Patiromer Treatment in Patients With CKD, Hyperkalemia, and Hyperphosphatemia: A Post Hoc Analysis of 3 Clinical Trials.

RATIONALE & OBJECTIVE: Patients with chronic kidney disease (CKD), hyperkalemia (serum potassium [sK+]>5.0 mEq/L), and hyperphosphatemia experience poor clinical outcomes. Patiromer, a potassium binder that uses calcium as the exchange ion, may also reduce serum phosphorus (sP). We characterized the effect of patiromer on sP in patients with CKD, hyperkalemia, and hyperphosphatemia. STUDY DESIGN: A post hoc pooled analysis of individual-level data from the AMETHYST-DN, OPAL-HK, and TOURMALINE trials of patiromer. SETTING & PARTICIPANTS: Patients with CKD and hyperkalemia. EXPOSURE: Patients treated with patiromer (8.4-33.6 g/day). OUTCOME: Mean changes from baseline in sP, sK+, serum calcium (sCa2+), and serum magnesium (sMg2+) after 2 and 4 weeks of treatment. ANALYTICAL APPROACH: Descriptive statistics to summarize pooled data on the study outcomes from the 3 studies. RESULTS: We included 578 patients in the analysis. Of these participants, 86 patients (14.9%) had baseline hyperphosphatemia of whom 75.6% (65 of 86) had CKD stage 4/5 and 31.1% (153 of 492) with sP≤4.5mg/dL had CKD stage 4/5. Among the patients with elevated sP and sK+at baseline, the mean±SD reduction in sP and sK+after 4 weeks of patiromer treatment was-0.62±1.09mg/dL and-0.71± 0.51 mEq/L, respectively. Additionally, the mean±SD reduction in sMg2+in these patients was -0.25±0.23mg/dL while sCa2+remained unchanged. Both sMg2+and sCa2+remained within the normal range. Patiromer was generally well tolerated, and no serious adverse events were considered related to patiromer. LIMITATIONS: These were post hoc analyses, no placebo comparison was performed due to the design of the original studies, and the follow-up period was limited to 4 weeks. CONCLUSIONS: Reductions in sP and sK+to the normal range were observed after 2 weeks of patiromer treatment, and the reduction was sustained during 4 weeks of treatment among patients with non-dialysis-dependent CKD, hyperkalemia, and hyperphosphatemia. Future controlled trials are needed to establish if patiromer is useful to reduce both sK+and sP in hyperkalemic patients with CKD and hyperphosphatemia.

Kidney stone formation and the gut microbiome are altered by antibiotics in genetic hypercalciuric stone-forming rats.

Antibiotics can alter the gut microbiome (GMB), which may be associated with stone disease. We sought to determine the effect that antibiotics have on the GMB, urine ion excretion and stone formation in genetic hypercalciuric stone-forming (GHS) rats. 116th generation GHS rats were fed a fixed amount of a normal calcium (1.2%) and phosphate (0.65%) diet, and divided into three groups (n = 10): control (CTL) diet, or supplemented with ciprofloxacin (Cipro, 5 mg/day) or Bactrim (250 mg/day). Urine and fecal pellets were collected over 6, 12 and 18 weeks. Fecal DNA was amplified across the 16S rRNA V4 region. At 18 weeks, kidney stone formation was visualized by Faxitron and blindly assessed by three investigators. After 18 weeks, urine calcium and oxalate decreased with Bactrim compared to CTL and Cipro. Urine pH increased with Bactrim compared to CTL and Cipro. Urine citrate increased with Cipro compared to CTL and decreased by half with Bactrim. Calcification increased with Bactrim compared to CTL and Cipro. Increased microbial diversity correlated with decreased urinary oxalate in all animals (R = - 0.46, p = 0.006). A potential microbial network emerged as significantly associated with shifts in urinary pH. Bactrim and Cipro differentially altered the GMB of GHS rats. The Bactrim group experienced a decrease in urine calcium, increased CaP supersaturation and increased calcification. The GMB is likely a contributing factor to changes in urine chemistry, supersaturation and stone risk. Further investigation is required to fully understand the association between antibiotics, the GMB and kidney stone formation.

Association between dietary zinc intake and abdominal aortic calcification in US adults.

