John R. Asplin

Effects of Phosphate Binders in Moderate CKD

Some propose using phosphate binders in the CKD population given the association between higher levels of phosphorus and mortality, but their safety and efficacy in this population are not well understood. Here, we aimed to determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with moderate to advanced CKD. We randomly assigned 148 patients with estimated GFR=20-45 ml/min per 1.73 m(2) to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline to the average of months 3, 6, and 9. Serum phosphorus decreased from a baseline mean of 4.2 mg/dl in both active and placebo arms to 3.9 mg/dl with active therapy and 4.1 mg/dl with placebo (P=0.03). Phosphate binders, but not placebo, decreased mean 24-hour urine phosphorus by 22%. Median serum intact parathyroid hormone remained stable with active therapy and increased with placebo (P=0.002). Active therapy did not significantly affect plasma C-terminal fibroblast growth factor 23 levels. Active therapy did, however, significantly increase calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1% versus 0.6%, P=0.05; abdominal aorta: median increases of 15.4% versus 3.4%, P=0.03). In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. The safety and efficacy of phosphate binders in CKD remain uncertain.

Vegetarian Compared with Meat Dietary Protein Source and Phosphorus Homeostasis in Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Patients with advanced chronic kidney disease (CKD) are in positive phosphorus balance, but phosphorus levels are maintained in the normal range through phosphaturia induced by increases in fibroblast growth factor-23 (FGF23) and parathyroid hormone (PTH). This provides the rationale for recommendations to restrict dietary phosphate intake to 800 mg/d. However, the protein source of the phosphate may also be important. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a crossover trial in nine patients with a mean estimated GFR of 32 ml/min to directly compare vegetarian and meat diets with equivalent nutrients prepared by clinical research staff. During the last 24 hours of each 7-day diet period, subjects were hospitalized in a research center and urine and blood were frequently monitored. RESULTS The results indicated that 1 week of a vegetarian diet led to lower serum phosphorus levels and decreased FGF23 levels. The inpatient stay demonstrated similar diurnal variation for blood phosphorus, calcium, PTH, and urine fractional excretion of phosphorus but significant differences between the vegetarian and meat diets. Finally, the 24-hour fractional excretion of phosphorus was highly correlated to a 2-hour fasting urine collection for the vegetarian diet but not the meat diet. CONCLUSIONS In summary, this study demonstrates that the source of protein has a significant effect on phosphorus homeostasis in patients with CKD. Therefore, dietary counseling of patients with CKD must include information on not only the amount of phosphate but also the source of protein from which the phosphate derives.

Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6

Urolithiasis is one of the most common urologic diseases in industrialized societies. Calcium oxalate is the predominant component in 70–80% of kidney stones, and small changes in urinary oxalate concentration affect the risk of stone formation. SLC26A6 is an anion exchanger expressed on the apical membrane in many epithelial tissues, including kidney and intestine. Among its transport activities, SLC26A6 mediates Cl−-oxalate exchange. Here we show that mutant mice lacking Slc26a6 develop a high incidence of calcium oxalate urolithiasis. Slc26a6-null mice have significant hyperoxaluria and elevation in plasma oxalate concentration that is greatly attenuated by dietary oxalate restriction. In vitro flux studies indicated that mice lacking Slc26a6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate. We conclude that the anion exchanger SLC26A6 has a major constitutive role in limiting net intestinal absorption of oxalate, thereby preventing hyperoxaluria and calcium oxalate urolithiasis.

The contribution of malabsorption to the reduction in net energy absorption after long-limb Roux-en-Y gastric bypass

BACKGROUND Roux-en-Y gastric bypass (RYGB) restricts food intake, and when the Roux limb is elongated to 150 cm, the procedure is believed to induce malabsorption. OBJECTIVE Our objective was to measure total reduction in intestinal absorption of combustible energy after RYGB and the extent to which this was due to restriction of food intake or malabsorption of ingested macronutrients. DESIGN Long-limb RYGB was performed in 9 severely obese patients. Dietary intake and intestinal absorption of fat, protein, carbohydrate, and combustible energy were measured before and at 2 intervals after bypass. By using coefficients of absorption to measure absorptive function, equations were developed to calculate the daily gram and kilocalorie quantities of ingested macronutrients that were not absorbed because of malabsorption or restricted food intake. RESULTS Coefficients of fat absorption were 92 ± 1.3% before bypass, 72 ± 5.5% 5 mo after bypass, and 68 ± 8.7% 14 mo after bypass. There were no statistically significant effects of RYGB on protein or carbohydrate absorption coefficients, although protein coefficients decreased substantially in some patients. Five months after bypass, malabsorption reduced absorption of combustible energy by 124 ± 57 kcal/d, whereas restriction of food intake reduced energy absorption by 2062 ± 271 kcal/d. Fourteen months after bypass, malabsorption reduced energy absorption by 172 ± 60 kcal/d compared with 1418 ± 171 kcal/d caused by restricted food intake. CONCLUSION On average, malabsorption accounted for ≈6% and 11% of the total reduction in combustible energy absorption at 5 and 14 mo, respectively, after this gastric bypass procedure.

