A Higher Concentration of Dialysate Magnesium to Reduce the Frequency of Muscle Cramps: A Narrative Review.

PURPOSE OF REVIEW: Strategies to mitigate muscle cramps are a top research priority for patients receiving hemodialysis. As hypomagnesemia is a possible risk factor for cramping, we reviewed the literature to better understand the physiology of cramping as well as the epidemiology of hypomagnesemia and muscle cramps. We also sought to review the evidence from interventional studies on the effect of oral and dialysate magnesium-based therapies on muscle cramps. SOURCES OF INFORMATION: Peer-reviewed articles. METHODS: We searched for relevant articles in major bibliographic databases including MEDLINE and EMBASE. The methodological quality of interventional studies was assessed using a modified version of the Downs and Blacks criteria checklist. KEY FINDINGS: The etiology of muscle cramps in patients receiving hemodialysis is poorly understood and there are no clear evidence-based prevention or treatment strategies. Several factors may play a role including a low concentration of serum magnesium. The prevalence of hypomagnesemia (concentration of <0.7 mmol/L) in patients receiving hemodialysis ranges from 10% to 20%. Causes of hypomagnesemia include a low dietary intake of magnesium, use of medications that inhibit magnesium absorption (eg, proton pump inhibitors), increased magnesium excretion (eg, high-dose loop diuretics), and a low concentration of dialysate magnesium. Dialysate magnesium concentrations of ≤0.5 mmol/L may be associated with a decrease in serum magnesium concentration over time. Preliminary evidence from observational and interventional studies suggests a higher dialysate magnesium concentration will raise serum magnesium concentrations and may reduce the frequency and severity of muscle cramps. However, the quality of evidence supporting this benefit is limited, and larger, multicenter clinical trials are needed to further determine if magnesium-based therapy can reduce muscle cramps in patients receiving hemodialysis. In studies conducted to date, increasing the concentration of dialysate magnesium appears to be well-tolerated and is associated with a low risk of symptomatic hypermagnesemia. LIMITATIONS: Few interventional studies have examined the effect of magnesium-based therapy on muscle cramps in patients receiving hemodialysis and most were nonrandomized, pre-post study designs.

CONTEXTE MOTIVANT LA REVUE: Les stratégies visant à atténuer les crampes musculaires sont parmi les principales priorités de recherche des patients hémodialysés. L'hypomagnésémie étant un possible facteur de risque, nous avons procédé à une revue de la littérature afin de mieux en comprendre l'épidémiologie, et d'examiner la physiologie et l'épidémiologie des crampes musculaires. Nous souhaitions également examiner les données probantes issues d'études interventionnelles portant sur l'effet des thérapies à base de dialysat de magnésium et de magnésium oral sur les crampes musculaires. SOURCES: Articles examinés par les pairs. MÉTHODOLOGIE: Nous avons cherché les articles pertinents dans les principales bases de données bibliographiques, notamment MEDLINE et EMBASE. La qualité méthodologique a été évaluée à l'aide d'une version modifiée des critères de contrôle de la qualité des études de Downs et Black. PRINCIPAUX RÉSULTATS: L'étiologie des crampes musculaires chez les patients hémodialysés est mal comprise et il n'existe aucune stratégie de prévention ou traitement clairement fondé sur des données probantes. Plusieurs facteurs pourraient jouer un rôle, notamment de faibles concentrations sériques de magnésium. La prévalence de l'hypomagnésémie (concentration inférieure à 0,7 mmol/L) chez les patients hémodialysés variait de 10 à 20 %. Une faible consommation de magnésium dans l'alimentation, la prise de médicaments inhibant l'absorption du magnésium (ex. les inhibiteurs de la pompe à protons), l'excrétion accrue du magnésium (ex. dose élevée de diurétiques de l'anse) et une faible concentration de dialysat de magnésium figuraient parmi les causes d'hypomagnésémie. Un taux de dialysat de magnésium inférieur ou égal à 0,5 mmol/L pourrait être associé à une diminution de la concentration sérique de magnésium au fil du temps. Les résultats préliminaires de certaines études observationnelles et interventionnelles suggèrent qu'une concentration sérique plus élevée de magnésium dans le dialysat augmenterait les concentrations sériques de magnésium et pourrait réduire la fréquence et la sévérité des épisodes de crampes musculaires. La qualité des preuves appuyant ce bienfait est cependant limitée. Des essais multicentriques et à plus vaste échelle sont nécessaires pour juger si un traitement à base de magnésium peut véritablement réduire les crampes musculaires chez les patients hémodialysés. Dans les études menées jusqu'à maintenant, l'augmentation de la concentration de dialysat de magnésium semblait bien tolérée et a été associée à un faible risque d'hypermagnésémie symptomatique. LIMITES: Peu d'études interventionnelles ont examiné l'effet de la prise de magnésium sur les crampes musculaires des patients hémodialysés, et la plupart de celles-ci constituaient des plans pré- ou post-études non randomisées.

