[Citrate and renal stones]. / Citrato y litiasis renal.

Citrate is a powerful inhibitor of the crystallization of calcium salts. Hypocitraturia is a biochemical common alteration in calcium stone formation in adults and especially in children. The acid pH (systemic, tubular and intracellular) is the main determinant of citrate excretion in the urine. While the etiology of hypocitraturia is idiopathic in most patients with kidney stones, there are a number of causes for this abnormality including distal renal tubular acidosis, hypokalemia, diets rich in animal protein and / or diets low in alkali and certain drugs, such as acetazolamide, topiramate, ACE inhibitors and thiazides. Dietary modifications that benefit these patients include high intake of fluids and fruits, especially citrus, sodium and protein restriction, with normal calcium intake. Treatment with potassium citrate is effective in patients with primary or secondary hypocitraturia and acidification disorders, which cause unduly acidic urine pH persistently. Adverse effects are low and are referred to the gastrointestinal tract. While there are various preparations of citrate (potassium citrate, sodium citrate, potassium citrate, magnesium) in our country is available only potassium citrate powder that is useful to correct both the hypocitraturia and the low urinary pH and reduce markedly the recurrence of kidney stones.

[Diet in the treatment of renal lithiasis. Pathophysiological basis]. / La dieta en el tratamiento de la litiasis renal. Bases fisiopatológicas.

The composition of urine is influenced by diet and changes in dietary factors have been proposed to modify the risk of recurrent nephrolithiasis. Nutrients that have been implicated include calcium, oxalate, sodium, animal protein, magnesium and potassium. There is significant evidence showing that a high calcium diet is associated with a reduction of lithogenic risk. One of the possible mechanisms to explain this apparent paradox is that the higher intake of calcium in the intestine binds with dietary oxalate, reducing its absorption and urinary excretion. Oxalate from the diet seems to provide only a small contribution to excretion and dietary restriction is appropriate only in those with hyperoxaluria and hyperabsorption. Observational studies have shown a positive and independent association between sodium intake and the formation of new kidney stones. Consumption of animal protein creates an acid load that increases urinary excretion of calcium and uric acid and reduced citrate, all factors that could participate in the genesis of stones. Potassium-rich foods increase urinary citrate because of its alkali content. In prospective observational studies, diets rich in magnesium were associated with a lower risk of kidney stone formation in men. In conclusion, diet is a key element in the management of the patient with kidney stones but always subordinated to present metabolic risk factors.

[Guidelines for the diagnosis, prevention and treatment of osteoporosis, 2012]. / Guías 2012 para el diagnóstico, la prevención y el tratamiento de la osteoporosis.

Osteoporosis is a constantly growing disease which affects over 200 million people worldwide. The present recommendations are guidelines for its diagnosis, prevention and treatment, but they do not constitute standards for clinical decisions in individual patients. The physician must adapt them to individual patients and special situations, incorporating personal factors that transcend the limits of these guidelines and are dependent on the knowledge and art of the physician. These guidelines should be reviewed and updated periodically as new, better and more effective diagnostic and therapeutic tools become available.

Phosphate binders, cardiovascular calcifications and mortality: do we need another survival study with sevelamer?

In chronic renal failure patients, hyperphosphatemia has been associated with vascular calcifications and increased cardiovascular morbidity and mortality. In vitro observations have shown that calcium and phosphate independently and synergistically induce calcifications in human vascular smooth muscle cells, suggesting an important role for both in the calcification process. Because non-calcium phosphate binders reduce serum phosphate without increasing the calcium load, as is the case with calcium-based phosphate binders, it has been speculated that treatment with sevelamer leads to less vascular calcification and better survival in chronic kidney disease. Although the use of sevelamer may slow the progression of vascular calcifications compared with calcium-based phosphate binders, the relationship of this surrogate marker with patients' cardiovascular mortality and survival is far from certain. To resolve this uncertainty and to determine the most cost-effective way to treat hyperphosphatemia in patients with end-stage renal disease, another randomized study analyzing mortality comparing sevelamer with calcium phosphate binders should be undertaken.

[FRAX: a new instrument for calculating 10-year absolute fracture risk]. / FRAX: un nuevo instrumento para calcular el riesgo absoluto de fracturas a 10 años.

