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Rationale & Objective The pathogenesis of disordered mineral metabolism in chronic kidney disease (CKD) is largely informed by cross-sectional studies of humans and longitudinal animal studies. We sought to characterize the longitudinal evolution of disordered mineral metabolism during the course of CKD. Study Design Retrospective analysis nested in a cohort study. Setting & Participants Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had up to 5 serial annual measurements of estimated glomerular filtration rate, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), serum phosphate, and serum calcium and who subsequently reached end-stage kidney disease (ESKD) during follow-up (n = 847). Exposure Years before ESKD. Outcomes Serial FGF-23, PTH, serum phosphate, and serum calcium levels. Analytical Approach To assess longitudinal dynamics of disordered mineral metabolism in human CKD, we used "ESKD-anchored longitudinal analyses" to express time as years before ESKD, enabling assessments of mineral metabolites spanning 8 years of CKD progression before ESKD. Results Mean FGF-23 levels increased markedly as time before ESKD decreased, while PTH and phosphate levels increased modestly and calcium levels declined minimally. Compared with other mineral metabolites, FGF-23 levels demonstrated the highest rate of change (velocity: first derivative of the function of concentration over time) and magnitude of acceleration (second derivative). These changes became evident approximately 5 years before ESKD and persisted without deceleration through ESKD onset. Rates of changes in PTH and phosphate levels increased modestly and without marked acceleration around the same time, with modest deceleration immediately before ESKD, when use of active vitamin D and phosphate binders increased. Limitations Individuals who entered the CRIC Study at early stages of CKD and who did not progress to ESKD were not studied. Conclusions Among patients with progressive CKD, FGF-23 levels begin to increase 5 years before ESKD and continue to rapidly accelerate until transition to ESKD.

Rationale & Objective Low serum magnesium level has been shown to be associated with increased mortality, but its role as a predictor of cardiovascular disease is unclear. This study evaluates the association between serum magnesium level and cardiovascular events and all-cause mortality in a large cohort of individuals with chronic kidney disease (CKD). Study Design Prospective cohort study. Setting & Participants 3,867 participants with CKD, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Exposures Serum magnesium measured at study baseline. Outcomes Composite cardiovascular events (myocardial infarction, cerebrovascular accident, heart failure, and peripheral arterial disease) and all-cause mortality. Analytical Approach Cox proportional hazards models adjusted for demographic, clinical, and laboratory characteristics. Results During the 14.6 (4.4) years (standard deviation) of follow-up, 1,384 participants died (36/1,000 person-years), and 1,227 (40/1,000 person-years) had a composite cardiovascular event. There was a nonlinear association between serum magnesium level and all-cause mortality. Low and high magnesium levels were associated with greater rates of all-cause mortality after adjusting for demographics, comorbid conditions, medications including diuretics, estimated glomerular filtration rate, and proteinuria (P 2.1 mg/dL was associated with increased risk for all-cause mortality. Low magnesium level was associated with incident atrial fibrillation but not with composite cardiovascular disease events. Further studies are needed to determine the optimal range of serum magnesium in CKD to prevent adverse clinical outcomes., Graphical abstract

Rationale & Objective Prior studies of patients receiving maintenance hemodialysis have shown that, on average, blood pressure (BP) measured predialysis is higher than BP measured at home. We hypothesized that a subset of hemodialysis patients has BP that is higher when measured at home than when measured predialysis and this subgroup of patients has a higher prevalence of left ventricular hypertrophy. Study Design Prospective cohort. Setting & Participants 97 hypertensive hemodialysis patients enrolled in the Blood Pressure in Dialysis Study (BID), a randomized trial of comparing target predialysis BP ≤140/90 to 155-165/90 mm Hg. Exposure Differences between predialysis and next-day home systolic BP measured ≥6 times over 1 year. Outcome Left ventricular mass index (LVMI) by cardiac magnetic resonance imaging. Analytical Approach A hierarchical clustering analysis divided patients into 3 clusters based on the average and variability of differences in systolic predialysis and home BP. Clusters were compared with respect to clinical factors and LVMI. Results Mean differences between predialysis and home systolic BP were 19.1 (95% CI, 17.0 to 21.1) mm Hg for cluster 1 ("home lower"), 3.7 (95% CI, 1.6 to 5.8) mm Hg for cluster 2 ("home and predialysis similar"), and −9.7 (95% CI, −12.0 to −7.4) mm Hg for cluster 3 ("home higher"). Systolic BP declined during dialysis in clusters 1 and 2 but increased in cluster 3. Interdialytic weight gains did not differ. After adjusting for sex and treatment arm, LVMI was higher in cluster 3 than in clusters 1 and 2: differences in means of 10.6 ± 4.96 (SE) g/m2 (P = 0.04) and 12.0 ± 5.08 g/m2 (P = 0.02), respectively. Limitations Limited statistical power. Conclusions Nearly one-third of participants had home BPs higher than predialysis BPs. These patients had LVMI higher than those with similar or lower BPs at home, indicating that their BP may have been undertreated.