Transition Between Different Renal Replacement Modalities: Gaps in Knowledge and Care-The Integrated Research Initiative.

Patients with end-stage kidney disease (ESKD) have different options to replace the function of their failing kidneys. The "integrated care" model considers treatment pathways rather than individual renal replacement therapy (RRT) techniques. In such a paradigm, the optimal strategy to plan and enact transitions between the different modalities is very relevant, but so far, only limited data on transitions have been published. Perspectives of patients, caregivers, and health professionals on the process of transitioning are even less well documented. Available literature suggests that poor coordination causes significant morbidity and mortality.This review briefly provides the background, development, and scope of the INTErnational Group Research Assessing Transition Effects in Dialysis (INTEGRATED) initiative. We summarize the literature on the transition between different RRT modalities. Further, we present an international research plan to quantify the epidemiology and to assess the qualitative aspects of transition between different modalities.

Boundaries of frequency and treatment time in conventional hemodialysis: Balancing convenience, economics, and health outcomes.

Since the inception of hemodialysis (HD) for patients with chronic kidney disease, the "perfect" dialysis prescription has remained elusive. Part of this may relate to the heterogeneity among populations, individual patients, and differences in access to health provision. The optimal balance between dialysis frequency and duration to achieve reductions in patient morbidity and mortality continues to be debated. The concept of dialysis adequacy originated from a post hoc mathematical analysis of the National Cooperative Study and has evolved to become a way of calculating dialysis dose and standardizing the dialysis prescription. In contrast, in its originally conceived sense, dialysis adequacy referred to the effective clearance of small solutes. Given the evolution of dialysis practice, we now aim to consider dialysis adequacy in a broader and more holistic manner particularly in view of our aging population and focus toward important patient-centered outcomes. While the traditional thrice weekly, HD regimen remains the default renal replacement modality, alternative strategies including short daily HD, long conventional HD, and long nocturnal HD are being widely implemented. We aim for optimal solute clearance, effective ultrafiltration to achieve normotension (while avoiding intradialytic symptoms) and maintenance of nutritional parameters all within the caveat that quality of life and autonomy are preserved.

Ex vivo study of human visceral nociceptors.

OBJECTIVE: The development of effective visceral analgesics free of deleterious gut-specific side effects is a priority. We aimed to develop a reproducible methodology to study visceral nociception in human tissue that could aid future target identification and drug evaluation. DESIGN: Electrophysiological (single unit) responses of visceral afferents to mechanical (von Frey hair (VFH) and stretch) and chemical (bradykinin and ATP) stimuli were examined. Thus, serosal afferents (putative nociceptors) were used to investigate the effect of tegaserod, and transient receptor potential channel, vanilloid 4 (TRPV4) modulation on mechanical responses. RESULTS: Two distinct afferent fibre populations, serosal (n=23) and muscular (n=21), were distinguished based on their differences in sensitivity to VFH probing and tissue stretch. Serosal units displayed sensitivity to key algesic mediators, bradykinin (6/14 units tested) and ATP (4/10), consistent with a role as polymodal nociceptors, while muscular afferents are largely insensitive to bradykinin (0/11) and ATP (1/10). Serosal nociceptor mechanosensitivity was attenuated by tegaserod (-20.8±6.9%, n=6, p<0.05), a treatment for IBS, or application of HC067047 (-34.9±10.0%, n=7, p<0.05), a TRPV4 antagonist, highlighting the utility of the preparation to examine the mechanistic action of existing drugs or novel analgesics. Repeated application of bradykinin or ATP produced consistent afferent responses following desensitisation to the first application, demonstrating their utility as test stimuli to evaluate analgesic activity. CONCLUSIONS: Functionally distinct subpopulations of human visceral afferents can be demonstrated and could provide a platform technology to further study nociception in human tissue.