The efficacy of new pharmacological agents for the prevention of osteoporotic fractures and the clinical decision to intervene with that purpose in daily medical practice have been guided by the evaluation of bone mineral density (BMD). However, given the multifactorial nature of the proposed endpoint, a new calculator has been proposed: Fracture Risk Assessment Tool FRAX, which follows the same objectives of previous models, but integrates and combines several of those factors according to their relative weight. It can estimate absolute risk of hip fracture (or a combination of osteoporotic fractures) for the following 10 years. The calculator could be adapted for use in any country by the incorporation of hip fracture incidence and age- and sex-adjusted life expectancy in the same country. This instrument has been presented as a new paradigm to assist in clinical and therapeutic decision-making. In the present review some of its characteristics are discussed, such as: the purported applicability to different populations, the convenience of using 10-year absolute fracture risk for the whole age range under consideration, and whether the efficacy of pharmacological treatment for the prevention of bone fractures in osteoporotic patients can be expected to be equally effective among patients selected for treatment on the basis of this model. Finally, we would like to call attention to the fact that risk thresholds for intervention are not yet clearly defined; those thresholds can obviously be expected to have a profound impact on the number of patients amenable to treatment.

Chronic prolonged hyponatremia and risk of hip fracture in elderly patients with chronic kidney disease.

BACKGROUND: Chronic prolonged hyponatremia (CPH) is a risk factor for hip fracture in the general population. Whether CPH increases hip fracture risk in chronic kidney disease (CKD) patients is unknown. METHODS: Case-control study in patients over 60 years of age with stage 3 or greater CKD. Patients who had a hip fracture were referred to as cases (n = 1236) and controls had no hip fracture (n = 4515). Patients were classified as having CPH if serum sodium was <135 mEq/L on at least two occasions separated by a minimum of 90 days prior to the diagnosis of hip fracture (cases) or at any time during the study period (controls). Conditional logistic regression models were used to test the association between CPH and hip fracture. Analyses were conducted for patients with and without osteoporosis and falls and for patients with age >70 years versus ≤70 years. RESULTS: CPH was present in 21% of cases and 10% of controls (p < 0.001; sodium level: 131-134 mEq/L). In univariate logistic regression analysis, CPH was associated with higher odds of hip fracture (odds ratio [OR] 2.44, (95% [CI] 2.07-2.89). In a multivariate model adjusted for comorbidities, medications and laboratory parameters CPH association with higher odds of Hip fracture was attenuated but remained significant (OR 1.36, 95% CI 1.04-1.78). The association between CPH and risk of hip fracture was consistent in patients with or without osteoporosis and falls and across the age strata. CONCLUSION: Chronic prolonged hyponatremia is a risk factor for hip fracture in CKD patients older than 60 years of age.

Prevalence of 25(OH) vitamin D insufficiency and deficiency in chronic kidney disease stage 5 patients on hemodialysis.

Little is known about the magnitude of vitamin D deficiency in patients with stage 5 chronic kidney disease (CKD-5) on hemodialysis (HD). In the present study, we examined the prevalence of vitamin D deficiency in patients with CKD-5 undergoing HD, evaluating the relationship between calcidiol levels with other parameters of mineral metabolism, nutrition/inflammation, functional capacity (FC), and sunlight exposure. Serum 25(OH) vitamin D levels were evaluated in 84 stable patients on chronic HD not receiving vitamin D supplements, with a mean age 58.9+/-16.6 years, during the month of September (end of winter in the southern hemisphere). 25(OH) vitamin D serum levels, intact PTH (iPTH), as well as serum albumin, calcium, phosphorus, and alkaline phosphatase were analyzed in fasting samples. Similarly, protein catabolic rate (PCR) and body mass index (BMI) were determined as nutritional parameters. Functional capacity according to the Karnofsky index, and sunlight exposure were also analyzed. In this study, we considered adequate vitamin D levels those above 30 ng/mL (U.S.A. National Kidney Foundation DOQI Guidelines), vitamin D insufficiency when levels were between 15 and 30 ng/mL, and vitamin D deficiency when levels were below 15 ng/mL. The mean 25(OH) D levels were significantly higher in men than in women (28.6 vs. 18.9 ng/mL; p=0.001). Vitamin D insufficiency was found in 53.5% of the patients (n=45) and vitamin D deficiency in 22.6% (n=19). In the univariate analysis, there were no correlations between 25(OH) D levels with age, iPTH, calcium, or phosphorus. There were positive correlations between serum 25(OH) D levels and degrees of sunlight exposure (R=0.55; p<0.0001), serum creatinine (r=0.38; p<0.001), serum albumin (r=0.22; p=0.04), and a negative correlation with BMI (r=-0.26; p=0.01). In the multiple regression analysis, only sunlight exposure (B=0.361), BMI (B=-0.23), and gender (B=-0.27) were significantly associated with 25(OH) D levels. Patients with FC 1 to FC 2 (n: 70%, 83.3%) had significantly higher 25(OH) D serum levels compared with FC 3 to FC 4 patients (n: 14%, 16.6%): 25.9 vs. 17.1 ng/mL (p=0.03). These results indicate that vitamin D insufficiency/deficiency is highly prevalent (76.1%) at the end of winter, in stage 5 CKD patients on HD, and lower values seem to be related to decreased sunlight exposure, female gender, increased BMI, and worse functional class.