Monoclonal immunoglobulin paraproteins can deposit in the kidney in variable forms and eliciting differing patterns of injury. Crystalglobulin-induced nephropathy is a rare form of monoclonal immunoglobulin deposition in the kidney, characterized by glomerular capillary endoluminal crystalline material evident by light and electron microscopy that exhibits immunoglobulin restriction via immunofluorescence studies. We present a case of a patient with acute kidney injury, and a subsequent kidney biopsy notably revealed concurrent monoclonal immunoglobulin deposition disease (MIDD) and crystalglobulin-induced nephropathy secondary to an IgM/κ monoclonal protein that resulted in a membranoproliferative pattern of glomerular injury. The two process were distinctly evident by ultrastructural crystalline and non-crystalline (as seen with cases of more conventional MIDD) deposits in the glomeruli. The paraprotein constituency is novel (IgM/κ) for crystalglobulin-induced nephropathy (prior cases exhibited IgG/κ restriction) as was the finding of the two monoclonal immunoglobulin deposition processes contributing to development of an active glomerulitis characterized by a membranoproliferative pattern of glomerular injury (crystalglobulin-induced nephropathy has not been associated with an active glomerulitis before). .

Background: The vitamin D system is essential for optimal health in humans. Circulating calcitriol, a key metabolite in maintaining calcium and phosphorus homeostasis, is produced in the kidney. In kidney failure, calcitriol levels progressively decrease, contributing to the development of renal secondary hyperparathyroidism (SHPT). Summary: For years, SHPT had a central role in the disturbed mineral metabolism of renal patients. As calcitriol deficiency contributes to SHPT development, treatment with calcitriol or other compounds able to activate the vitamin D receptor (VDR) was one of the mainstays of therapy for renal patients in the last 40 years. In this review, we discuss how the treatment with VDR activators (VDRA) evolved during this time in the United States, as well as the main factors responsible for these changes. Key Messages: Management of SHPT with VDRA in renal patients has undergone a few paradigm shifts over the last 40 years. When treating SHPT, the newly developed therapies as well as VDRA need to be carefully considered and used appropriately. Nephrologists need to use an integrated approach that avoids excessive use of VDRA, ensures replenishment of vitamin D stores, and avoids hypercalcemia and hyperphosphatemia.

Inflammation is a consequence of chronic kidney disease (CKD) and is associated with adverse outcomes in many clinical settings. Inflammation stimulates production of fibroblast growth factor 23 (FGF23), high levels of which are independently associated with mortality in CKD. Few large-scale prospective studies have examined inflammation and mortality in patients with CKD, and none tested the interrelationships between inflammation, FGF23 and risk of death. Therefore, we conducted a prospective investigation of 3875 participants in the Chronic Renal Insufficiency Cohort (CRIC) study with CKD stages 2 to 4 to test the associations of baseline plasma interleukin-6, high sensitivity C-reactive protein, and FGF23 levels with all-cause mortality, censoring at the onset of end-stage renal disease. During a median follow-up of 6.9 years, 550 participants died (20.5/1000 person-years) prior to end stage renal disease. In separate multivariable-adjusted analyses, higher levels of interleukin-6 (hazard ratio per one standard deviation increase of natural log-transformed levels) 1.35 (95% confidence interval, 1.25–1.46), C-reactive protein 1.28 (1.16–1.40), and FGF23 1.45 (1.32–1.60) were each independently associated with increased risk of death. With further adjustment for FGF23, the risks of death associated with interleukin-6 and C-reactive protein were minimally attenuated. Compared to participants in the lowest quartiles of inflammation and FGF23, the multivariable-adjusted hazard ratio of death among those in the highest quartiles of both biomarkers was 4.38 (2.65–7.23) for interleukin-6 and FGF23, and 5.54 (3.04–10.09) for C-reactive protein and FGF23. Thus, elevated levels of interleukin-6, C-reactive protein and FGF23 are independent risk factors for mortality in CKD.

