Anna L. Zisman

Impact of Ergocalciferol Treatment of Vitamin D Deficiency on Serum Parathyroid Hormone Concentrations in Chronic Kidney Disease

Background: Vitamin D deficiency is highly prevalent and associated with secondary hyperparathyroidism in patients with chronic kidney disease (CKD). The Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines recommend treatment of vitamin D deficiency starting with CKD stage 3, though no data are available showing an impact on serum parathyroid hormone (PTH) concentrations. The goal of this analysis, therefore, was to determine the effect of ergocalciferol treatment on plasma PTH concentrations in vitamin D-deficient patients with stage 3 and stage 4 CKD. Methods: A prospective, nonrandomized observational analysis was conducted in an academic community hospital CKD clinic. Fifty-two patients with stage 3 or stage 4 CKD with vitamin D deficiency and elevated PTH concentrations received ergocalciferol dosed per a modified K/DOQI guidelines protocol and adjusted every 3 months. Serum PTH, 25-vitamin D, 1,25-vitamin D, calcium, phosphorus, and albumin levels were drawn at initiation of therapy and repeated every 3 months. Results: The mean 25-vitamin D levels normalized in patients with stage 3 and 4 CKD, with values of 31.6 ± 2.2 ng/ml (78.8 ± 5.49 nmol/l) and 35.4 ± 1.9 ng/ml (88.4 ± 4.74 nmol/l), respectively (p < 0.0001). A median decrease in PTH concentrations of 13.1 and 2.0% was noted in patients with stage 3 and stage 4 CKD, respectively (p = 0.041, p = nonsignificant). Conclusions: Ergocalciferol therapy is a reasonable initial therapy for vitamin D deficiency associated with elevated PTH levels in stage 3 CKD. It does not appear to have equivalent benefits in stage 4 CKD.

KIDNEY STONES: AN UPDATE ON CURRENT PHARMACOLOGICAL MANAGEMENT AND FUTURE DIRECTIONS

Introduction: Kidney stones are a common problem worldwide with substantial morbidities and economic costs. Medical therapy reduces stone recurrence significantly. Much progress has been made in the last several decades in improving therapy of stone disease. Areas covered: This review discusses i) the effect of medical expulsive therapy on spontaneous stone passage, ii) pharmacotherapy in the prevention of stone recurrence and iii) future directions in the treatment of kidney stone disease. Expert opinion: Fluid intake to promote urine volume of at least 2.5 L each day is essential to prevent stone formation. Dietary recommendations should be adjusted based on individual metabolic abnormalities. Properly dosed thiazide treatment is the standard therapy for calcium stone formers with idiopathic hypercalciuria. Potassium alkali therapy is considered for hypocitraturia, but caution should be taken to prevent potential risk of calcium phosphate stone formation. For absorptive hyperoxaluria, low oxalate diet and increased dietary calcium intake are recommended. Pyridoxine has been shown effective in some cases of primary hyperoxaluria type I. Allopurinol is used in calcium oxalate stone formers with hyperuricosuria. Treatment of cystine stones remains challenging. Tiopronin can be used if urinary alkalinization and adequate fluid intake are insufficient. For struvite stones, complete surgical removal coupled with appropriate antibiotic therapy is necessary.

Pancreatic cancer patients who smoke and drink are diagnosed at younger ages.

BACKGROUND & AIMS Cigarette smoking is an established risk factor for pancreatic cancer, but there is conflicting evidence regarding the effects of alcohol consumption. The effects of cigarettes and alcohol on age of sporadic pancreatic cancer diagnosis have not been examined; we evaluated the independent and synergistic effects of lifetime cigarette smoking and alcohol consumption on age at pancreatic cancer diagnosis in the United States. METHODS We analyzed data on cigarette smoking and alcohol consumption from the IMPAC Services, Inc Cancer Information Resource File (CIRF), collected from June 1, 1993, to December 31, 2003, for 29,239 reported, histologically confirmed cases of pancreatic adenocarcinoma. We also analyzed data on cigarette smoking and alcohol consumption for 820 histologically confirmed cases of pancreatic adenocarcinoma from the University of Michigan Pancreatic Cancer Registry (UMPCR), collected from January 2004 to October 2007. RESULTS Current cigarette smokers were diagnosed at significantly younger ages than never smokers, according to data from the CIRF and UMPCR (8.3 and 6.3 y, respectively); the UMPCR data indicated dose effects. Past and current alcohol consumption were associated with younger age at diagnosis in both databases. Current smokers who were current drinkers were diagnosed significantly earlier (CIRF, 10.2 y; UMPCR, 8.6 y) than abstainers. Past cigarette smoking was associated modestly with younger diagnosis age. CONCLUSIONS Cigarette smoking and alcohol consumption were associated with younger age at pancreatic cancer presentation and have a combined effect on diagnosis age. Past cigarette smoking is less influential. Smoking cessation programs could help prevent pancreatic cancer.