The klotho gene: a gene predominantly expressed in the kidney is a fundamental regulator of aging and calcium/phosphorus metabolism.

A unique short lifespan mouse strain was developed in which a single gene mutation caused multiple aging-related disorders. The gene responsible has been identified as the klotho gene. The most characteristic phenotypes of klotho mice seem caused by abnormalities in calcium metabolism. Klotho plays a critical role in the regulation of calcium and phosphorus homeostasis by negatively regulating active vitamin D synthesis. A defect in klotho gene expression causes the independent impairment both of osteoblast and osteoclast differentiation, leading to low-turnover osteopenia. In humans, two klotho gene polymorphisms were significantly associated with bone density in aged postmenopausal women, but not in pre-menopausal or younger postmenopausal women in two genetically distinct racial populations. The klotho gene is predominantly expressed in the kidney and the expression level of klotho RNA was shown to be greatly reduced in the kidneys of chronic renal failure (CRF) patients. Angiotensin II induced renal klotho down-regulation through angiotensin type 1 receptor-dependent but pressor-independent events, while dietary P(i) restriction induced klotho expression. The down-regulation of the renal klotho gene could increase renal damage induced by angiotensin II, while klotho gene induction could have therapeutic possibilities in treating angiotensin II-induced kidney damage.

Weekly high-dose ergocalciferol to correct vitamin D deficiency/insufficiency in hemodialysis patients: a pilot trial.

Controversy exists on which vitamin D (D2 or D3) and which dosage scheme is the best to obtain and maintain adequate 25 OH D levels in dialysis patients safely. We tried to determine whether high-dose vitamin D2 supplementation could obtain optimal vitamin D status without inducing hypercalcemia. We studied 82 patients on dialysis not taking active vitamin D therapy and supplemented them with oral vitamin D2 72,000 IU/week for 12 weeks followed by 24,000 IU/week as maintenance therapy during 36 weeks. By week 12, serum 25(OH)D increased from 15.2 ± 5.4 to 42.5 ± 13.2 ng/mL (P < 0.01) at week 12 and remained optimal (34.7 ± 12.0); 84.8% of the patients reached values ≥30 ng/mL. iPTH and alkaline phosphatase did not change at 48 weeks compared with baseline, but bone alkaline phosphatase decreased significantly (54.3 ± 46.0 to 44.3 ± 25.0; P = 0.02). Uncorrected serum Ca increased significantly at the end of follow-up (9.03 ± 0.42 to 9.14 ± 0.62; P = 0.04); hypercalcemia was presented in two patients in the first control visit (week 12), in one patient in the second control (week 30), and in one patient in the third control (week 48). In 222 serum calcium determinations during follow-up, hypercalcemia was observed in only 1.8% of cases. This vitamin D2 oral regimen with initial high doses was safe and sufficient to obtain and maintain optimal serum 25(OH)D concentrations and prevent vitamin D insufficiency in chronic kidney disease patients on dialysis.

Lean mass estimation by creatinine kinetics and dual-energy x-ray absorptiometry in peritoneal dialysis.