Objective Dietary supplementation with grains containing high β-glucan fiber has been shown to attenuate the progression of chronic kidney disease (CKD) and vascular calcification in animal models. The aim of this study was to investigate the feasibility of consuming an oat β-glucan supplement and to assess its effects on certain uremic toxins and markers of mineral metabolism in patients with CKD. Design This is a 20-week, nonrandomized, single-center, pretest-posttest study. Twenty-eight subjects with CKD stages 3-4 were enrolled. The mean age was 67.6 ± 8.9 years, and the mean estimated glomerular filtration rate was 35 ± 14 mL/min/1.73 m2. Subjects received a dietary supplement containing 3 g of oat β-glucan per day for 12 weeks. The 4-week period before the start of the intervention was used as a baseline comparison for each subject. The primary outcome was pre-post supplement changes in plasma levels of two uremic toxins: trimethylamine N-oxide (TMAO) and asymmetric dimethylarginine. Secondary outcomes were pre-post supplement changes in serum calcium, phosphorus, and Klotho levels. Repeated-measures analysis of variance was used to test the differences in outcomes over the three-month–long intervention. Results Serum levels of TMAO decreased by a median of −17% (interquartile range: −46%, 7%) at the end of the intervention. A nonstatistically significant change was observed for asymmetric dimethylarginine (median −0.6% [−12%, 20%]) and serum Klotho (median −3% [−8%, 7%]). There were no changes in serum levels of calcium and phosphorus. One month after discontinuation of β-glucan therapy, TMAO levels increased by a median of 16% (−12%, 36%) but remained slightly below the pretreatment levels. Eight subjects experienced side effects and discontinued the treatment. Conclusion A diet supplemented with β-glucan is safe and potentially efficacious in lowering serum concentrations of TMAO in patients with CKD. Larger trials with longer follow-up times are needed to determine whether such reductions translate into clinical benefits.

Very little is known about the pharmacokinetics of chemotherapeutic agents in patients also being treated with continuous ambulatory peritoneal dialysis. We sought to evaluate the pharmacokinetics of cisplatin and 5-fluorouracil in plasma and peritoneal dialysate in a patient being treated for esophageal adenocarcinoma.A single patient with esophageal adenocarcinoma and on peritoneal dialysis for end-stage renal disease was treated with cisplatin 25 mg/m(2) on day 1 of weeks 1 and 5 and continuous infusional 5-fluorouracil 1000 mg/m(2)/day on days 1-4 of weeks 1 and 5 along with daily radiation therapy. Intense plasma and dialysate sampling was performed during the week 5 administration, followed by quantitation of platinum by atomic absorption spectrophotometry and 5-fluorouracil by LC-MS/MS.Following systemic administration, clearance of ultrafilterable (active) platinum over the first 6 h was 20.8 L/h, which is lower than previously reported clearance levels of ultrafilterable platinum. Total platinum AUC was 131 μg h/mL, also higher than an AUC previously reported for total platinum in patients with normal renal function. Platinum-related material was detected in the peritoneal cavity, but this is likely inactive. 5-Fluorouracil penetrated the intraperitoneal cavity, but the contribution of peritoneal dialysis to drug clearance was negligible at 0.072 %.Administration of intravenous cisplatin and 5-fluorouracil chemotherapy to a patient treated with continuous ambulatory peritoneal dialysis is feasible, but clearance in dialysate is nominal, thus suggesting that dose reduction is indicated for cisplatin. Systemic drug administration results in limited intraperitoneal penetration of 5-fluorouracil and inactive platinum species.