A Single 24-Hour Urine Collection Is Inadequate For The Medical Evaluation Of Nephrolithiasis

PURPOSE We determined the adequacy of a single 24-hour urine sample for evaluating patients for medical renal stone prevention. MATERIALS AND METHODS A total of 459 patients from a private urology practice specializing in the treatment of urolithiasis and 683 from a university stone research clinic provided 2 and 3, 24-hour urine samples, respectively. We used samples 1 and 2 from private practice patients, and 1 and 3 from university clinic patients for analysis, and compared each to the others by correlation coefficients and calculation of the mean difference plus or minus standard deviation (SD) of the difference. Urine risk factors were measured by standard methods. RESULTS Although the correlation of urine values 1 and 2 was excellent for all stone risk factors, SD values for the differences were large enough that within 1 SD on either side of 0, which included 68.8% of cases, by chance urine 1 would depart from urine 2 by clinically important amounts. These departures would be more than sufficient to misdiagnose common metabolic disorders. CONCLUSIONS A single 24-hour sample is not sufficient for evaluating patients before metabolic treatment for stone prevention because misdiagnosis is common, leading to inappropriate treatment.

Prevalence of Hyperoxaluria After Bariatric Surgery

PURPOSE Recent investigations have shown increased oxalate excretion in patients in whom kidney stones formed after contemporary bariatric surgery. We determined whether there is an increased prevalence of hyperoxaluria after such procedures performed in nonstone formers. MATERIALS AND METHODS A total of 58 nonstone forming adults who underwent laparoscopic Roux-en-Y (52) or a biliopancreatic diversion-duodenal switch procedure (6) collected 24-hour urine specimens 6 months or greater after bariatric surgery. Standard stone risk parameters were assessed. Comparisons were made with a group of healthy nonstone forming adults and stone formers in a commercial database. RESULTS The bariatric group had a significantly higher mean urinary oxalate excretion compared to that in controls and stone formers (67.2 vs 34.1 and 37.0 mg per day, respectively, p <0.001). Mean oxalate excretion of patients who underwent a biliopancreatic diversion-duodenal switch procedure was higher than in the Roux-en-Y group (90 vs 62 mg per day, p <0.05). There was a significant correlation between urine oxalate excretion on the 2 collection days but some patients showed significant variability. Of the patients 74% showed hyperoxaluria in at least 1, 24-hour urine collection and 26% demonstrated profound hyperoxaluria, defined as oxalate excretion more than 100 mg per day, in at least 1 collection. This occurred in 3 of the 6 patients in the biliopancreatic diversion-duodenal switch group and in 12 of the 52 in the Roux-en-Y cohort. Hyperoxaluria was not uniformly expressed. CONCLUSIONS There is a high prevalence of hyperoxaluria in patients without a history of kidney stones who undergo bariatric surgery. A significant proportion of these patients have profound hyperoxaluria, which is not uniformly expressed.

CLINICAL USE OF CYSTINE SUPERSATURATION MEASUREMENTS

PURPOSE We measured the concentration and solubility of cystine in urine from patients with cystinuria or calcium stones and from normal subjects to determine whether urine cystine supersaturation can be calculated from a standard nomogram of solubility versus pH or needs to be measured directly. We also evaluated whether increasing pH of the 24-hour collection recovered enough crystallized cystine to increase cystine supersaturation. MATERIALS AND METHODS Cystine concentration, pH and usual stone risk factors were measured on 50 ml. aliquots of 24-hour collections from 24 patients with cystinuria, 22 calcium stone formers and 15 normal subjects. After 48 hours of incubation with sodium bicarbonate, a second aliquot was taken from the 24-hour collection for cystine concentration. The original urine at its ambient pH was incubated with an excess of cystine crystals for 24, 48, 72 or 96 hours at 37C to determine solubility and kinetics of equilibration. RESULTS Cystine solubility varied so widely at any pH range that no predictive nomogram could be relied on for calculating supersaturation. Addition of sodium bicarbonate to the 24-hour urine significantly increased cystine concentration. Urine from stone formers had higher cystine solubility than urine from normal subjects. CONCLUSIONS Clinical management of cystinuria can be improved by direct measurement of cystine solubility because it varies widely at any given pH. Increasing 24-hour collection pH with sodium bicarbonate additionally improves accuracy of supersaturation measurement by recovering crystallized cystine.

Obesity and urolithiasis.