BACKGROUND: In animal studies, zinc supplementation inhibited phosphate-induced arterial calcification. We tested the hypothesis that higher intake of dietary zinc was associated with lower abdominal aortic calcification (AAC) among adults in the USA. We also explored the associations of AAC with supplemental zinc intake, total zinc intake and serum zinc level. METHODS: We performed cross-sectional analyses of 2535 participants from the National Health and Nutrition Examination Survey 2013-14. Dietary and supplemental zinc intakes were obtained from two 24-h dietary recall interviews. Total zinc intake was the sum of dietary and supplemental zinc. AAC was measured using dual-energy X-ray absorptiometry in adults ≥40 years of age and quantified using the Kauppila score system. AAC scores were categorized into three groups: no AAC (AAC = 0, reference group), mild-moderate (AAC >0-≤6) and severe AAC (AAC >6). RESULTS: Dietary zinc intake (mean ± SE) was 10.5 ± 0.1 mg/day; 28% had AAC (20% mild-moderate and 8% severe), 17% had diabetes mellitus and 51% had hypertension. Higher intake of dietary zinc was associated with lower odds of having severe AAC. Per 1 mg/day higher intake of dietary zinc, the odds of having severe AAC were 8% lower [adjusted odds ratio 0.92 (95% confidence interval 0.86-0.98), P = 0.01] compared with those without AAC, after adjusting for demographics, comorbidities and laboratory measurements. Supplemental zinc intake, total zinc intake and serum zinc level were not associated with AAC. CONCLUSIONS: Higher intake of dietary zinc was independently associated with lower odds of having severe AAC among noninstitutionalized US adults.

Chlorthalidone Is Superior to Potassium Citrate in Reducing Calcium Phosphate Stones and Increasing Bone Quality in Hypercalciuric Stone-Forming Rats.

BACKGROUND: The pathophysiology of genetic hypercalciuric stone-forming rats parallels that of human idiopathic hypercalciuria. In this model, all animals form calcium phosphate stones. We previously found that chlorthalidone, but not potassium citrate, decreased stone formation in these rats. METHODS: To test whether chlorthalidone and potassium citrate combined would reduce calcium phosphate stone formation more than either medication alone, four groups of rats were fed a fixed amount of a normal calcium and phosphorus diet, supplemented with potassium chloride (as control), potassium citrate, chlorthalidone (with potassium chloride to equalize potassium intake), or potassium citrate plus chlorthalidone. We measured urine every 6 weeks and assessed stone formation and bone quality at 18 weeks. RESULTS: Potassium citrate reduced urine calcium compared with controls, chlorthalidone reduced it further, and potassium citrate plus chlorthalidone reduced it even more. Chlorthalidone increased urine citrate and potassium citrate increased it even more; the combination did not increase it further. Potassium citrate, alone or with chlorthalidone, increased urine calcium phosphate supersaturation, but chlorthalidone did not. All control rats formed stones. Potassium citrate did not alter stone formation. No stones formed with chlorthalidone, and rats given potassium citrate plus chlorthalidone had some stones but fewer than controls. Rats given chlorthalidone with or without potassium citrate had higher bone mineral density and better mechanical properties than controls, whereas those given potassium citrate did not. CONCLUSIONS: In genetic hypercalciuric stone-forming rats, chlorthalidone is superior to potassium citrate alone or combined with chlorthalidone in reducing calcium phosphate stone formation and improving bone quality.

Effect of Potassium Citrate on Calcium Phosphate Stones in a Model of Hypercalciuria.

Potassium citrate is prescribed to decrease stone recurrence in patients with calcium nephrolithiasis. Citrate binds intestinal and urine calcium and increases urine pH. Citrate, metabolized to bicarbonate, should decrease calcium excretion by reducing bone resorption and increasing renal calcium reabsorption. However, citrate binding to intestinal calcium may increase absorption and renal excretion of both phosphate and oxalate. Thus, the effect of potassium citrate on urine calcium oxalate and calcium phosphate supersaturation and stone formation is complex and difficult to predict. To study the effects of potassium citrate on urine supersaturation and stone formation, we utilized 95th-generation inbred genetic hypercalciuric stone-forming rats. Rats were fed a fixed amount of a normal calcium (1.2%) diet supplemented with potassium citrate or potassium chloride (each 4 mmol/d) for 18 weeks. Urine was collected at 6, 12, and 18 weeks. At 18 weeks, stone formation was visualized by radiography. Urine citrate, phosphate, oxalate, and pH levels were higher and urine calcium level was lower in rats fed potassium citrate. Furthermore, calcium oxalate and calcium phosphate supersaturation were higher with potassium citrate; however, uric acid supersaturation was lower. Both groups had similar numbers of exclusively calcium phosphate stones. Thus, potassium citrate effectively raises urine citrate levels and lowers urine calcium levels; however, the increases in urine pH, oxalate, and phosphate levels lead to increased calcium oxalate and calcium phosphate supersaturation. Potassium citrate induces complex changes in urine chemistries and resultant supersaturation, which may not be beneficial in preventing calcium phosphate stone formation.

