David O. McGregor

Meta-analysis: vitamin D compounds in chronic kidney disease.

Context Clinicians often treat patients with kidney disease with vitamin D compounds to prevent secondary hyperparathyroidism. Contribution This meta-analysis of 76 randomized trials found no good evidence that vitamin D compounds reduced risk for death, bone pain, vascular calcification, or need for parathyroidectomy in patients with chronic kidney disease. Compared with placebo, established vitamin D sterols increased risk for hypercalcemia and hyperphosphatemia, whereas newer vitamin D analogues increased hypercalcemia but not hyperphosphatemia. Direct comparisons found no clear benefits of newer analogues over established agents. Implication Though commonly used, vitamin D compounds for chronic kidney disease have unclear benefits and potential harms. The Editors All stages of chronic kidney disease (CKD) are associated with significantly increased rates of all-cause and cardiovascular mortality (1). Several risk factors for death have been identified and targeted by interventions, but registry data have not shown substantial improvements in survival of people with end-stage kidney disease over the past 2 decades (2). Abnormalities of bone metabolism and mineralization, which are risk factors for death in CKD, occur early and become universal as kidney function declines (3). A frequent pattern of biochemical abnormalities includes increased serum phosphorus and parathyroid hormone (PTH) levels, whereas levels of serum calcium may be low, normal, or elevated. These changes are associated with alterations in bone mineral homeostasis, increased bone fragility (4, 5), vascular and soft tissue calcification (6, 7), muscle dysfunction (8), adverse cardiovascular outcomes, and increased mortality (9). Compared with PTH levels of 16.5 to 33.0 pmol/L (150 to 300 pg/mL), levels greater than 66 pmol/L (600 pg/mL) are reported to be associated with a 10% increased risk for death (10). Similar mortality data have been observed for increased serum phosphorus and calcium levels (10). Interventions that are widely used to improve biochemical markers of bone and mineral metabolism include active vitamin D compounds, calcium supplements and noncalcium-containing phosphate binders, and calcimimetics. Vitamin D therapy has historically been based on alfacalcidol (1 -hydroxyvitamin D3) or calcitriol, both of which attenuate secondary hyperparathyroidism (1114). Although these compounds may reduce PTH levels, they increase calcium and phosphorus levels (9, 10, 15, 16). Support for use of the newer vitamin D analogues (22-oxacalcitriol, doxercalciferol, paricalcitol, and falecalcitriol) is based on reports of similar or superior dose-equivalent suppression of PTH, less calcemic and phosphatemic activity, and the possibility of improved survival when compared with established vitamin D sterols (calcitriol or alfacalcidol) (17, 18). Guidelines have suggested that doxercalciferol and paricalcitol may be preferable to calcitriol and alfacalcidol (19). We evaluated available randomized trials to determine the effects of established vitamin D sterols and newer analogues on biochemical, bone, and cardiovascular end points in CKD together with their optimal dose and route of administration. Methods Data Sources and Searches Literature searches for randomized, controlled trials (RCTs) of vitamin D sterols in CKD were performed in MEDLINE (January 1966 to July 2007) and EMBASE (January 1980 to July 2007) using optimally sensitive search strategies (20). The Cochrane Renal Group Renal Health Library and the Cochrane Central Register of Controlled Trials (CENTRAL) were also searched. The complete search strategy is outlined in Appendix Table 1. Authors followed a standardized published protocol for identification of eligible trials (21). Appendix Table 1. Summary of Search Strategy Study Selection We included randomized and quasi-randomized, controlled trials conducted in patients with CKD and that compared vitamin D compounds with placebo, different vitamin D compounds directly, and different vitamin D dose and administration regimens. Studies enrolling patients with any stage of CKD and measuring the effect of these agents on surrogate biochemical end points at the end of treatment (for example, levels of PTH, calcium, phosphorus, and calciumphosphorus product) and hard patient-level end points (for example, all-cause and cardiovascular mortality, fracture, toxicity) were included. We excluded trials enrolling only participants who had parathyroidectomy or kidney transplantation. We also excluded RCTs of vitamin D compounds in osteoporosis because results of these studies were presented without reference to kidney function or CKD was an exclusion criterion. Data Extraction and Quality Assessment Two independent authors assessed each trial. They extracted data on the characteristics of participants, interventions, comparisons, and clinical outcomes, when reported. Hypercalcemia was defined as a