We report a case of hydralazine-induced alveolar hemorrhage and anti-neutrophil cytoplasmic antibody (ANCA)-positive pauci-immune glomerulonephritis, with serum anti-histone antibodies present, features not previously described in the literature with this drug. A 50-year-old Caucasian female had hypertension treated with hydralazine 75mg TID for three years, and a lung nodule followed up periodically with chest-computed tomographies. She was admitted to the hospital for hemoptysis and newly discovered diffuse pulmonary ground-glass opacities. Transbronchial lung biopsy showed alveolar hemorrhage. Serum creatinine was 3.5 mg/dL and urinalysis showed 2+blood, 30-50RBC/hpf and red blood cell casts. ANCA against myeloperoxidase were present. Anti-double-stranded DNA, ANA, and anti-histone antibodies were positive. Serum complements were normal. Renal biopsy revealed focal crescentic necrotizing glomerulonephritis with negative immunofluorescence, consistent with pauci-immune ANCA-positive vasculitis. Serum creatinine returned to baseline three days after hydralazine was discontinued, and the hemoptysis resolved after treatment with cyclophosphamide and prednisone was started. We concluded that this case represents a hydralazine-induced small vessel vasculitis rather than an idiopathic one. The possibility of hydralazine-induced vasculitis should be considered when patients treated with hydralazine develop a pulmonary-renal syndrome. Anti-histone antibodies may be present in the absence of full classification criteria of drug-induced lupus.

Background: The optimal blood pressure (BP) target for hypertensive hemodialysis (HD) patients is unknown. Current KDOQI guidelines have been extrapolated from data in the general population. The BID pilot, funded by NIDDK and DCI, is the first trial to randomize hypertensive HD patients to intensive (110-140 mm Hg) vs. usual (155-165 mm Hg) control of systolic blood pressure (SBP). The study’s goal is to assess the feasibility of conducting a full-scale trial. Methods: BID consortium consists of 5 clinical centers, a cardiac MRI reading center and a data coordinating center. Standardized predialysis SBP, measured in the dialysis unit in accord with AHA recommendations (SDUSBP), guide therapy. To be eligible for randomization patients needed a 2-week running mean SDUSBP ≥ 155 mm Hg. Home BP measurements (HBPM) are obtained twice on the day after the midweek dialysis. Ambulatory Blood Pressure Monitoring (ABPM) during a 44h interdialytic period is obtained quarterly. We compared SDUSBP, HBPM and ABPM. Results: We enrolled 281 and randomized 126 participants. Major reasons for drop out during the baseline period were 2-week mean SDUSBP < 155 mm Hg (40.6%), no cardiac MRI (13.0%) and perception of protocol as burdensome (11.2%). Adherence with prescribed SDUSBP was satisfactory. The percent of patients with ≥ 4, ≥ 8 and ≥12 SBP per month were 96, 88 and 57% in month 1 and 78, 68 and 37% in month 12. In a constant cohort of participants followed ≥ 330 days 2-week mean SDUSBP were 144 ± 17.4 and 156 ± 15.2 mm Hg in the intensive and usual arms, respectively. Major reasons that participants in the intensive arm did not achieve target SBP included large interdialytic weight gain (27.2%), non-adherence with medications or dialysis prescription (40.9%), and intradialytic hypotension (31.9%). Differences between the SDUSBP and both HBPM and ABPM were often ≥ 10 mm Hg. Optimal control of BP requires measurements in and out of the dialysis unit. Rates of adverse events were similar to those in other NIDDK funded ESRD studies. Conclusion: The difference in BP between arms was achieved and maintained throughout the study. It is feasible to conduct a full-scale clinical trial of intensive vs. usual treatment of hypertension in HD patients.

OBJECTIVE Disordered mineral metabolism is a common complication of chronic kidney disease (CKD) and a novel risk factor for CKD progression, cardiovascular disease, and mortality. Although diabetes is the leading cause of CKD and is associated with worse clinical outcomes than other etiologies, few studies have evaluated mineral metabolism in CKD according to diabetes status. RESEARCH DESIGN AND METHODS Using the Chronic Renal Insufficiency Cohort Study, we tested the hypothesis that diabetes is independently associated with lower serum calcium and higher serum phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23). RESULTS Compared with participants without diabetes (n = 1,936), those with diabetes (n = 1,820) were more likely to have lower estimated glomerular filtration rate (eGFR), lower serum albumin, and higher urinary protein excretion (all P < 0.001). Unadjusted serum phosphate, PTH, and FGF23 levels were higher and calcium was lower among those with compared with those without diabetes (all P < 0.001). After multivariate adjustment, diabetes remained a significant predictor of serum phosphate, PTH, and FGF23 but not calcium. The eGFR cut point at which 50% of participants met criteria for secondary hyperparathyroidism or elevated FGF23 was higher in participants with diabetes compared with those without (PTH: eGFR 30–39 vs. 20–29, P < 0.001; FGF23: eGFR 50–59 vs. 40–49, P < 0.001). CONCLUSIONS Disordered mineral metabolism begins earlier in the course of CKD and is more severe among CKD patients with compared with those without diabetes. Future studies should explore mechanisms for these differences and whether they contribute to excess risks of adverse clinical outcomes among diabetic patients with CKD.