BACKGROUND: Malnutrition is widely prevalent in dialysis. Malnourished patients present depletion of somatic protein stores and a decrease in lean body mass (LBM) that can be measured by different techniques. AIMS: (1) To assess the reliability of lean mass measurements obtained by creatinine kinetics (CrK) in a group of stable peritoneal dialysis (PD) patients, using dual-energy x-ray absorptiometry (DEXA) measurements as the reference method; (2) to establish the reproducibility of LBM estimated by CrK in individual patients analyzing repeated measurement in the short term, and (3) to correlate measurements of LBM with laboratory determinations that assess nutritional status. METHODS: We performed a cross-sectional evaluation of LBM by DEXA and CrK in 39 PD patients. In 14 patients we performed repeated measurements of LBM by CrK in the short term. RESULTS: No significant difference was found in mean lean mass values estimated by both methods: mean DEXA LBM was 41.7 kg, 36.1 +/- 4.5 kg in females and 52.7 +/- 6.4 kg in males and mean CrK LBM was 41.08 kg, 37.5 +/- 6.1 kg in females and 48.1 +/- 8.4 kg in males. A good correlation was found between both techniques (r = 0.71; p < 0.003). The mean difference between the two methods was 0.638 +/- 6.95 kg (95% confidence limits: -12.98 and +14.26). A wide scatter of the differences between both methods was seen throughout the range of measurements of LBM. When LBM by CrK was repeatedly (2-3 times) measured in a period of 3-4 months in 14 patients, it had a coefficient of variation (CV) of 15.39% (range 2.89-42.88%), while body weight CV in the same period was 0.69% (range 0-1.9%). CONCLUSIONS: CrK is an unsatisfactory method for the assessment of LBM in PD patients.

Bone mineral density: serum markers of bone turnover and their relationships in peritoneal dialysis.

BACKGROUND: The usefulness of bone mass measurements and bone turnover markers to estimate the risk of fracture and the type of underlying renal osteodystrophy are not well established in patients on peritoneal dialysis (PD). OBJECTIVE: To assess bone mass using total and regional bone densitometry in a group of patients on PD and to determine if serum markers of bone turnover identify patients with low bone mass. METHODS: Bone densitometry was studied by dual-energy x-ray absorptiometry (DEXA), and bone turnover using several serum markers, in 65 patients on PD. Bone mass was classified as normal, osteopenic, or osteoporotic according to World Health Organization criteria based on bone mineral density (BMD) T scores. RESULTS: T scores in the osteopenia range were present at the lumbar spine (LS) in 44.6% (45% of men and 44.4% of women) of patients and at the femoral neck (FN) in 56.9% (55% of men and 58% of women). T scores in the osteoporosis range were present at the LS in 13.8% of patients (10% of men and 15.5% of women) and at the FN in 21.5% (30% of men and 17.7% of women). Patients with BMD T scores in the osteoporosis range at both regions had increased serum intact parathyroid hormone (iPTH) levels compared to patients in the osteopenic/normal range. Bone mineral content in the whole skeleton (TBMC) correlated negatively with iPTH (r = -0.34) and with total time on dialysis (r = -0.26); in multivariate analysis, only iPTH correlated negatively with TBMC (B = -0.26, p = 0.03). No correlations were found between the other bone markers and BMD T scores at the FN or LS. There were no significant differences in absolute BMD or BMD T scores at the LS or FN between patients with and patients without fractures. CONCLUSIONS: BMD T scores in the osteopenia/osteoporosis range were observed at the LS in 58.4% of these patients on PD and at the FN in 78.4%. TBMC correlated negatively with iPTH. There were no correlations between markers of bone turnover and bone mass measurements at the two skeletal regions, although patients with BMD T scores in the osteoporosis range had increased serum iPTH levels. Bone mass measurements were not different between patients with and patients without fractures.

[Calcimimetic agents in the treatment of hyperparathyroidism secondary to chronic renal failure]. / Agentes calciomiméticos en el tratamiento del hiperparatiroidismo secundario a la insuficiencia renal crónica.