serum calcium level of 2.63 mmol/L or greater (10.5 mg/dL), and hyperphosphatemia was defined as a serum phosphorus level greater than 1.62 mmol/L (>5.0 mg/dL). Because trial investigators generally did not report change in values from beginning to end of treatment for continuous variables, we only considered the end-of-treatment values. Where published outcome data were not provided in sufficient detail, an author contacted the trial investigators by electronic or standard mail requesting additional information. Review authors resolved discrepancies in data extraction and quality assessment through discussion. Data Synthesis and Analysis We summarized treatment effects as relative risks (RRs) for categorical variables and weighted mean differences for continuous variables, with 95% CIs. We pooled estimates from individual trials by using the DerSimonian and Laird random-effects model (22). We repeated all analyses by adding 1/n to treatment groups with zero events and using the odds ratio as the measure of effect. Neither method resulted in substantive differences in any clinical outcome. We formally assessed heterogeneity of treatment effects between studies with the Cochran Q and the I 2 statistics (23). We performed subgroup analysis and random-effects metaregression to explore the effect of potential sources of variability on observed treatment effects. We investigated the impacts of the following plausible effect modifiers on treatment outcomes: newer vitamin D analogues versus established vitamin D sterols, baseline PTH concentration (<33 pmol/L, 33 to 66 pmol/L, 66 to 110 pmol/L, and >110 pmol/L), method of PTH assay (amino-terminal, carboxy-terminal, intact, full-length PTH [1-84], or not specified), method of calcium assay (total, corrected, or ionized), baseline serum calcium concentration (<2.63 mmol/L and 2.63 mmol/L [10.5 mg/dL]), baseline serum phosphorus concentration (<1.29 mmol/L and 1.29 mmol/L [4.0 mg/dL]), dialysis modality (peritoneal or hemodialysis) and duration, stage of CKD (CKD stage 3 [estimated glomerular filtration rate, 30 to 59 mL/min per 1.73 m2], 4 [estimated glomerular filtration rate, 15 to 29 mL/min per 1.73 m2], or 5 [estimated glomerular filtration rate <15 mL/min per 1.73 m2]), pediatric versus adult cohorts, use of calcium-based phosphate binders as a co-intervention, prior use of vitamin D sterols, duration of intervention, trial quality, and dose of vitamin D compound (high or low). All analyses were undertaken using RevMan 4.2 (The Cochrane Collaboration, Copenhagen, Denmark) and STATA version 8.0 (STATA, College Station, Texas). Role of the Funding Source The funding source had no role in the study design; collection, analysis, or interpretation of data; or writing of the report. The corresponding author had full access to all study data and had final responsibility for the decision to submit the manuscript for publication. Results The combined search of MEDLINE, EMBASE, the Cochrane Controlled Trial Register, and the Renal Health Library of the Cochrane Renal Group identified a total of 1608 articles (Appendix Figure 1). After full-text analysis, we included 76 eligible RCTs that enrolled a total of 3667 participants with CKD. Two publications each represented combined data from 3 RCTs (24, 25). We identified 3 ongoing studies from trial registries (2628). The number of individuals in each trial ranged from 6 to 266 patients, and 60 out of 76 (79%) studies enrolled fewer than 60 patients. Authors of 18 trials provided additional information, which was included in our analyses (14, 24, 2944). Appendix Figure 1. Study flow diagram. Reasons for exclusions and the number of trials reporting each outcome are provided. RCT = randomized, controlled trial. Trial Characteristics Appendix Tables 2 and 3 list the characteristics of the samples and interventions in the trials of vitamin D included in this meta-analysis. We divided the 76 eligible trials into 3 major groups of studies based on the randomized interventions: vitamin D compounds versus placebo, other vitamin D compounds, or calcium; different routes of administration of vitamin D; and different doses of vitamin D. Appendix Table 2. Characteristics of Populations and Interventions in Trials Comparing Vitamin D Compounds with Placebo, No Treatment, or Other Vitamin D Compounds in People with Chronic Kidney Disease* Appendix Table 3. Characteristics of Populations and Interventions in Trials of Vitamin D and Its Analogues Comparing Different Routes and Schedules of Administration in People with Chronic Kidney Disease* The first group compared established vitamin D compounds with another vitamin D compound, placebo, or calcium alone. This group included 19 trials (981 patients) comparing established vitamin D with placebo, of which 12 trials (669 patients) administered calcitriol (11, 13, 4554), 5 trials (275 patients) administered alfacalcidol (12, 14, 42, 55, 56), and 2 trials (37 patients) administered 24,25-(OH)2 vitamin D3 (31, 44). Fifteen studies (1