Thyroid function in end stage renal disease and effects of frequent hemodialysis.

INTRODUCTION: End-stage renal disease (ESRD) is associated with perturbations in thyroid hormone concentrations and an increased prevalence of hypothyroidism. Few studies have examined the effects of hemodialysis dose or frequency on endogenous thyroid function. METHODS: Within the Frequent Hemodialysis Network (FHN) trials, we examined the prevalence of hypothyroidism in patients with ESRD. Among those with endogenous thyroid function (without overt hyper/hypothyroidism or thyroid hormone supplementation), we examined the association of thyroid hormone concentration with multiple parameters of self-reported health status, and physical and cognitive performance, and the effects of hemodialysis frequency on serum thyroid stimulating hormone (TSH), free thyroxine (FT4), and free tri-iodothyronine (FT3) levels. Conventional thrice-weekly hemodialysis was compared to in-center (6 d/wk) hemodialysis (Daily Trial) and Nocturnal (6 nights/wk) home hemodialysis (Nocturnal Trial) over 12 months. FINDINGS: Among 226 FHN Trial participants, the prevalence of hypothyroidism was 11% based on thyroid hormone treatment and/or serum TSH ≥8 mIU/mL. Among the remaining 195 participants (147 Daily, 48 Nocturnal) with endogenous thyroid function, TSH concentrations were modestly (directly) correlated with age (r = 0.16, P = 0.03) but not dialysis vintage. Circulating thyroid hormone levels were not associated with parameters of health status or physical and cognitive performance. Furthermore, frequent in-center and nocturnal hemodialysis did not significantly change (baseline to month 12) TSH, FT4, or FT3 concentrations in patients with endogenous thyroid function. DISCUSSION: Among patients receiving hemodialysis without overt hyper/hypothyroidism or thyroid hormone treatment, thyroid indices were not associated with multiple measures of health status and were not significantly altered with increased dialysis frequency.

Novel advances in the treatment of osteoporosis.

INTRODUCTION: Osteoporosis is a significant public health issue affecting over half of women aged over 50. With an aging population, its importance is set to increase further over time. Prevention of fragility fractures avoids significant mortality and morbidity as well as saving significant direct and indirect costs to the economy. In this review, we discuss existing treatments to contextualize the treatment landscape, and demonstrate how our understanding of bone pathophysiology has led to novel therapies-in the form of combinations and altered durations of existing treatments, as well as newer drug therapies. SOURCES OF DATA: PubMed and Embase were searched for randomized controlled trials of new therapies for osteoporosis. These searches were supplemented with material presented in abstract form at international meetings. AREAS OF AGREEMENT: New drugs that appear promising in the treatment of osteoporosis include the cathepsin K inhibitor, monoclonal antibodies against sclerostin and parathyroid hormone-related protein analog. AREAS OF CONTROVERSY: Separate to the development of novel drug therapies is the issue of how best to use agents that are currently available to us; specifically which agent to choose, alone or in combination; duration of therapy; how best to identify patients at highest risk of fracture, and to ensure the highest possible adherence to medication. Many of these issues have been addressed in other excellent review papers, and will not be considered in detail here. GROWING POINTS: As with all new treatments, we await results of long-term use and experience in 'real life' patient populations. AREAS TIMELY FOR DEVELOPING RESEARCH: As alluded to above, data are urgently required regarding the optimal duration of therapy; use of combination therapy; ordering of therapies for best therapeutic effect. As stratified medicine becomes more strongly considered in all areas of therapy, its merits in osteoporosis as in other musculoskeletal conditions, is timely and valuable.

Cognitive changes associated with switching to frequent nocturnal hemodialysis or renal transplantation.

