The Effect of Magnesium Supplementation on Vascular Calcification in CKD: A Randomized Clinical Trial (MAGiCAL-CKD).

SIGNIFICANCE STATEMENT: Magnesium prevents vascular calcification in animals with CKD. In addition, lower serum magnesium is associated with higher risk of cardiovascular events in CKD. In a randomized, double-blinded, placebo-controlled trial, the authors investigated the effects of magnesium supplementation versus placebo on vascular calcification in patients with predialysis CKD. Despite significant increases in plasma magnesium among study participants who received magnesium compared with those who received placebo, magnesium supplementation did not slow the progression of vascular calcification in study participants. In addition, the findings showed a higher incidence of serious adverse events in the group treated with magnesium. Magnesium supplementation alone was not sufficient to delay progression of vascular calcification, and other therapeutic strategies might be necessary to reduce the risk of cardiovascular disease in CKD. BACKGROUND: Elevated levels of serum magnesium are associated with lower risk of cardiovascular events in patients with CKD. Magnesium also prevents vascular calcification in animal models of CKD. METHODS: To investigate whether oral magnesium supplementation would slow the progression of vascular calcification in CKD, we conducted a randomized, double-blinded, placebo-controlled, parallel-group, clinical trial. We enrolled 148 subjects with an eGFR between 15 and 45 ml/min and randomly assigned them to receive oral magnesium hydroxide 15 mmol twice daily or matching placebo for 12 months. The primary end point was the between-groups difference in coronary artery calcification (CAC) score after 12 months adjusted for baseline CAC score, age, and diabetes mellitus. RESULTS: A total of 75 subjects received magnesium and 73 received placebo. Median eGFR was 25 ml/min at baseline, and median baseline CAC scores were 413 and 274 in the magnesium and placebo groups, respectively. Despite plasma magnesium increasing significantly during the trial in the magnesium group, the baseline-adjusted CAC scores did not differ significantly between the two groups after 12 months. Prespecified subgroup analyses according to CAC>0 at baseline, diabetes mellitus, or tertiles of serum calcification propensity did not significantly alter the main results. Among subjects who experienced gastrointestinal adverse effects, 35 were in the group receiving magnesium treatment versus nine in the placebo group. Five deaths and six cardiovascular events occurred in the magnesium group compared with two deaths and no cardiovascular events in the placebo group. CONCLUSIONS: Magnesium supplementation for 12 months did not slow the progression of vascular calcification in CKD, despite a significant increase in plasma magnesium. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov ( NCT02542319 ).

Family History is Important to Identify Patients with Monogenic Causes of Adult-Onset Chronic Kidney Disease.

Monogenic causes of chronic kidney disease (CKD) are more prevalent in adults than previously thought, as causative gene variants are found in almost 10% of unselected patients with CKD. Even so, genetic testing in patients with adult-onset CKD is uncommon in clinical practice and the optimal criteria for patient selection remain unclear. A family history of kidney disease emerges as one marker associated with a high diagnostic yield of genetic testing. We present 3 cases of adult-onset CKD with underlying monogenic causes exemplifying different modes of inheritance. Case 1 is a 60-year-old male with slowly progressive CKD initially ascribed to hypertension and diabetes despite a family history with several affected first-degree relatives. A pathogenic MUC1 variant was found, and thus we identified the first Danish family of MUC1-associated autosomal dominant tubulointerstitial kidney disease. Case 2 is a 40-year-old female with nephrocalcinosis, nephrolithiasis, and unexplainable hypercalcemia consistent with vitamin D intoxication. The family history indicated autosomal recessive inheritance, and genetic testing revealed 2 pathogenic CYP24A1 variants in compound heterozygous form associated with idiopathic infantile hypercalcemia. Case 3 is a 50-year-old male with microscopic hematuria, proteinuria, and hearing loss. Electron microscopy of renal biopsy showed thin basal membrane syndrome, and the family history indicated X-linked inheritance. A novel missense variant in COL4A5 was identified, suggesting an atypical late-onset form of X-linked Alport syndrome. This case series illustrates the heterogeneous presentations of monogenic kidney disease in adults and emphasizes the importance of family history for initiating genetic testing to identify underlying monogenic causation. Moreover, we discuss the potential impact of genetic diagnostics on patient management and genetic family counseling.