A Comparative Study of Blood Pressure Control with Short In-Center versus Long Home Hemodialysis

We conducted a randomized crossover trial to establish, within patients, whether long-slow hemodialysis (HD) was associated with better blood pressure (BP) control than standard HD. Nine home HD patients, not on antihypertensive drugs, were dialyzed to the same eKt/Vurea and target weights for 6–8 h (LD) at home and for 3.5–4.5 h (SD) in the dialysis center 3 times weekly in randomized sequence, with each phase lasting 8 weeks. Ambulatory BP, bioimpedance, neurohormones and autonomic function were measured in each phase. Pre- and postdialysis systolic, ambulatory systolic and diastolic BP were all higher with SD than with LD and intradialysis hypotension was more common. Weight, ECF volume and neurohormones did not differ between treatments. Muscle sympathetic activity was increased in both phases and cardiac sympathetic activity tended higher during SD. These findings suggest that additional factors to ECF volume may contribute to the superior BP control produced by long-slow HD.

A Controlled Trial of the Effect of Folate Supplements on Homocysteine, Lipids and Hemorheology in End-Stage Renal Disease

Elevated plasma homocysteine (Hcy), dyslipidemia and hemorheological abnormalities all occur commonly in end-stage renal disease (ESRD) and are recognized risk factors for arteriosclerosis. To study the effect of folate supplementation on these factors we conducted a randomized controlled trial. Thirteen hemodialysis (HD) and 8 continuous ambulatory peritoneal dialysis (CAPD) patients received either 5 mg folic acid daily or placebo for 3 months. After 1 and 3 months, fasting blood samples were taken for Hcy, lipid profile, blood and plasma viscosity, red blood cell (RBC) osmotic fragility, plasma fibrinogen concentration and in vivo platelet aggregability. At baseline, the CAPD patients had a higher mean plasma fibrinogen concentration than the HD patients and they also tended to have higher mean plasma viscosity. Folate-treated patients showed marked increases in RBC folate and an average decrease in plasma Hcy concentration of 33%. Mean total cholesterol, LDL cholesterol and triglyceride concentrations decreased significantly in the CAPD patients who took folate. Folate had no significant effect on hemorheology. In conclusion, folate supplements in ESRD reduce plasma Hcy concentrations and may improve lipid profiles. In our patients, hemorheological abnormalities were more marked in patients on CAPD than in those on HD and were not improved by folate supplementation.

Hypotensive and Natriuretic Actions of Adrenomedullin in Subjects With Chronic Renal Impairment

Abstract—Plasma levels of adrenomedullin are increased in chronic renal failure. The significance of this finding is uncertain, because the biological effects of adrenomedullin in renal impairment are unknown. Therefore, we studied the effects of adrenomedullin infusion in subjects with chronic renal impairment. Eight males with IgA nephropathy and plasma creatinine of 0.19±0.03 mmol/L (mean±SEM) were studied in a vehicle-controlled crossover design. Each subject was studied twice; subjects were administered either adrenomedullin at a low dose and then a high dose (2.9 and 5.8 pmol/kg per minute, respectively, for 2 hours each) or a 4-hour vehicle control (Hemaccel), in random order, on day 4 of controlled metabolic diets. Adrenomedullin infusion achieved plasma adrenomedullin concentrations in the pathophysiological range after the low (31.2±5.1 pmol/L) and high (47.4±4.3 pmol/L) dose, and plasma cAMP was increased. Compared with vehicle control, high-dose adrenomedullin increased peak heart rate (+21.7±3.3 bpm, P <0.01) and cardiac output (+2.9±0.2 L/min, P <0.01) and lowered both systolic and diastolic blood pressures by >10 mm Hg (P <0.05). Plasma renin activity, angiotensin II, and norepinephrine increased by up to 50% above baseline levels (P <0.05 for all), whereas aldosterone and epinephrine were unchanged. Urinary volume and sodium excretion increased significantly (P <0.05) with low-dose adrenomedullin, whereas creatinine clearance was stable, and proteinuria tended to decrease. In subjects with chronic renal impairment due to IgA nephropathy, adrenomedullin infusion lowered blood pressure, stimulated sympathetic activity and renin release, and caused diuresis and natriuresis. Adrenomedullin may have a role in modulating blood pressure and kidney function in renal disease.

Autonomic dysfunction and ambulatory blood pressure in renal transplant recipients.