BACKGROUND: It is uncertain whether switching to frequent nocturnal hemodialysis improves cognitive function in well-dialyzed patients and how this compares to patients who receive a kidney transplant. METHODS: We conducted a multicenter observational study with longitudinal follow-up of the effect on cognitive performance of switching dialysis treatment modality from conventional thrice-weekly hemodialysis to frequent nocturnal hemodialysis, a functioning renal transplant or remaining on thrice-weekly conventional hemodialysis. Neuropsychological tests of memory, attention, psychomotor processing speed, executive function and fluency as well as measures of solute clearance were performed at baseline and again after switching modality. The change in cognitive performance measured by neuropsychological tests assessing multiple cognitive domains at baseline, 4 and 12 months after switching dialysis modality were analyzed using a linear mixed model. RESULTS: Seventy-seven patients were enrolled; 21 of these 77 patients were recruited from the randomized Frequent Hemodialysis Network (FHN) Nocturnal Trial. Of these, 18 patients started frequent nocturnal hemodialysis, 28 patients received a kidney transplant and 31 patients remained on conventional thrice-weekly hemodialysis. Forty-eight patients (62 %) returned for the 12-month follow-up. Despite a significant improvement in solute clearance, 12 months treatment with frequent nocturnal hemodialysis was not associated with substantial improvement in cognitive performance. By contrast, renal transplantation, which led to near normalization of solute clearance was associated with clinically relevant and significant improvements in verbal learning and memory with a trend towards improvements in psychomotor processing speed. Cognitive performance in patients on conventional hemodialysis remained stable with the exception of an improvement in psychomotor processing speed and a decline in verbal fluency. CONCLUSIONS: In patients on conventional thrice-weekly hemodialysis, receiving a functioning renal transplant was associated with improvement in auditory-verbal memory and psychomotor processing speed, which was not observed after 12 months of frequent nocturnal hemodialysis.

Prospective clinical audit of two neuromodulatory treatments for fecal incontinence: sacral nerve stimulation (SNS) and percutaneous tibial nerve stimulation (PTNS).

BACKGROUND AND PURPOSE: Two types of neuromodulation are currently practised for the treatment of fecal incontinence (FI): sacral nerve stimulation (SNS) and percutaneous tibial nerve stimulation (PTNS). This study compares these therapies, as no data exist to prospectively assess their relative efficacy and costs. METHODS: The subjects of this study were two distinct cohorts undergoing SNS (between 2003 and 2008) or PTNS (2008-onwards) for FI. Clinical outcomes assessed at 3 months included incontinence scores and the number of weekly incontinence episodes. The direct medical costs for each procedure were calculated from the audited expenditure of our unit. RESULTS: Thirty-seven patients (94.6 % women) underwent permanent SNS and 146 (87.7 % women) underwent PTNS. The mean pre-treatment incontinence score (± SD) was greater in the SNS cohort (14 ± 4 vs. 12 ± 4) and the mean post-treatment incontinence scores were similar for the two therapies (9 ± 5 vs. 10 ± 4), with a greater effect size evident in the SNS patients. In a 'pseudo case-control' analysis with 37 "matched" patients, the effect of both treatments was similar. The cost of treating a patient for 1 year was £ 11,374 ($ 18,223) for permanent SNS vs. £ 1740 ($ 2784) for PTNS. CONCLUSION: Given the lesser cost and invasive nature of PTNS, where both techniques are available, a trial of PTNS could be considered for all patients.

Electrically stimulated gracilis neosphincter for end-stage fecal incontinence: the long-term outcome.