Comparison of self- and nurse-measured office blood pressure in patients with chronic kidney disease.

OBJECTIVE: As blood pressure (BP) control is very important in chronic kidney disease (CKD), we investigated how office BP is influenced by the measurement circumstances and compared nonautomated self- and nurse-measured BP values. MATERIALS AND METHODS: Two hundred stage 1-5 CKD patients with scheduled visits to an outpatient clinic were randomized to either self-measured office BP (SMOBP) followed by nurse-measured office BP (NMOBP) or NMOBP followed by SMOBP. The participants had been educated to perform the self-measurement in at least one previous visit. The SMOBP and NMOBP measurement series both consisted of three recordings, and the means of the last two recordings during SMOBP and NMOBP were compared for the 174 (mean age 52.5 years) with complete BP data. RESULTS: SMOBP and NMOBP showed similar systolic (135.3 ± 16.6 vs 136.4 ± 17.4 mmHg, Δ = 1.1 mmHg, P = 0.13) and diastolic (81.5 ± 10.2 vs 82.2 ± 10.4 mmHg, Δ = 0.6 mmHg, P = 0.09) values. The change in BP from the first to the third recording was not different for SMOBP and NMOBP. In 17 patients, systolic SMOBP was ≥10 mmHg higher than NMOBP and in 28 patients systolic NMOBP exceeded SMOBP by ≥10 mmHg. The difference between systolic SMOBP and NMOBP was independent of CKD stage and the number of medications, but significantly more pronounced in patients above 60 years. CONCLUSION: In a population of CKD patients, there is no clinically relevant difference in SMOBP and NMOBP when recorded at the same visit. However, in 25% of the patients, systolic BP differs ≥10 mmHg between the two measurement modalities.

The effect of spironolactone on calcineurin inhibitor induced nephrotoxicity: a multicenter randomized, double-blind, clinical trial (the SPIREN trial).

BACKGROUND: Calcineurin inhibitor induced nephrotoxicity contributes to late allograft failure in kidney transplant patients. Evidence points towards aldosterone to play a role in the development of fibrosis in multiple organs. Animal studies have indicated a beneficial effect of mineralocorticoid receptor antagonists preventing calcineurin inhibitor induced nephrotoxicity. Only few studies have explored this effect in humans. The objective of this study is to evaluate the effect of spironolactone on glomerular filtration rate and fibrosis in kidney transplant patients. METHOD: Prospective, double-blind, randomized, clinical trial including 170 prevalent kidney transplant patients. Patients are randomized to spironolactone 25-50 mg/day or placebo for three years. Primary outcome is glomerular filtration rate evaluated by chrome-EDTA clearance. Secondary outcomes are 24-h protein excretion, amount of interstitial fibrosis in renal allograft biopsies, and cardiovascular events. As an exploratory outcome, we aim to identify markers of fibrosis in blood and urine. DISCUSSION: Long term allograft survival remains a key issue in renal transplantation, partly due to calcineurin inhibitor induced nephrotoxicity. Evidence from animal- and small human studies indicate a beneficial effect of mineralocorticoid receptor antagonism on renal function and fibrosis. This study aims to test this hypothesis in a sufficiently powered randomized clinical trial. Results might influence the future management of long term allograft survival in renal transplantation. TRIAL REGISTRATION: ClinicalTrials.gov identifier (05/17/2012): NCT01602861 . EudraCT number (05/31/2011): 2011-002243-98.

Non-parathyroid hypercalcemia associated with paraffin oil injection in 12 younger male bodybuilders: a case series.