Background. Abnormal circadian blood pressure (BP) rhythm (nondipping) and autonomic dysfunction are both common in end-stage renal disease (ESRD). It is not known whether these abnormalities are related or if they are associated with greater left ventricular hypertrophy. Methods. Nineteen renal transplantation (RT) recipients, aged 22–67 years, who were transplanted at least 12 months (1–29 years) previously, were studied with 24-hr ambulatory blood pressure monitoring (ABPM). Autonomic function was tested by automated analysis of heart rate variations and echocardiography was used to estimate left ventricular mass index (LVMI). Results. Thirteen patients (68%) were nondippers. Although seven (37%) patients had significant parasympathetic dysfunction, this was not related to dipper status. Neither abnormality showed a tendency to diminish with time after RT. Systolic hypertension, diagnosed by ABPM, occurred in 5% of patients during the awake period and in 52% during sleep, whereas diastolic hypertension occurred in 47% when awake and in 63% when asleep. Awake systolic BP was the strongest predictor of LVMI (r=0.7, P <0.001), and was considerably better than systolic BPs recorded at the clinic (r=0.48, P <0.05). Conclusions. Nondipping is common after RT but is not related to the degree of autonomic dysfunction. These findings suggest that autonomic dysfunction is not a major contributor to nondipping in ESRD. In RT patients, ABPM is a more sensitive measure of hypertension and a stronger predictor of LVMI than clinic BP.

Bioactivity of adrenomedullin and proadrenomedullin N-terminal 20 peptide in man

Although the biological effects of adrenomedullin (AM) and PAMP have been reported extensively in animal studies and from in-vitro experiments, relatively little information is available on responses to the hormone administered to man. This review summarizes data from the few studies carried out in man. In healthy volunteers, i.v. infusion of AM reduces arterial pressure, probably at a lower rate of administration than is required to elicit other responses. AM stimulates heart rate, cardiac output, plasma levels of cAMP, prolactin, norepinephrine and renin whilst inhibiting any concomitant response in plasma aldosterone. Little or no increase in urine volume or sodium excretion has been observed. Patients with essential hypertension differ only in showing a greater fall in arterial pressure and in the development of facial flushing and headache. In patients with heart failure or chronic renal failure, i.v. AM has similar effects to those seen in normal subjects but also induces a diuresis and natriuresis, depending on the dose administered. Infusion of AM into the brachial artery results in a dose-related increase in forearm and skin blood flow, more prominent and more dependent on endogenous nitric oxide in healthy volunteers than in patients with cardiac failure. When infused into a dorsal hand vein, AM partially reversed the venoconstrictor action of norepinephrine. Although much more information is required to clarify the role of AM under physiological and pathophysiological circumstances, it is clear that it has prominent hemodynamic and neurohormonal effects, though generally lesser urinary effects when administered short-term in doses sufficient to raise its levels in plasma to those seen in a number of clinical disorders. The only study of PAMP in man showed that its skeletal muscle vasodilator potency, when infused into the brachial artery of healthy volunteers, was less than one hundredth that of AM, and it was without effect on skin blood flow.

Rationale and design of the Sodium Lowering In Dialysate (SoLID) trial: a randomised controlled trial of low versus standard dialysate sodium concentration during hemodialysis for regression of left ventricular mass.

BackgroundThe current literature recognises that left ventricular hypertrophy makes a key contribution to the high rate of premature cardiovascular mortality in dialysis patients. Determining how we might intervene to ameliorate left ventricular hypertrophy in dialysis populations has become a research priority. Reducing sodium exposure through lower dialysate sodium may be a promising intervention in this regard. However there is clinical equipoise around this intervention because the benefit has not yet been demonstrated in a robust prospective clinical trial, and several observational studies have suggested sodium lowering interventions may be deleterious in some dialysis patients.Methods/designThe Sodium Lowering in Dialysate (SoLID) study is funded by the Health Research Council of New Zealand. It is a multi-centre, prospective, randomised, single-blind (outcomes assessor), controlled parallel assignment 3-year clinical trial. The SoLID study is designed to study what impact low dialysate sodium has upon cardiovascular risk in dialysis patients. The study intends to enrol 118 home hemodialysis patients from 6 sites in New Zealand over 24 months and follow up each participant over 12 months. Key exclusion criteria are: patients who dialyse more frequently than 3.5 times per week, pre-dialysis serum sodium of <135 mM, and maintenance hemodiafiltration. In addition, some medical conditions, treatments or participation in other dialysis trials, which contraindicate the SoLID study intervention or confound its effects, will be exclusion criteria. The intervention and control groups will be dialysed using dialysate sodium 135 mM and 140 mM respectively, for 12 months. The primary outcome measure is left ventricular mass index, as measured by cardiac magnetic resonance imaging, after 12 months of intervention. Eleven or more secondary outcomes will be studied in an attempt to better understand the physiologic and clinical mechanisms by which lower dialysate sodium alters the primary end point.DiscussionThe SoLID study is designed to clarify the effect of low dialysate sodium upon the cardiovascular outcomes of dialysis patients. The study results will provide much needed information about the efficacy of a cost effective, economically sustainable solution to a condition which is curtailing the lives of so many dialysis patients.Trial registrationAustralian and New Zealand Clinical Trials Registry number: ACTRN12611000975998