BACKGROUND: Electrically stimulated gracilis neosphincter is an established treatment for patients with end-stage fecal incontinence. Few data, however, describe its long-term efficacy. OBJECTIVE: This study aimed to assess the long-term functional outcome associated with this procedure. DESIGN: Patients who underwent gracilis neosphincter construction between1989 and 2001 were identified from a prospectively recorded database. Demographics and pretreatment anorectal physiologic data were available for all patients. SETTINGS: This study was conducted at an academic colorectal unit in a tertiary center. PATIENTS: Sixty patients (median age, 42 years; 46 females) with fecal incontinence and a Williams continence score ≥5 were recruited to the study. The causes of incontinence included obstetric injury (n = 22), anal surgery (n = 17), atresia (n = 7), idiopathic incontinence (n = 6), anorectal excision (n = 4), and ileoanal pouch incontinence (n = 4). MAIN OUTCOME MEASURE: The primary outcomes measured were the Williams continence score and the proportion of patients with a Williams score ≤3 who avoided permanent stoma formation. RESULTS: Continence improved for the cohort postoperatively at 2 years (2(2-5); p < 0.001) but no significant difference was found between continence scores preoperatively and at 13 years (5(3-6); p = not significant). However, a sustained improvement at 13 years was noted for patients in the anal surgery (3(2-5);p < 0.001) and obstetric injury groups (4.5(3-6); p = 0.001). Twenty-six patients (43%) had a Williams score ≤3 and avoided permanent stoma after 13 years. Eighteen patients developed postoperative rectal evacuatory disorder; 10 of them required a conduit to facilitate colonic irrigation. Postoperative evacuatory disorder was more frequent in patients with a history of obstetric injury (p = 0.008). LIMITATIONS: This study was limited by the lack of bowel diaries and quality-of-life scores. CONCLUSION: Gracilis neosphincter is associated with clinically significant and sustained symptom improvement in patients with end-stage fecal incontinence secondary to obstetric injury or anal surgery. These data support the continued use of this procedure in highly selected patients.

Outcome of percutaneous tibial nerve stimulation (PTNS) for fecal incontinence: a prospective cohort study.

OBJECTIVES: The aim of this study was to assess the long-term efficacy of percutaneous tibial nerve stimulation (PTNS) in fecal incontinence (FI). BACKGROUND: There is extensive evidence regarding the efficacy of PTNS in urinary incontinence. Data on the efficacy of PTNS for FI are limited to a few small case series with relatively short-follow up. METHODS: A prospective cohort of patients with FI was studied. Incontinence scores were measured using a validated questionnaire (Cleveland Clinic Florida-FI score) at specific time points: before treatment, after completion of a treatment course (12 PTNS sessions), and before the last maintenance ("top-up") therapy. Deferment time and average number of weekly incontinence episodes were also estimated from a prospective bowel dairy kept by the patient at these time points. Quality of life was assessed with the Rockwood Fecal Incontinence Quality of Life questionnaire. RESULTS: A total of 150 patients were recruited to the study between January 2008 and June 2012. Analysis was performed on 115 patients who continued to receive PTNS after a median follow-up of 26 (range, 12-42) months. The baseline Cleveland Clinic Florida-FI score ±SD (12.0 ± 3.9) improved after 12 PTNS sessions (9.4 ± 4.6, P < 0.0001) and after "top-up" treatments (10.0 ± 4.3, P < 0.0001). The increase in the Cleveland Clinic Florida-FI score between the end of the 12th session and the last "top-up" therapy was also significant (P = 0.04). A similar pattern was seen for the deferment time and the quality of life scores. The median time between "top-up" sessions was 12 months (range, 1-40 months), significantly longer than the recommended interval of 6 months. CONCLUSIONS: PTNS is a well-tolerated treatment with high acceptability in the majority of patients. It provides a sustained improvement in FI up to 42 months in a relatively noninvasive manner. The effect of PTNS diminishes with time and additional therapy sessions at 6 monthly intervals may result in greater improvements. PTNS ought to be considered as the first step in all patients with FI refractory to maximum conservative therapies.

Outcome of sacral nerve stimulation for fecal incontinence in patients refractory to percutaneous tibial nerve stimulation.