1,25(OH)2D3 induces a mineralization defect and loss of bone mineral density in genetic hypercalciuric stone-forming rats.

Genetic hypercalciuric stone-forming (GHS) rats, bred to maximize urine (u) calcium (Ca) excretion, demonstrate increased intestinal Ca absorption, increased bone Ca resorption, and reduced renal Ca reabsorption, all leading to elevated uCa compared to the parental Sprague-Dawley (SD) rats. GHS rats have increased numbers of vitamin D receptors (VDRs) at each site, with normal levels of 1,25(OH)2D3 (1,25D), suggesting their VDR is undersaturated with 1,25D. We have shown that 1,25D induces a greater increase in uCa in GHS than SD rats. To examine the effect of the increased VDR on the osseous response to 1,25D, we fed GHS and SD rats an ample Ca diet and injected either 1,25D [low dose (LD) 12.5 or high dose (HD) 25 ng/100 g body weight/day] or vehicle (veh) daily for 16 days. Femoral areal bone mineral density (aBMD, by DEXA) was decreased in GHS+LD and GHS+HD relative to GHS+veh, while there was no effect on SD. Vertebral aBMD was lower in GHS compared to SD and further decreased in GHS+HD. Both femoral and L6 vertebral volumetric BMD (by µCT) were lower in GHS and further reduced by HD. Histomorphometry indicated a decreased osteoclast number in GHS+HD compared to GHS+veh or SD+HD. In tibiae, GHS+HD trabecular thickness and number increased, with a 12-fold increase in osteoid volume but only a threefold increase in bone volume. Bone formation rate was decreased in GHS+HD relative to GHS+veh, confirming the mineralization defect. The loss of BMD and the mineralization defect in GHS rats contribute to increased hypercalciuria; if these effects persist, they would result in decreased bone strength, making these bones more fracture-prone. The enhanced effect of 1,25D in GHS rats indicates that the increased VDRs are biologically active.

Making sense of the latest advice on vitamin D therapy.

The Institute of Medicine recently published recommendations for the daily intake and optimal serum levels of vitamin D based on an extensive review of the existing literature. Here we examine the issue and put levels of vitamin D in context for the general population and in patients with chronic kidney disease. Large randomized controlled trials are necessary to ensure that current recommendations are appropriate.

Contribution of intestine, bone, kidney, and dialysis to extracellular fluid calcium content.

Calcium (Ca) balance is the net of Ca intake and output from the body over a period of time. The concept of Ca balance does not consider the redistribution of Ca that often occurs in patients with chronic kidney disease (CKD), especially those who are on dialysis, which is often in the form of soft tissue and/or vascular calcification. In this article, we consider movement of Ca with respect to the extracellular fluid (ECF) and develop a mathematical formulation for Ca homeostasis with respect to the ECF that includes input and output from the diet, the bone, the kidney, and dialysis. We consider calcium homeostasis in healthy individuals and in patients with excess parathyroid hormone, excess 1,25-dihydroxyvitamin D(3), and metabolic acidosis; patients who have CKD and are not on dialysis; and, finally, patients who have CKD and are on dialysis. On the basis of a number of assumptions, dialysis patients with a daily intake of >37.5 mmol of elemental Ca (1.5 g) have movement of Ca into the ECF even without supplemental activated vitamin D. Addition of activated vitamin D, which increases intestinal Ca absorption and can increase resorption of Ca from bone, leads to the movement of Ca into the ECF at virtually all levels of intake; however, there are numerous unanswered questions regarding Ca homeostasis in patients with CKD, including how much of the Ca, administered as a phosphate binder, is absorbed and what is the fate of this absorbed Ca. Until these pressing questions are answered with well-designed experiments, we do not know whether we are doing more harm than good for our dialysis patients by administering additional Ca as a phosphate binder, especially when they also receive activated vitamin D.