The current obesity epidemic in the United States has deleterious effects on the health of the population. Temporally related to the increase in obesity is an increase in the prevalence of urolithiasis. Epidemiologic studies have shown that the incident stone risk increases with body mass index. Obesity can increase stone risk in multiple ways. Excess nutritional intake increases traffic of lithogenic substances such as calcium, oxalate, and uric acid. Metabolic syndrome, commonly associated with obesity, alters renal acid-base metabolism, resulting in a lower urine pH and increased risk of uric acid stone disease. The low urine pH is caused by deficient ammonia production, which appears to be related to insulin resistance. Even weight-loss programs to combat obesity can influence stone risk. Contemporary bariatric surgery has been shown to frequently cause hyperoxaluria with associated stone formation and even oxalate nephropathy. Commonly used low-carbohydrate diets increase the risk of both calcium and uric acid stones. Certainly, the many health risks of obesity, including urolithiasis, necessitate weight loss, but recognition of the potential complications of such therapies is required to prevent induction of new and equally severe medical problems. The optimal approach to weight control that minimizes stone risk needs to be determined.

EFFECT OF GRAPEFRUIT JUICE ON URINARY LITHOGENICITY

PURPOSE An increased risk of nephrolithiasis has been associated with the ingestion of grapefruit juice in epidemiological studies. To our knowledge the basis of this effect of grapefruit juice has not been studied previously. We studied the effect of grapefruit juice consumption on urinary chemistry and measures of lithogenicity. MATERIALS AND METHODS Ten healthy men and women between ages of 25 and 40 years participated. Each subject drank 240 ml. of tap water at least 3 times daily for 7 days during the control period. This period was followed by a second 7 days experimental period during which they drank 240 ml. of grapefruit juice 3 times daily. In each 7-day period urine was collected for 24 hours during the last 3 days. Urine chemical analysis was performed, supersaturations of calcium oxalate, calcium phosphate and uric acid were calculated and urinary lithogenicity was measured. RESULTS Urine volume and creatinine excretion were the same during the control and experimental periods. Grapefruit juice ingestion was associated with an increase in mean oxalate excretion plus or minus standard deviation of 41.1 +/- 9.2 to 51.9 +/- 12.0 mg. per 24 hours (p = 0.001) and in mean citrate excretion of 504.8 +/- 226.5 to 591.4 +/- 220.0 mg. per 24 hours (p = 0.01). There was no net change in the supersaturation or upper limit of metastability of calcium oxalate, calcium phosphate or uric acid. Crystal aggregation and growth inhibition by urinary macromolecules was not affected by grapefruit juice ingestion. CONCLUSIONS Offsetting changes in urine chemistry caused by the ingestion of grapefruit juice led to no net change in calculated supersaturation. No changes in lithogenicity were demonstrated. The results do not demonstrate an effect of grapefruit juice for increasing lithogenicity. The basis of the observations of epidemiological studies remain unexplained.

Responsiveness of Hypercalciuria to Thiazide in Dent’s Disease

Hypercalciuria is the major risk factor promoting stone formation in Dents disease, also known as X-linked recessive nephrolithiasis, but the effects of diuretics on calcium excretion and other stone risk factors in this disease are unknown. This study examined urine composition in eight male patients with Dents disease, ages 6 to 49 yr, all of whom were hypercalciuric and had inactivating mutations of CLCN5. Eight males, ages 7 to 34 yr, with idiopathic hypercalciuria (IH) served as controls. Patients were instructed to maintain a consistent intake of sodium, potassium, calcium, and protein. Two consecutive 24-h urine collections were obtained after a baseline period and after 2 wk of chlorthalidone (25 mg), amiloride (5 mg), and the two diuretics in combination, with a week off drug separating the treatment periods in a randomized crossover design. Doses were reduced by half in boys under age 12 yr. Chlorthalidone alone (P < 0.002) and the combination of chlorthalidone and amiloride (P < 0.003) reduced calcium excretion significantly in either patient group. With chlorthalidone, calcium excretion fell to normal (<4.0 mg/kg per d) in all but one patient in each group. Amiloride alone had no significant effect on urinary calcium excretion, in either patient group. In patients with Dents disease during chlorthalidone therapy, the supersaturation ratios for calcium oxalate and calcium phosphate fell by 25% and 35%, respectively. Mean citrate excretion was reduced by chlorthalidone (P <.04) and by chlorthalidone in combination with amiloride (P <.02). There were no significant differences in the responses to these diuretics between the patient groups in any of the urinary parameters. The intact hypocalciuric response to a thiazide diuretic indicates that inactivation of the ClC-5 chloride channel does not impair calcium transport in the distal convoluted tubule and indicates that thiazides should be useful in reducing the risk of kidney stone recurrence in patients with Dents disease.