The Use of N-of-1 Trials to Individualize Treatment in Patients With Renal Magnesium Wasting

Patients with chronic renal magnesium wasting often experience fatigue and neuromuscular symptoms. Most patients require lifelong treatment with high doses of magnesium salts. However, sufficient magnesium replenishment is difficult because high doses of magnesium salts induce diarrhea and other gastrointestinal symptoms. Another difficulty in treating hypomagnesemia is the lack of randomized controlled trials (RCTs) comparing different magnesium salts.1Firoz M. Graber M. Bioavailability of US commercial magnesium preparations.Magnes Res. 2001; 14: 257-262PubMed Google Scholar, 2Ranade V.V. Somberg J.C. Bioavailability and pharmacokinetics of magnesium after administration of magnesium salts to humans.Am J Ther. 2001; 8: 345-357Crossref PubMed Scopus (92) Google Scholar Although the double-blind RCT is the standard scientific strategy for determining efficacy of therapy, in rare diseases the number of patients is usually too small to perform an RCT. Moreover, RCTs are less suitable if outcome variables are largely discrepant between patients. An appealing alternative is the single-subject trial design. The most common example is the N-of-1 trial, a prospectively planned trial conducted within an individual patient to compare the effectiveness of 2 or more treatments.3Kravitz R.L. Duan N. Eslick I. et al.Design and Implementation of N-of-1 Trials: A User's Guide. Agency for Healthcare Research and Quality, Rockville, MD2014Google Scholar These trials mostly consist of multiple randomized crossover periods, so are particularly appropriate for stable ongoing conditions and treatments that have effects that are quick in both onset and termination.4Zucker D.R. Deo A. Schmid C.H. Dialysis research and N-of-1 trials: made for each other?.Am J Kidney Dis. 2010; 55: 635-638Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Despite its attractive methodology with direct clinical implications for the individual patient, N-of-1 trials are sparsely used in medical research. To our knowledge, only three N-of-1 trials have been described in nephrology.5Samuel J.P. Samuels J.A. Brooks L.E. et al.Comparative effectiveness of antihypertensive treatment for older children with primary hypertension: study protocol for a series of n-of-1 randomized trials.Trials. 2016; 17: 16Crossref PubMed Scopus (8) Google Scholar, 6Rostoker G. Griuncelli M. Loridon C. Bourlet T. Illouz E. Benmaadi A. A pilot study of routine colloid infusion in hypotension-prone dialysis patients unresponsive to preventive measures.J Nephrol. 2011; 24: 208-217Crossref PubMed Scopus (11) Google Scholar, 7Saito T. Saito O. Maeda T. et al.Metabolic and hemodynamic advantages of an acetate-free citrate dialysate in a uremic case of congenital methylmalonic acidemia.Am J Kidney Dis. 2009; 54: 764-769Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar We describe using N-of-1 trials to compare the efficacy of three different magnesium salts (magnesium gluconate, magnesium aspartate, and magnesium lactate) in the treatment of patients with renal magnesium wasting. These N-of-1 trials were randomized double-blinded multi-crossover trials. Each magnesium salt was given during 4-week treatment periods, with a total study duration of 36 weeks. The maximal amount of magnesium fitting the capsules was used, which differed between magnesium salts. The first treatment period started with 3 capsules thrice daily and patients were instructed to increase the dose with an additional 3 capsules each 3 days if symptoms persisted. Main outcome parameters were patient-reported outcome measures. At 2-week intervals, patients completed a personalized questionnaire and a general quality-of-life (QoL) questionnaire. In addition, laboratory investigations were performed. Differences in treatment effect were analyzed using Bayesian analysis, which has the major advantage of using complex models in which all parameters in time can be weighed and taken into account. A detailed description of the methods is given in Item S1. We included four patients (2 men) with renal magnesium wasting. Two patients had Gitelman syndrome, one had ADTKD-HNF1B (autosomal dominant tubulointerstitial kidney disease related to a mutation in HNF1B), and 1 had autosomal dominant hypomagnesemia. Ages