Inhibition of Parathyroid Hormone: A Dose Equivalency Study of Paricalcitol and Doxercalciferol

Introduction: Paricalcitol and doxercalciferol are effective in reducing parathyroid hormone PTH concentrations in patients with secondary hyperparathyroidism. The purpose of this study was to determine the relative dose of doxercalciferol (compared to paricalcitol) required to maintain equivalent PTH concentrations in dialysis patients. Methods: Chronic hemodialysis patients treated with a stable dose of paricalcitol for at least 3 months were randomized to receive doxercalciferol at either 35, 50, or 65% of the paricalcitol dose for 6 weeks. Serum iPTH, calcium, phosphorus, and albumin were determined at baseline and monitored every 2 weeks. A linear regression analysis of percent change in iPTH values by dose group was performed to determine the conversion factor. Results: 27 patients were enrolled. Initial iPTH, adjusted serum calcium, serum phosphorus, and Ca×P were similar among the treatment groups. Linear regression analysis demonstrated a conversion factor of 0.57 for the dose of doxercalciferol relative to paricalcitol resulting in equivalent suppression of iPTH. Corrected serum calcium, phosphorus, Ca×P product, as well as incidence of hypercalcemia, hyperphosphatemia and Ca×P >50 were similar for all groups. Conclusion: In patients on a maintenance dose of paricalcitol, dosing doxercalciferol at 55–60% of the paricalcitol dose results in comparable inhibition of PTH.

Recent advances in the rapidly evolving field of fibroblast growth factor 23 in chronic kidney disease

Purpose of reviewIn recent years, there has been an increasing awareness of the central regulatory role of fibroblast growth factor 23 (FGF23) in mineral metabolism and its particular prominence in patients with chronic kidney disease (CKD). Recent findingsFGF23 is a powerful predictor of adverse clinical outcomes in CKD that appears to be superior to existing mineral metabolism markers such as serum phosphate and parathyroid hormone. Interesting new data suggest a central role of bone health in the regulation of FGF23 secretion, whereas another important new study reported that virtually all circulating FGF23 in advanced renal failure is biologically intact. Finally, new data demonstrate the ability to alter FGF23 levels using common CKD therapies such as phosphate binders, active vitamin D, and cinacalcet. SummaryAlthough FGF23 was originally discovered in studies of rare diseases, we expect that its primary utility in mainstream clinical practice will ultimately lie in the management of CKD. Emerging data highlight the potential of FGF23 as a novel diagnostic to identify CKD patients at the highest risk for disease progression, cardiovascular disease, and death, and those who might benefit from early phosphorus-related therapies before the onset of overt hyperphosphatemia.

Evidence for net renal tubule oxalate secretion in patients with calcium kidney stones

Little is known about the renal handling of oxalate in patients with idiopathic hypercalciuria (IH). To explore the role of tubular oxalate handling in IH and to evaluate whether differences exist between IH and normal controls, we studied 19 IH subjects, 8 normal subjects, and 2 bariatric stone formers (BSF) during a 1-day General Clinical Research Center protocol utilizing a low-oxalate diet. Urine and blood samples were collected at 30- to 60-min intervals while subjects were fasting and after they ate three meals providing known amounts of calcium, phosphorus, sodium, protein, oxalate, and calories. Plasma oxalate concentrations and oxalate-filtered loads were similar between patients (includes IH and BSF) and controls in both the fasting and fed states. Urinary oxalate excretion was significantly higher in patients vs. controls regardless of feeding state. Fractional excretion of oxalate (FEOx) was >1, suggesting tubular secretion of oxalate, in 6 of 19 IH and both BSF, compared with none of the controls (P < 0.00001). Adjusted for water extraction along the nephron, urine oxalate rose more rapidly among patients than normal subjects with increases in plasma oxalate. Our findings identify tubular secretion of oxalate as a key mediator of hyperoxaluria in calcium stone formers, potentially as a means of maintaining plasma oxalate in a tight range.

Do Kidney Stone Formers Have A Kidney Disease

Nephrolithiasis is a highly prevalent disorder affecting approximately one in eleven people and is associated with multiple complications including hypertension, cardiovascular disease, and chronic kidney disease. Significant epidemiologic associations with chronic kidney disease and ESRD have been noted and are reviewed herein, but debate persists in the literature as to whether kidney stone formation is a pathogenic process contributing to kidney disease. Corroborating evidence supporting the presence of kidney disease in stone formers includes the variability of renal function by stone type, the positive association of stone size with renal dysfunction, the presence of markers of renal injury in the urine of even asymptomatic stone formers, and direct evidence of renal tissue injury on histopathology. Proposed pathogenic mechanisms include recurrent obstruction and comorbid conditions such as recurrent urinary tract infections and structural abnormalities. Recent work evaluating the renal histopathology of different groups of stone formers adds further granularity, suggesting variability in mechanisms of renal injury by stone type and confirming the pathogenic effects of crystal formation. Genetic abnormalities leading to stone formation including cystinuria and primary hyperoxaluria, among others, contribute to the burden of disease in the stone-forming population.