A variety of analogs of 1,25-(OH)2D3 with less calcemic activity and lower receptor binding affinity than 1,25-(OH)2D3 have been developed. However, these compounds have equal or greater ability to differentiate leukemia cells and psoriatic fibroblasts and to suppress PTH synthesis and secretion. The mechanism for this selectivity has not been elucidated. Because the lower potency of ergocalciferol compared to cholecalciferol in preventing or curing rickets in chicks was associated with a lower affinity of the avian vitamin D binding protein (DBP) for vitamin D2, we tested five analogs with low calcemic activity including 22-oxa-1,25-(OH)2D3 (OCT), MC903, 1,25-(OH)2-16 ene-23-yne D3, 1,25-(OH)2-26,27 dihomo-22-ene-D3, and 1,25-(OH)2-24-trihomo-22-ene-D3 for their affinity for rat serum DBP. All analogs had a low affinity for DBP, ranging from 50-3000 times less than that of 1,25-(OH)2D3. OCT also bound with low affinity to dog and human serum DBP. We tested with OCT the possible consequences of its low affinity for serum DBP. One of the functions of DBP is to prolong the lifetime of 1,25-(OH)2D3 in circulation. Quantification of the metabolic clearance rate (MCR) of OCT in 8 normal dogs using a single bolus injection technique showed that OCT was cleared at a rate of 48.2 +/- 7.5 ml/min, approximately 6-7 times more rapidly than 1,25-(OH)2D3 (6.8 +/- 0.4 ml/min). The estimated half-life of OCT in the circulation was 2.5 +/- 0.3 h compared to 7.0 +/- 0.6; n = 7 for 1,25-(OH)2D3. As our primary interest is the potential of OCT in treating the secondary hyperparathyroidism of CRF, we also measured the MCR of OCT in 5/6 nephrectomized dogs. Uremia does not affect the rate of clearance of OCT from the circulation (MCR: 56.8 +/- 4.5; t1/2 = 2.1 +/- 0.2 n = 4). Despite its shorter half-life, OCT suppressed PTH secretion in vivo in uremic dogs. The effects of low binding to DBP on the percentage uremic dogs. The effects of low binding to DBP on the percentage of free sterol were determined using an ultrafiltration procedure. We compared the proportion of free (unbound) OCT and 1,25-(OH)2D3 in 0.1% BSA-PBS with concentrations of human serum ranging from 0-25%. The proportion of OCT in the free form was significantly higher than that of 1,25-(OH)2D3 for every serum concentration tested. The physiological relevance of a higher percentage of free OCT was tested in normal human macrophages.(ABSTRACT TRUNCATED AT 400 WORDS)

Previous studies from our laboratory have shown 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] production by rat liver homogenates and a low affinity of the hepatic enzyme for 25-hydroxyvitamin D3. Because the liver microsomal vitamin D-25-hydroxylase is the main source of systemic 25(OH)D3, we examined the subcellular location and the kinetics of liver 1,25(OH)2D3 production. Unlike the renal 1 alpha-hydroxylase activity which was assayed simultaneously, 1,25(OH)2D3 synthesis was undetectable in rat liver mitochondria, whereas in microsomes, 1,25(OH)2D3 production followed typical Michaelis Menten kinetics with a Km for 25(OH)D3 of 13.4 microM and a Vmax of 109.8 pg/min per mg protein accounting for most of the 1,25(OH)2D3 synthesized by rat liver cytosol free homogenates. Thus, microsomes are the site for 1,25(OH)2D3 synthesis in the rat liver. This microsomal compartmentalization of the two major steps in the activation of vitamin D to 1,25(OH)2D3 suggests a role for the liver as an autocrine/paracrine organ for 1,25(OH)2D3.