ranged from 35 to 62 years. All patients used the maximal dose of 36 capsules per day of each magnesium salt at the end of the first treatment period. Patients therefore used a fixed dose of 36 capsules for the rest of the trial. Outcome measures for patient 1 are shown in Table 1, and an example of a probability plot from Bayesian analyses is shown in Figure 1. Patient 1 had the highest serum magnesium levels with magnesium lactate and experienced the least symptoms and the best overall QoL score while using magnesium aspartate. Results of the other patients are shown in Item S1. Patient 2 did not show differences in serum magnesium levels but experienced the least symptoms and highest QoL score while using magnesium lactate. Patient 3 had the highest serum magnesium levels with magnesium acetate but the least symptoms while using magnesium aspartate. Patient 4 did not show a difference in serum magnesium levels or symptoms between the different magnesium salts.Table 1Outcome Measures at the End of Treatment Periods of Patient 1Magnesium SaltGluconateAspartateLactatePersonalized questionnaireaScore ranges from 0 to 10, with higher scores indicating more severe symptoms. Muscle pain8 (7-8)4 (4-6)6 (6-6) Fatigue8 (8-8)7 (6-8)7 (7-8) Overall symptom burden GS8 (8-8)6 (5-6)7 (7-9) Side effects8 (8-8)6 (5-6)7 (7-7)SF-36 questionnairebScore ranges from 0 to 100, with higher scores indicating less severe symptoms. Physical functioning30 (25-30)65 (50-75)55 (0-60) Social functioning25 (0-25)38 (38-63)38 (0-38) Role functioning physical0 (0-0)0 (0-0)0 (0-0) Role functioning emotional100 (100-100)100 (100-100)100 (100-100) Mental health76 (64-76)80 (72-80)72 (44-80) Vitality20 (15-20)30 (25-35)25 (15-25) Pain12 (0-23)67 (45-78)22 (0-45) General health perception20 (15-25)25 (20-25)20 (20-25) Change in health75 (50-75)75 (75-75)75 (50-75)SF-36 component scores Physical component score19 (15-20)32 (27-34)25 (15-27) Mental component score49 (49-52)51 (50-52)20 (43-51)Stool frequency, as total no.47 (44-53)51 (47-51)48 (37-71)Serum magnesium, mEq/L0.60 (0.57-0.60)0.60 (0.55-0.60)0.66 (0.62-0.70)Serum potassium, mEq/L3.2 (3.1-3.3)3.4 (3.4-3.6)3.4 (3.1-3.6)Note: Data are given as median values (minimum-maximum). Each magnesium supplement was given during 3 treatment periods.Abbreviations: GS, Gitelman syndrome; SF-36, 36-Item Short Form Health Survey.a Score ranges from 0 to 10, with higher scores indicating more severe symptoms.b Score ranges from 0 to 100, with higher scores indicating less severe symptoms. Open table in a new tab Note: Data are given as median values (minimum-maximum). Each magnesium supplement was given during 3 treatment periods. Abbreviations: GS, Gitelman syndrome; SF-36, 36-Item Short Form Health Survey. The N-of-1 trial method thus was able to successfully identify the optimum magnesium salt in 3 of 4 patients, although the interventions did not result in complete correction of serum magnesium levels. Serum magnesium levels did not correlate well with self-reported symptoms or QoL, which suggests that serum magnesium is not a good representation of body magnesium content or intracellular magnesium levels. This is not surprising because <1% of total-body magnesium is present in serum.8Elin R.J. Magnesium metabolism in health and disease.Dis Mon. 1988; 34: 161-218Crossref PubMed Scopus (216) Google Scholar, 9Elin R.J. Assessment of magnesium status for diagnosis and therapy.Magnes Res. 2010; 23: S194-S198PubMed Google Scholar The main limitation of our N-of-1 trials was the different elemental magnesium content of the capsules. As patients reached the maximum number of (tolerable) capsules for each magnesium salt, the maximum dose of ingested magnesium differed between the magnesium salts. A solution for this problem could be the use of magnesium salts in liquid form, with a standardized amount of magnesium per milliliter. In conclusion, N-of-1 trials are an elegant method to determine the best therapeutic option(s) for individual patients. Especially in rare diseases for which large RCTs are generally lacking or in patients who do not fulfil the inclusion criteria of previously performed trials, this method can be of great value for clinical practice. Download .pdf (.74 MB) Help with pdf files Supplementary Item S1 (PDF)Detailed methods and individual patient data.