Calcium and phosphorus homeostasis.

Calcium and phosphorus homeostasis relies on a complex, tightly regulated system involving many ions and hormones. The regulation of calcium and phosphorus is controlled by the actions of these ions and hormones on the intestine, kidneys and bone. Disturbances in the serum level of calcium and/or phosphorus can lead to significant pathology, including kidney stones and bone disease. In addition to parathyroid hormone and vitamin D, recently identified factors such as fibroblast growth factors and klotho play an important role in maintaining mineral ion homeostasis. The identification of subfamily V transient receptor potential cation channels (TRPV channels), Na/P(i) cotransporters, the vitamin D receptor and the calcium-sensing receptor have further advanced our understanding of this complex physiology. In this review we discuss the current understanding of the relationships between the ions, hormones, and transporters that maintain calcium and phosphorus homeostasis.

Combined therapy with cinacalcet and low doses of vitamin D sterols in patients with moderate to severe secondary hyperparathyroidism.

BACKGROUND: Adequate control of all four KDOQI biochemical targets for chronic kidney disease, bone and mineral disorder (CKD-MBD), which include parathyroid hormone (PTH), calcium (Ca), phosphorus (P) and Ca x P, remains difficult and is accomplished in <6% of patients receiving haemodialysis. The objective of the current study was to determine whether treatment with cinacalcet combined with low doses of vitamin D sterols improves control of both PTH and Ca x P among haemodialysis patients with secondary hyperparathyroidism (sHPT). METHODS: This multicentre, open-label study enrolled haemodialysis subjects (N = 444) with moderate to severe sHPT (mean serum biPTH > 160-430 pg/mL) (approximately iPTH 300-800 pg/mL or ng/L). Cinacalcet was titrated sequentially (30-180 mg/day) during an 8-week dose-titration phase to achieve biPTH

Efficacy of early treatment with calcimimetics in combination with reduced doses of vitamin d sterols in dialysis patients.

Vitamin D is an important physiologic regulator of bone and mineral metabolism. In chronic kidney disease, reduced renal production of calcitriol contributes to secondary hyperparathyroidism (SHPT). Consequently, supplementation with vitamin D sterols is an important treatment for SHPT and its associated mineral and bone disorders. However, doses of vitamin D sterols required to suppress parathyroid hormone (PTH) secretion often promote hypercalcaemia and hyperphosphataemia. Therefore, there is a trade-off between reduced serum PTH and increased levels of serum calcium, phosphorus and calcium-phosphorus product. It has been suggested that treatment of SHPT with cinacalcet, a type II calcimimetic, with reduced doses of vitamin D sterols could enhance achievement of calcium and phosphorus treatment targets while maintaining goals for PTH. Recent clinical trials have evaluated this hypothesis and demonstrated that treatment with cinacalcet in combination with reduced doses of vitamin D sterols is an effective treatment for the management of SHPT.

First- and second-generation immunometric PTH assays during treatment of hyperparathyroidism with cinacalcet HCl.

BACKGROUND: First-generation immunometric assays for "intact" parathyroid hormone (iPTH) also measure large N-terminally truncated PTH fragments, whereas second-generation assays, such as the "bio-intact" PTH (biPTH) assay, measure only full-length biologically active PTH(1-84). This study compared iPTH and biPTH assays during cinacalcet treatment in subjects with secondary HPT receiving dialysis. METHODS: Four hundred and ten subjects were enrolled in a 26-week randomized, double-blind, placebo-controlled trial of oral cinacalcet (or placebo), 30 to 180 mg once daily, and efficacy was assessed using biPTH and iPTH assays. RESULTS: Compared with control treatment, cinacalcet improved the management of secondary HPT. Both biPTH and iPTH decreased by 38%+/- 3% during weeks 13 to 26 in the cinacalcet group; biPTH increased by 23%+/- 4% and iPTH increased by 9.5%+/- 3% in the control group (P < 0.001). Fifty-six percent of cinacalcet subjects and 10% of control subjects had a > or = 30% reduction in biPTH, and 61% and 11%, respectively, had a > or = 30% reduction in iPTH. Significant correlations between biPTH and iPTH levels were observed throughout the study. Both assays correlated similarly with bone-specific alkaline phosphatase levels. The ratio of biPTH to iPTH was maintained at 56% +/- 1% after treatment in both treatment groups. Increasing serum calcium levels were associated with a decreasing ratio of biPTH to (iPTH-biPTH). CONCLUSION: These data show that PTH can be monitored with either iPTH or biPTH assays during therapy with cinacalcet, and that cinacalcet therapy does not exert a major influence on the ratio between PTH(1-84) and large, N-terminally truncated PTH fragments.