Variability of plasma and urine betaine in diabetes mellitus and its relationship to methionine load test responses: an observational study.

BackgroundSince betaine is an osmolyte and methyl donor, and abnormal betaine loss is common in diabetes mellitus (>20% patients), we investigated the relationship between betaine and the post-methionine load rise in homocysteine, in diabetes and control subjects. The post-methionine load test is reported to be both an independent vascular risk factor and a measure of betaine sufficiency.MethodsPatients with type 2 diabetes (n = 34) and control subjects (n = 17) were recruited. We measured baseline fasting plasma and 4-hour post-methionine load (L-methionine, 0.1 mg/kg body weight) concentrations of homocysteine, betaine, and the betaine metabolite N,N-dimethylglycine. Baseline urine excretions of betaine, dimethylglycine and glucose were measured on morning urine samples as the ratio to urine creatinine. Statistical determinants of the post-methionine load increase in homocysteine were identified in multiple linear regression models.ResultsPlasma betaine concentrations and urinary betaine excretions were significantly (p < 0.001) more variable in the subjects with diabetes compared with the controls. Dimethylglycine excretion (p = 0.00014) and plasma dimethylglycine concentrations (p = 0.039) were also more variable. In diabetes, plasma betaine was a significant negative determinant (p < 0.001) of the post-methionine load increase in homocysteine. However, it was not conclusive that this was different from the relationship in the controls. In the patients with diabetes, a strong relationship was found between urinary betaine excretion and urinary glucose excretion (but not with plasma glucose).ConclusionsBoth high and low plasma betaine concentrations, and high and low urinary betaine excretions, are more prevalent in diabetes. The availability of betaine affects the response in the methionine load test. The benefits of increasing betaine intake should be investigated.

Trigonelline is not responsible for the acute increase in plasma homocysteine following ingestion of instant coffee

Objective: To determine whether trigonelline contributes to the effect of coffee on homocysteine (Hcy).Design and interventions: This was a randomised crossover study. Subjects consumed 50 mg trigonelline, 5 g of instant coffee (≈50 mg trigonelline) or water, consumed as a single dose in 100 ml, with 1 week between each treatment. Blood samples were drawn fasting and hourly for 8 h. Urine samples were collected pretreatment and every 2 h for 8 h.Setting: Christchurch Clinical Studies Trust, Christchurch, New Zealand.Subjects: Eight healthy male subjects.Results: Instant coffee raised plasma Hcy concentrations compared with water (P=0.019) and trigonelline (P=0.037). Plasma Hcy concentrations were not different between water and trigonelline treatments (P=0.789). The change in plasma Hcy concentration was higher (mean±s.e.) 4 h (0.7±0.2 μmol/l, P=0.006), 5 h (0.7±0.2 μmol/l, P=0.013) and 7 h (0.7±0.2 μmol/l, P=0.024) following coffee consumption. Urinary glycine betaine excretion was increased by coffee but not by trigonelline.Conclusion: Ingestion of instant coffee acutely elevated plasma Hcy; however, trigonelline is not responsible for this rise.Sponsorship: Supported by the Health Research Council, the Canterbury Medical Foundation, the Foundation of Research, Science and Technology.

Over 11 Years of Stable Renal Function after Remission of Nephrotic-Range Proteinuria in Type I Diabetics Treated with an ACE Inhibitor

It has previously been considered inevitable that a progressive deterioration in renal function would occur in type I diabetics who have proteinuria in the nephrotic range. We have reviewed all type I diabetic patients presenting with nephrotic-range albuminuria to this department over a 13-year period. Of 16 patients identified, 4 have demonstrated a prolonged stability of renal function, with 2 losing their albuminuria. The latter 2 patients, who have been treated with an angiotensin-converting enzyme inhibitor for over 11 years, are presented in detail. The possible factors contributing to progression and the role of angiotensin-converting enzyme inhibitors in the treatment of advanced diabetic nephropathy are discussed.