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. CKD is a significant public health concern; roughly 13% of the US population has an estimated GFR (eGFR) below 60 ml/min per 1.73 m 2 or albuminuria. 1 The risks of death and cardiovascular disease in CKD are not fully explained by associated diabetes, hypertension, and other conventional risk factors. 2 With declining kidney function, serum phosphorus concentration increases but generally remains within the normal range until late in stage 4 or 5 CKD. A normal or near-normal serum phosphorus concentration is maintained at the expense of elevated levels of the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). 3,4 Serum concentrations of phosphorus and hormones responsible for its regulation have been implicated as putative cardiovascular risk factors. [5][6][7][8][9]

BOUT three fourths-mf-all kidney stones arexorn-A posed o f e l c i u m oxaiate'; most calcium oxalate stones also contain a small ambunt of hvdroxva~atite. I I and 10 to 12 percent contain some uric&.'-Ten-20 perwnt.ol~stonas-conta~n%tmyite (magnesium ammonium phosphate) produced by a urinary tract infection with bacteri; that express the enzyme urease? F~e~p e r~e~-~f +~t~~~~~~~~~~~i~~c-. a 1 :~ 4 e-nt 'P contain-more~-rhan~QQ~c~ccnt-hydroxy-apatl or calcium monoh.y-drogen phosphate (brushite), and less than d-pe~~&e..%emp&gfTs~&e. Whereas most calcium oxalate s t 0 5 are less than 2 cm in diameter. struvite, uric acid, and cystine stones may fill the renal collecting system (staghorn calculi). Tiny flecks of calcium salts that encrust calyces can make kidney radiographs seem like pictures of the night sky (nephrocalcinosis). Calcium oxalate, uric acid, or cystine crystallites can scour the urinary tract, cause pain and bleeding, and then dispersea process commonly described as "passing gravel" and more formally termed "crystalluria." The-composition of every stone should be analyzed. Polarization microscopy4 is an inexpensive guide to differentiation; infrared and x-ray diffraction techniques surpass microscopy in precision and sensitivity: but we have not found their use essential. Galoiurn exalate and-calcium phosphate stones are black, gray, or white; on x-ray films they are small (< 1 cm in diameter), dense, opaque, and sharply circumscribed. Uaic.aeid stones are white or orange, and uric acid gravel is orange but nearly transparent radiograph;cally-unless mixed with calcium crystah or struvite. Uric acid stones are typically seen as filling defects on intravenous pyelograms. C T scanning can distinguish them from kidney tissue or blood clots and reveal their sizes and shapes6 Struvite stones seem gnarled and laminated on radiographs; they look like ginger root. Cystine stones are greenish yellow and flecked with shiny crystallites, like mica. On x-ray films, they look like homogeneous pieces of sculpted wax or soap. Urinalysis can reveal the presence of crystals and provide From the S c c t h of Ncphrobgy. Uninrriy of Qligo, Rin);cr S c h d of Mdicinc. 5841 S. Marylud A u. MC 5100. C h i g o. LL60637. w h nprin~ fcquescs should be ddFCgCd I O Dr. COC. Suppated in puc by gmm (POI-33949 ud DK-3349) fran the Narrml LRaitva d Halth. clues to the type of stone; some of the common types are shown in Figure 1.

SummaryBackground 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, & measurementsWe 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. ResultsThe 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.

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.

Crystalline materials are crucial to the function of living organisms, in the shells of molluscs, the matrix of bone, the teeth of sea urchins, and the exoskeletons of coccoliths. However, pathological biomineralization can be an undesirable crystallization process associated with human diseases. The crystal growth of biogenic, natural and synthetic materials may be regulated by the action of modifiers, most commonly inhibitors, which range from small ions and molecules to large macromolecules. Inhibitors adsorb on crystal surfaces and impede the addition of solute, thereby reducing the rate of growth. Complex inhibitor-crystal interactions in biomineralization are often not well elucidated. Here we show that two molecular inhibitors of calcium oxalate monohydrate crystallization--citrate and hydroxycitrate--exhibit a mechanism that differs from classical theory in that inhibitor adsorption on crystal surfaces induces dissolution of the crystal under specific conditions rather than a reduced rate of crystal growth. This phenomenon occurs even in supersaturated solutions where inhibitor concentration is three orders of magnitude less than that of the solute. The results of bulk crystallization, in situ atomic force microscopy, and density functional theory studies are qualitatively consistent with a hypothesis that inhibitor-crystal interactions impart localized strain to the crystal lattice and that oxalate and calcium ions are released into solution to alleviate this strain. Calcium oxalate monohydrate is the principal component of human kidney stones and citrate is an often-used therapy, but hydroxycitrate is not. For hydroxycitrate to function as a kidney stone treatment, it must be excreted in urine. We report that hydroxycitrate ingested by non-stone-forming humans at an often-recommended dose leads to substantial urinary excretion. In vitro assays using human urine reveal that the molecular modifier hydroxycitrate is as effective an inhibitor of nucleation of calcium oxalate monohydrate nucleation as is citrate. Our findings support exploration of the clinical potential of hydroxycitrate as an alternative treatment to citrate for kidney stones.