INTRODUCTION: Injection of paraffin oil to augment muscles size is a troubling phenomenon known to cause a foreign body reaction with formation of granulomas. In a few case reports, long-term side effects have been reported in terms of hypercalcemia and renal failure. METHODS: We identified a case series of 12 male bodybuilders presenting with non-parathyroid hypercalcemia who previously had injected paraffin oil to increase muscles size. RESULTS: At admission, all patients had moderate-to-severe hypercalcemia with suppressed PTH levels and impaired renal function. Calcitriol levels were within the normal range or slightly elevated. Follow-up measurements showed marked hypercalciuria with nearly normal levels of bone turnover markers. A correlation was found between levels of peptidyl dipeptidase and calcitriol (R = 0.812, P = 0.050). Treatment with antiresorptive agents seemed less effective than glucocorticoids, which resulted in a significantly lowering of ionized calcium levels and improved renal function, although no patients were cured by this treatment. Immunosuppression with azathioprine or mycophenolate may have a glucocorticoid-saving effect. One patient had surgery with removal of affected muscle tissue, without any apparent effect on plasma calcium levels. CONCLUSION: The hypercalcemia and associated hypercalciuria seems to be due to an intestinal hyperabsorption of calcium. It remains to be elucidated, whether an increased calcitriol synthesis within granulomas is the only (main) mechanism by which intestinal calcium absorption is increased. Glucocorticoids seem most appropriate as the first choice for treatment. Bodybuilders should be warned against use of intramuscular oil injections (and other substances), as this may have severe adverse health consequences.

A case report of hereditary apolipoprotein A-I amyloidosis associated with a novel APOA1 mutation and variable phenotype.

Apolipoprotein A-I (apo A-I) amyloidosis is a non-AL, non-AA, and non-transthyretin type of amyloidosis associated with mutations in the APOA1 gene inherited in an autosomal dominant fashion. It is a form of systemic amyloidosis, but at presentation, can also mimic localized amyloidosis. The renal presentation generally involves interstitial and medullary deposition of apo A-I amyloid protein. We describe the identification of apo A-I amyloidosis by mass spectrometry in a 52-year old male, with no family history of amyloidosis, presenting with nephrotic syndrome and associated with heterozygosity for a novel APOA1 mutation (c.220 T > A) which encodes the known amyloidogenic Trp50Arg variant. Renal amyloid deposits in this case were confined to the glomeruli alone, and the patient developed progressive renal impairment. One year after diagnosis, the patient had a successful kidney transplant from an unrelated donor. Pathogenic mutations in the APOA1 gene are generally associated with symptoms of amyloidosis. In this family however, genotyping of family members identified several unaffected carriers suggesting a variable disease penetrance, which has not been described before in this form of amyloidosis and has implications when counselling those with APOA1 mutations.

No difference between alfacalcidol and paricalcitol in the treatment of secondary hyperparathyroidism in hemodialysis patients: a randomized crossover trial.

Alfacalcidol and paricalcitol are vitamin D analogs used for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease, but have known dose-dependent side effects that cause hypercalcemia and hyperphosphatemia. In this investigator-initiated multicenter randomized clinical trial, we originally intended two crossover study periods with a washout interval in 86 chronic hemodialysis patients. These patients received increasing intravenous doses of either alfacalcidol or paricalcitol for 16 weeks, until parathyroid hormone was adequately suppressed or calcium or phosphate levels reached an upper threshold. Unfortunately, due to a period effect, only the initial 16-week intervention period for 80 patients was statistically analyzed. The proportion of patients achieving a 30% decrease in parathyroid hormone levels over the last four weeks of study was statistically indistinguishable between the two groups. Paricalcitol was more efficient at correcting low than high baseline parathyroid hormone levels, whereas alfacalcidol was equally effective at all levels. There were no differences in the incidence of hypercalcemia and hyperphosphatemia. Thus, alfacalcidol and paricalcitol were equally effective in the suppression of secondary hyperparathyroidism in hemodialysis patients while calcium and phosphorus were kept in the desired range.