prednisone+hydration vs. hydration alone). Oral prednisone 1 mg/kg was administered 12 hours before, at 6 am on the same day, and 24 hours following the procedure. Serum creatinine was tested immediately before and again 24-48 hours after the procedure; neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), protein and albumin were assayed in spot urine before and 6 hours after the procedure.
 RESULTS: NGAL and KIM-1 tended to rise after the procedure, but to a lesser degree in the prednisone group (delta NGAL: hydration = +128%, prednisone = +46%; p = 0.26; delta KIM-1: hydration = +99%, prednisone = +11%; p = 0.02). Proteinuria and albuminuria decreased significantly in the prednisone group. In 5 patients developing CI-AKI, their delta NGAL and delta KIM-1 did not differ from the values seen in patients without CI-AKI. Hypertension, peripheral arteriopathy and use of low-dose aspirin or diuretics were positive predictors of baseline NGAL, while treatment with calcium channel blockers and statins were negative predictors. Statins were negative predictors of baseline KIM-1. CONCLUSIONS: A short course of prednisone reduces the procedure-induced changes in biomarkers of renal tubular damage. This study suggests that steroids had a tubule-protecting effect.

Age- and sex-tailored serum phosphate thresholds do not improve cardiovascular risk estimation in CKD.

BACKGROUND: Disordered metabolism of phosphorus is one of the hallmarks of chronic kidney disease (CKD), resulting in increased cardiovascular morbidity and mortality. Age and sex may affect the metabolism of phosphorus and subsequently its serum level. We evaluated if age- and sex-specific cutoffs for hyperphosphatemia may define cardiovascular risk better than the current guideline cutoffs. METHODS: We used data from 16,834 subjects participating in the 1999-2006 National Health and Nutrition Examination Survey (NHANES); the prevalence of self-reported cardiovascular disease (CVD) and mortality rates were analyzed in CKD patients for both the classic definitions (CH; i.e., NKF-KDOQI and K-DIGO) and a tailored definition (TH) of hyperphosphatemia by means of regression models adjusted for age, sex, race/ethnicity, smoking status and body mass index. The cutoffs for TH were represented by the 95th percentile of an age- and sex-matched non-CKD population. RESULTS: Serum phosphorus levels showed an inverse correlation with age (r = -0.12; p<0.001); females showed higher levels than males (3.78 ± 0.54 mg/dL vs. 3.62 ± 0.58 mg/dL; p<0.001). Even if the association between the TH definition and CVD was marginally better compared with the CH definition (odds ratio [OR] = 1.49, 95% confidence interval [95% CI], 1.04-2.13; p=0.030 vs. OR=1.55, 95% CI, 0.98-2.44; p = 0.059), the TH model was not superior in predicting CVD or mortality. CONCLUSIONS: Our data suggest that a tailored, age- and sex-specific definition of hyperphosphatemia is not superior to conventional definitions in predicting cardiovascular events in patients with CKD.

Combined treatment with renin-angiotensin system blockers and polyunsaturated fatty acids in proteinuric IgA nephropathy: a randomized controlled trial.

BACKGROUND: Currently, several therapeutic protocols exist for IgA nephropathy (IgAN); results in slowing the progression to end-stage renal disease (ESRD) are variable, but approximately 30-40% of patients require replacement therapy (dialysis or renal transplantation) by 20 years from the onset. The adverse effects brought by the chronic assumption of drugs can be a potential limit. Actually, the most used therapies for IgAN are renin-angiotensin system blockers (RASB), glucocorticoids and immunosuppressive agents. Trials with polyunsaturated fatty acids (PUFA) in IgAN have been done since the first successful attempt by Hamazaki in 1984, resulting in alternate answers, but no trials have ever been done testing the efficacy of combined therapy with RASB and PUFA. METHODS: We tested the effect of a 6-month course of PUFA (3 grams/day) in a group of 30 patients with biopsy-proven IgAN and proteinuria already treated with RASB randomized to receive PUFA supplementation or to continue their standard therapy. The primary end-point was the percent reduction of proteinuria from the baseline. Secondary end-points were modifications in glomerular filtration rate (GFR), blood pressure, serum triglycerides and erythrocyturia. RESULTS: At the end of the 6-month trial, the percent reduction of proteinuria was 72.9% in the PUFA group and 11.3% in the RASB group (P < 0.001). A reduction of >or=50% of baseline proteinuria was achieved in 80.0% of PUFA patients and 20.0% of RASB patients (P = 0.002). Erythrocyturia was significantly lower in the PUFA group (P = 0.031). No significant changes in renal function, blood pressure and triglycerides were observed. CONCLUSIONS: PUFA associated with RASB reduced proteinuria in patients with IgAN more than RASB alone.