BACKGROUND: Percutaneous tibial nerve stimulation and sacral nerve stimulation are both second-line treatments for fecal incontinence, but the comparative efficacy of the 2 therapies is unknown. In our institution, patients with refractory fecal incontinence are generally treated with percutaneous tibial nerve stimulation before being considered for sacral nerve stimulation. OBJECTIVE: The aim of this study was to assess the outcome associated with this treatment algorithm in order to guide future management strategies. DESIGN: All patients with fecal incontinence treated over a 3-year period with tibial nerve stimulation before receiving sacral nerve stimulation were identified from a prospectively recorded database. Demographics and pretreatment anorectal physiological data were available for all patients. SETTINGS: This study was conducted at an academic colorectal unit in a tertiary center. PATIENTS: Twenty patients (17 female:3 male, median age 55 (33-79) years) were identified to be refractory to percutaneous tibial nerve stimulation. MAIN OUTCOME MEASURES: Clinical outcome data were collected prospectively before and after treatment, including 1) Cleveland Clinic Florida-Fecal Incontinence scores and 2) number of incontinence episodes per week. RESULTS: The mean (±SD) pretreatment incontinence score (11.7 ± 3.5) did not differ from the mean incontinence score after 12 sessions of tibial nerve stimulation (10.9 ± 3.6, p = 0.42). All patients were subsequently counseled for sacral nerve stimulation, and 68.4% of them reported a significant therapeutic benefit with an improved incontinence score (7.7 ± 4.1, p = 0.014). LIMITATIONS: This was a nonrandomized study with a relatively small number of patients CONCLUSION: Sacral nerve stimulation appears to be an effective treatment for patients who do not gain an adequate therapeutic benefit from percutaneous tibial nerve stimulation and, thus, should be routinely considered for this patient cohort.

Intensive hemodialysis in the (nursing) home: the bright side of geriatric ESRD care?

Elderly ESRD patients often lose functionality when they start dialysis, which may be due to a variety of clinical problems. We recently postulated that intensive (longer and/or more frequent) hemodialysis (HD) may be the ideal strategy to try to prevent these ESRD- and dialysis-related complications, including dialysis-induced hypotension, cardiac and cerebral events, malnutrition, infections, sleep problems, and psychological issues. The feasibility of home dialysis therapies has been demonstrated in observational studies. As self-care dialysis is often a challenge in the elderly patient, assisted intensive home HD may facilitate the long-term continuation of this modality. Intensive nursing home HD seems to be an attractive goal for the future because many elderly ESRD patients reside in an extended care facility. Combination with rehabilitation and support by social worker and psychologist remains crucial in the holistic approach toward the elderly ESRD patient. Further studies are required to test the potential protective effects of intensive HD on functionality and quality of life in elderly ESRD patients, and to elucidate the mechanisms underlying frailty and other geriatric syndromes in this highly vulnerable patient population.

Improved survival with iron chelation therapy for red blood cell transfusion dependent lower IPSS risk MDS may be more significant in patients with a non-RARS diagnosis.

Retrospective analyses suggest iron overload is associated with inferior survival (OS) in lower risk MDS and iron chelation therapy (ICT) with improvement. However, an analysis of RARS patients found no such association. We analyzed subtypes of lower risk MDS. Median OS for non-RARS without and with ICT was 44 months and not reached (P<0.001), and for RARS 99 and 134.4 months (P=NS); in red blood cell (RBC) transfusion dependent RARS patients not receiving ICT, median OS was 73.8 months (P=0.025). These results suggest a stronger association between ICT and OS in non-RARS MDS than in RARS, with significantly superior OS in transfusion dependent patients receiving ICT.

Percutaneous tibial nerve stimulation for fecal incontinence: a video demonstration.

BACKGROUND: Fecal incontinence is an increasingly common condition with significant negative impact on quality on life and health care resources. It frequently presents a therapeutic challenge to clinicians. Emerging evidence suggests that percutaneous tibial nerve stimulation is an effective treatment for fecal incontinence with the added benefit of being minimally invasive and cost effective. METHOD: Pursuant to the preliminary report of our early experience of percutaneous tibial nerve stimulation in patients with fecal incontinence published in this journal in 2010, in this dynamic article, we now describe and demonstrate the actual technique that can be performed in a nurse-led clinic or outpatient or community setting. CONCLUSION: Percutaneous tibial nerve stimulation is a technically simple procedure that can potentially be performed in an outpatient or community setting. The overall early success rate of 68% following its use reported by our unit compares favorably with the success rate following other forms of neuromodulation, including sacral nerve stimulation. When completed, our long-term outcome data will provide further information on the efficacy of tibial nerve stimulation in a larger cohort of patients (n > 100). Future studies, including our currently planned randomized controlled trial of percutaneous tibial nerve stimulation vs sham stimulation, will provide controlled efficacy data and may provide information on its exact mechanism of action.