Effectiveness of Treatment Modalities on Kidney Stone Recurrence

Nephrolithiasis is highly prevalent across all demographic groups in the Western world and beyond, and its incidence rates are rising. In addition to the morbidity of the acute event, stone disease often becomes a lifelong problem that requires preventative therapy to diminish ongoing morbidity. Across the majority of stone types, increased fluid intake and targeted dietary modifications are mainstays of therapy. Specific dietary interventions associated with reduced calcium stone risk include adequate dietary calcium intake and restriction of sodium, protein, and oxalate intake, among others. Pharmaceutical therapy may be required if lifestyle changes are insufficient to minimize risk of stone recurrence, and must be targeted to the specific metabolic abnormalities portending risk for a given patient. Therapeutic options for idiopathic calcium stone disease include thiazides, citrate salts, and uric acid-lowering agents. Alkali salts are also the treatment of choice for uric acid stone disease. Management of struvite stone disease is largely surgical, but acetohydroxamic acid is a proven second line therapy. Cystinuria requires lifestyle modifications and may call for thiol-binding agents. Significant heterogeneity of the clinical population with stone disease has previously limited opportunities for large randomized controlled trials. However, as clinical phenotypes and genotypes are increasingly clarified, there are mounting opportunities for targeted randomized controlled trials in stone prevention. In the meantime, the currently available evidence for both lifestyle and pharmacologic interventions is reviewed herein.

MP95-16 RACIAL DIFFERENCES IN URINARY METABOLIC RISK FACTORS FOR NEPHROLITHIASIS

INTRODUCTION AND OBJECTIVES: Over the past two decades, the prevalence of kidney stones in black non-Hispanics has increased by 150%, yet there is a paucity of literature regarding African American (AA) stone-formers. Small studies suggest certain urinary parameters do not significantly differ between racial groups. We asked whether AA stone formers have any meaningful differences in urine and serum metabolic parameters when compared to Caucasians (C). METHODS: AA patients with known stone composition undergoingmetabolic stone evaluation (at least three 24-hour urine collections per patient and paired serum studies) were retrospectively identified by self-reported race from 1995-2016 and sex and age-matched 1:2 to C patients with known stone composition from the same years. Metabolic data were compared between groups by stone type and race using ANOVA. Majority stone type was defined as >50% of composition. RESULTS: Fifty-five AA (calcium oxalate (CaOx)1⁄429, Ca phosphate (CaP)1⁄49, Uric acid1⁄417) and 125 matched C (CaOx1⁄481, CaP1⁄427, Uric acid1⁄417) had complete pre-treatment metabolic data. Despite similar supersaturation (SS) for their stone type, AA had significantly lower 24-hr urine volumes thanC (1.5 vs. 1.9L, p<0.001). Likewise, 24-hr calcium (Ca) levels, were significantly lower than those for C (135 vs. 225 mg, p<0.0001). Urine oxalate and citrate did not differ by ANOVA. Significant differences between races persisted in volumewhen analyzed by stone type. CaOx AA had lower urine Ca than C, but oxalate and citrate excretions did not differ. Urine Ca did not differ for CaP stone formersby race. For uric acid stones,AAhad lower uric acid excretionand uric acid SS but higher urine pH. Serum phosphate also differed by race, and was lower in AA males than in C males; for women this did not differ. CONCLUSIONS: While physical chemistry dictates that SS drives risk for stone formation, we demonstrate racial differences in determinants of SS. Previously unknown and significant metabolic differences exist between AA and Caucasian stone formers.

Medical Management of Hypercalciuria

Hypercalciuria is the most commonly identified abnormality in 24-h urine studies of calcium stone formers. Typically no specific etiology is identified and the disorder is termed idiopathic, but secondary causes such as primary hyperparathyroidism, renal tubular acidosis, and states of vitamin D excess must be ruled out on initial evaluation. Timely therapy of hypercalciuria can decrease risk of kidney stone recurrence and may mitigate bone demineralization. In addition to lifestyle changes such as increased fluid intake, dietary changes, and sodium restriction, pharmacological therapy with thiazides and alkali supplementation is often necessary for successful treatment of hypercalciuria. Ongoing monitoring and therapy is necessary to maintain the decrement in risk of stone recurrence.