The recent discovery and cloning of the extra cellular calcium sensing receptor (CaSR) has allowed a better understanding of the regulation of normal calcium metabolism and of rare disturbances in mineral metabolism. In the parathyroid glands the CaSR is responsible for modulating parathyroid hormone release as a function of the extra cellular calcium level. This discovery has allowed the development of drugs that mimics or potentiates the actions of extra cellular calcium on the CaSR, called calcimimetics that decrease parathyroid hormone secretion without increasing serum calcium. The new calcimimetics are small organic molecules that act as allosteric activators of the CaSR and they are in their initial face of clinical development. Although the experience with these drugs is limited, they have shown to effectively lower parathyroid hormone levels in patients with hyperparathyroidism secondary to end-stage renal failure without inducing important side-effects. Thus calcimimetic compounds have considerable potential as new drugs for the treatment of secondary hyperparathyroidism and uremic bone disease.

Calcitriol resistance in hemodialysis patients with secondary hyperparathyroidism.

Nonselective vitamin D receptor activators (VDRA), such as calcitriol and alfacalcidol, have been successfully used in the treatment of secondary hyperparathyroidism (SHPT) in hemodialysis. Despite their beneficial effects on the control of serum PTH levels, their use has been limited by intolerance (development of hypercalcemia and hyperphosphatemia with consecutive cardiovascular toxicity). Apart from becoming intolerant, in 20-30 % of patients who use nonselective VDRA, serum PTH levels do not decrease appropriately despite increasing doses of these agents. These patients are considered calcitriol-resistant patients. Thus, calcitriol resistance and intolerance are two sides of the same coin: active vitamin D failure. Despite the clinical relevance of active vitamin D failure, definitions of resistance and intolerance are imprecise and have varied over time. More selective VDRA claim to produce less hypercalcemia and hyperphosphatemia and could help clinicians to overcome intolerance. Also, some studies have also shown that paricalcitol can be even useful in resistant patients. Significant limitations of iPTH as a reliable and useful clinical biomarker have been increasingly appreciated. There is evidence that intact PTH concentration must differ by 72 % between any two measurements before it can be considered a significant change. VDR polymorphisms could be involved in the development of SHPT in CKD patients. Interestingly, a higher incidence of the b allele of the VDR BsmI gene variant has been shown to be present in SHPT. The BsmI genotype can also affect the response of hemodialysis to IV calcitriol. A challenge for the future will be to establish biomarkers such as laboratory determinations or ultrasound findings that can help us to early identify those patients who will not respond appropriately to calcitriol or exhibit intolerable side effects .

Clinical practice guidelines for the prevention, diagnosis, evaluation and treatment of mineral and bone disorders in chronic kidney disease (CKD-MBD) in adults.

The clinical practice guidelines for the prevention, diagnosis, evaluation and treatment of chronic kidney disease mineral and bone disorders (CKD-BMD) in adults, of the Latin American Society of Nephrology and Hypertension (SLANH) comprise a set of recommendations developed to support the doctor in the management of these abnormalities in adult patients with stages 3-5 kidney disease. This excludes changes associated with renal transplantation. The topics covered in the guidelines are divided into four chapters: 1) Evaluation of biochemical changes, 2) Evaluation of bone changes, 3) Evaluation of vascular calcifications, and 4) Treatment of CKD-MBD. The guidelines are based on the recommendations proposed and published by the Kidney Disease: Improving Global Outcomes (KDIGO) for the prevention, diagnosis, evaluation and treatment of CKD-MBD (KDIGO Clinical practice guidelines for the diagnosis, evaluation, prevention and treatment of Chronic Kidney Disease Mineral and Bone Disorder [CKD-MBD]), adapted to the conditions of patients, institutions and resources available in Latin America, with the support of KDIGO. In some cases, the guidelines correspond to management recommendations directly defined by the working group for their implementation in our region, based on the evidence available in the literature. Each chapter contains guidelines and their rationale, supported by numerous updated references. Unfortunately, there are few controlled studies with statistically sufficient weight in Latin America to support specific recommendations for the region, and as such, most of the references used correspond to studies carried out in other regions. This highlights the need to plan research studies designed to establish the current status of mineral and bone metabolism disorders in Latin America as well as defining the best treatment options for our population.

Hypomagnesaemia/hypokalemia associated with the use of esomeprazole.