Thiazides reduce brushite, but not calcium oxalate, supersaturation, and stone formation in genetic hypercalciuric stone-forming rats.

Over 59 generations, a strain of rats has been inbred to maximize urine calcium excretion. The rats now excrete eight to 10 times as much calcium as controls. These rats uniformly form calcium phosphate (apatite) kidney stones and have been termed genetic hypercalciuric stone-forming (GHS) rats. The addition of a common amino acid and oxalate precursor, hydroxyproline, to the diet of the GHS rats leads to formation of calcium oxalate (CaOx) kidney stones. Hydroxyproline-supplemented GHS rats were used to test the hypothesis that the thiazide diuretic chlorthalidone would decrease urine calcium excretion, supersaturation, and perhaps stone formation. All GHS rats received a fixed amount of a standard 1.2% calcium diet with 5% trans-4-hydroxy-l-proline (hydroxyproline) so that the rats would exclusively form CaOx stones. Half of the rats had chlorthalidone (Thz; 4 to 5 mg/kg per d) added to their diets. Urine was collected weekly, and at the conclusion of the study, the kidneys, ureters, and bladders were radiographed for the presence of stones. Compared with control, the addition of Thz led to a significant reduction of urine calcium and phosphorus excretion, whereas urine oxalate excretion increased. Supersaturation with respect to the calcium hydrogen phosphate fell, whereas supersaturation with respect to CaOx was unchanged. Rats that were fed Thz had fewer stones. As calcium phosphate seems to be the preferred initial solid phase in patients with CaOx kidney stones, the reduction in supersaturation with respect to the calcium phosphate solid phase may be the mechanism by which thiazides reduce CaOx stone formation.

Calcium oxalate crystal localization and osteopontin immunostaining in genetic hypercalciuric stone-forming rats.

BACKGROUND: The inbred genetic hypercalciuric stone-forming (GHS) rats develop calcium phosphate (apatite) stones when fed a normal 1.2% calcium diet. The addition of 1% hydroxyproline to this diet does not alter the type of stone formed, while rats fed this diet with 3% hydroxyproline form mixed apatite and calcium oxalate stones and those with 5% hydroxyproline added form only calcium oxalate stones. The present study was designed to determine the localization of stone formation and if this solid phase resulted in pathologic changes to the kidneys. METHODS: GHS rats were fed 15 g of the standard diet or the diet supplemented with 1%, 3%, or 5% hydroxyproline for 18 weeks. A separate group of Sprague-Dawley rats (the parental strain of the GHS rats), fed the standard diet for a similar duration, served as an additional control. At 18 weeks, all kidneys were perfusion-fixed for structural analysis, detection of crystal deposits using the Yasue silver substitution method, and osteopontin immunostaining. RESULTS: There were no crystal deposits found in the kidneys of Sprague-Dawley rats. Crystal deposits were found in the kidneys of all GHS rats and this Yasue-stained material was detected only in the urinary space. No crystal deposits were noted within the cortical or medullary segments of the nephron and there was no evidence for tubular damage in any group. The only pathologic changes occurred in 3% and 5% hydroxyproline groups with the 5% group showing the most severe changes. In these rats, which form only calcium oxalate stones, focal sites along the urothelial lining of the papilla and fornix of the urinary space demonstrated a proliferative response characterized by increased density of urothelial cells that surrounded the crystal deposits. At the fornix, some crystals were lodged within the interstitium, deep to the proliferative urothelium. There was increased osteopontin immunostaining in the proliferating urothelium. CONCLUSION: Thus in the GHS rat, the initial stone formation occurred solely in the urinary space. Tubular damage was not observed with either apatite or calcium oxalate stones. The apatite stones do not appear to cause any pathological change while those rats forming calcium oxalate stones have a proliferative response of the urothelium, with increased osteopontin immunostaining, around the crystal deposits in the fornix.