Magnesium homeostasis is essential for many intracellular processes and depends on dynamic interplay of intestinal absorption, exchange with the bone reservoir, and renal excretion. Hypomagnesaemia may arise from various disorders. We review the case of a 59 year-old man whose only complaint was irritability with a routine analysis showing hypomagnesaemia and hypokalemia while using esomeprazole, a proton pump inhibitor (PPI). Fractional magnesium excretion was low, excluding excessive renal loss. Potassium excretion was 80 mEq/24 Hr in the presence of hypokalemia suggesting hypomagnesaemia-induced kaliuresis as its cause. Hypomagnesaemia partially resolved after oral magnesium supplementation. Esomeprazol suppression corrected hypomagnesaemia. A causal relationship with esomeprazol use was supported by the recurrence of hypomagnesaemia after rechallenge. We review the literature on hypomagnesaemia due to the use of proton pump inhibitors. In the past decade our understanding of transcellular magnesium transport was enhanced by the discovery of the magnesium channel, transient receptor potential (TR PM) 6 and 7 and other proteins that play an important role in its transport. In this light we discuss the possible etiology of proton pump inhibitor related hypomagnesaemia/hypokalemia.

Long-term treatment of renal lithiasis with potassium citrate.

OBJECTIVE: To evaluate the urine metabolic changes induced by sustained potassium citrate (KCit) treatment in patients with either hypocitraturia (HCit) or "unduly acidic urine pH" (UAUpH), and to determine the remission rate in those patients treated for more than 24 months. METHODS: We retrospectively reviewed the charts of 215 adult patients with recurrent renal stones whose only urinary metabolic risk factors were either HCit (n = 95) or UAUpH (n = 120) and had been treated with KCit for more than 3 months. RESULTS: In patients with Hcit (55 men and 40 women, mean age was 43 ± 14 years), Kcit therapy (average dose 48 ± 14.7 mEq/d) caused a sustained increase in urinary citrate to normal levels, in urinary potassium and pH and in serum potassium. In patients with UAUpH (73 men and 47 women; mean age 48.7 ± 12 years), Kcit therapy (average dose 42.8 ± 15.5 mEq/d) produced a significant increase in urinary pH, potassium, and uric acid. Remission rate was studied in 35 of these patients, whose median follow-up of 31.6 ± 14.3 months. All of these patients received a mean dose of potassium citrate of 45.4 ± 15.2 mEq/d. In 91% of these patients, there was no stone recurrence, similar for Hcit and UAUpH patients. CONCLUSIONS: Treatment with potassium citrate corrects the metabolic abnormalities seen in patients with Hcit and UAUpH. This was associated with a very high remission rate of stone disease.

Clinical and metabolic risk factor evaluation in young adults with kidney stones.

INTRODUCTION: The most frequent urine metabolic risk factor in adults is idiopathic hypercalciuria while in children is hypocitraturia. If there is really a change of metabolic abnormalities with age it would be interesting to study risk factors in the intermediate population: young adults. OBJECTIVE: We evaluated metabolic risk factors, clinical presentation and family history of stone formers between 17 and 27 years old. METHODS: A total of 160 patients (87 males and 73 females) were studied with a standard protocol. RESULTS: A single urine metabolic risk factor was present in 64% of the patients, and multiple risk factors were present in 27% of them. No metabolic abnormalities were found in the remaining 9%. The most common urine risk factor was idiopathic hypercalciuria (alone or in combination), which was identified in 42.5% followed by hypocitraturia (alone or in combination) found in 32.9% of the patients. In the subgroup of patients of 17-20 years (n = 75; mean age of 18.8 + or - 1.0 years), hypocitraturia (alone or in combination) was as frequent as idiopathic hypercalciuria (alone or in combination), which was identified in 38% (n = 30) and 36.7% (n = 29), respectively. The most frequent form of presentation was renal colic (72%). A positive family history of stone disease in first degree and second-degree relatives was found in 32.9 and 34.1%, respectively. CONCLUSIONS: Metabolic abnormalities were found in 91% of young adults with renal lithiasis, similar to our adult series. Hypercalciuria was the most frequent metabolic abnormality found. Yet, hypocitraturia (alone or in combination) was very frequent, and in the subgroup of patients of 17-20 years, it was as frequent as idiopathic hypercalciuria, similar to what we found in children.