Clinical efficacy and feasibility of whey protein isolates supplementation in malnourished peritoneal dialysis patients: A multicenter, parallel, open-label randomized controlled trial.

BACKGROUND AND AIMS: Poor dietary intake is commonly associated with malnutrition in the dialysis population and oral nutritional supplementation is strategized to redress dietary inadequacy. Knowledge on clinical efficacy of whey protein supplementation (WPS) as an option to treat malnutrition in continuous ambulatory peritoneal dialysis (CAPD) patients is limited. METHODS: This multicenter, parallel, open-label, randomized controlled trial investigated the clinical efficacy of WPS in 126 malnourished CAPD patients with serum albumin <40 g/L and body mass index (BMI) <24 kg/m2. Patients randomized to the intervention group (IG, n = 65) received protein powder (27.4 g) for 6 months plus dietary counseling (DC) while the control group (CG, n = 61) received DC only. Anthropometry, biochemistry, malnutrition-inflammation-score (MIS), dietary intake inclusive of dialysate calories, handgrip strength (HGS) and quality of life (QOL) were assessed at baseline and 6 months. Clinical outcomes were assessed by effect size (Cohen's d) comparisons within and between groups. RESULTS: Seventy-four patients (n = 37 per group) completed the study. Significantly more IG patients (59.5%) achieved dietary protein intake (DPI) adequacy of 1.2 g/kg per ideal body weight (p < 0.001) compared to CG (16.2%) although difference in the adequacy of dietary energy intake between groups was non-significant (p > 0.05). A higher DPI paralleled significant increases in serum urea (mean Δ: IG = +2.39 ± 4.36 mmol/L, p = 0.002, d = 0.57 vs CG = -0.39 ± 4.59 mmol/L, p > 0.05, d = 0.07) and normalized protein catabolic rate, nPCR (mean Δ: IG = +0.11 ± 0.14 g/kg/day, p < 0.001, d = 0.63 vs CG = +0.001 ± 0.17 g/kg/day, p > 0.05, d = 0.09) for IG compared to CG patients. Although not significant, comparison for changes in post-dialysis weight (mean Δ: +0.64 ± 1.16 kg vs +0.02 ± 1.36 kg, p = 0.076, d = 0.58) and mid-arm circumference (mean Δ: +0.29 ± 0.93 cm vs -0.12 ± 0.71 cm, p = 0.079, d = 0.24) indicated trends favoring IG vs CG. Other parameters remained unaffected by treatment comparisons. CG patients had a significant decline in QOL physical component (mean Δ = -6.62 ± 16.63, p = 0.020, d = 0.47). Using changes in nPCR level as a marker of WPS intake within IG, 'positive responders' achieved significant improvement in weight, BMI, skinfold measures and serum urea (all p < 0.05), while such changes within 'negative responders' were non-significant (all p > 0.05). CONCLUSION: A single macronutrient approach with WPS in malnourished CAPD patients was shown to achieve DPI adequacy and improvements in weight, BMI, skin fold measures, serum urea and nPCR level. CLINICAL TRIAL REGISTRY: www.clinicaltrials.gov (NCT03367000).

Development of Improved Dosing Regimens for Mycophenolate Mofetil Based on Population Pharmacokinetic Analyses in Adults with Lupus Nephritis.

BACKGROUND AND OBJECTIVE: Mycophenolic acid (MPA) provides effective treatment for lupus nephritis patients. Owing to its large pharmacokinetic variability, it is questionable whether standard fixed dose therapy can achieve optimal MPA exposure. The aim of this study was to develop a population pharmacokinetic model of MPA and its metabolite, 7-O-MPA-ß-glucuronide (MPAG), to identify important covariate influences and better predict patient dosing requirements. METHODS: MPA and MPAG concentration-time profiles were collected from 25 patients receiving mycophenolate mofetil (MMF) with or without cyclosporine (CsA) co-therapy. Samples were collected pre-dose and at 1, 2, 4, 6 and 8 h post-dose on one or two occasions. RESULTS: A total of 225 and 226 concentration-time measurements of MPA and MPAG, respectively, were used to develop the model, utilizing NONMEM® software. A two-compartment model with first-order absorption and elimination for MPA and a one-compartment model with first-order elimination and enterohepatic circulation (EHC) for MPAG best described the data. Apparent clearance of MPAG (CL/F MPAG) significantly decreased with reducing renal function and extent of EHC was reduced with concomitant CsA use. Simulations using the final model showed that a 70-kg subject with a creatinine clearance of 90 mL/min receiving concomitant CsA would require 1.25 g of MMF twice daily while a similar subject who did not receive concomitant CsA would require 0.75 g twice daily to achieve a MPA area under the concentration-time curve from 0 to 12 h (AUC0-12) of 45 mg·h/L. CONCLUSION: A 'tiered' dosing approach considering patient renal function and CsA co-therapy, rather than a 'one dose fits all' approach, would help individualize MMF therapy in adult lupus nephritis patients to ensure more patients have optimal MPA exposure.

Assessing protein energy wasting in a Malaysian haemodialysis population using self-reported appetite rating: a cross-sectional study.

BACKGROUND: Poor appetite could be indicative of protein energy wasting (PEW) and experts recommend assessing appetite in dialysis patients. Our study aims to determine the relationship between PEW and appetite in haemodialysis (HD) patients. METHODS: HD patients (n=205) self-rated their appetite on a scale of 1 to 5 as very good (1), good (2), fair (3), poor (4) or very poor (5). Nutritional markers were compared against appetite ratings. Using logistic regression analysis associations between dichotomized appetite with PEW diagnosis were determined as per the International Society of Renal Nutrition and Metabolism (ISRNM) criteria and alternate objective measures. Data was adjusted for socioeconomic and demographic characteristics. RESULTS: Poorer appetite ratings were significantly associated with lower income (P = 0.021), lower measurements (P < 0.05) for mid-arm muscle circumference, mid-arm muscle area and lean tissue mass (LTM), serum urea (P = 0.007) and creatinine (P = 0.005). The highest hsCRP (P = 0.016) levels occurred in patients reporting the poorest appetite. Serum albumin did not differ significantly across appetite ratings. Poor oral intake represented by underreporting (EI/BMR < 1.2) was evident for all appetite ratings. PEW was prevalent irrespective of appetite ratings (very good: 17.6 %, good: 40.2 %, fair: 42.3 % and poor: 83.3 %). After dichotomizing appetite ratings into normal and diminished categories, there was a marginal positive association between diminished appetite and overall PEW diagnosis (OR adj: 1.71; 95 % CI: 0.94-3.10, P = 0.079). Amongst individual ISRNM criteria, only BMI < 23 kg/m2 was positively associated with diminished appetite (OR adj: 2.17; 95 % CI: 1.18-3.99). However, patients reporting diminished appetite were more likely to have lower LTM (OR adj: 2.86; 95 % CI: 1.31-6.24) and fat mass (OR adj: 1.91; 95 % CI: 1.03-3.53), lower levels of serum urea (OR adj: 2.74; 95 % CI: 1.49-5.06) and creatinine (OR adj: 1.99; 95 % CI: 1.01-3.92), higher Dialysis Malnutrition Score (OR adj: 2.75; 95 % CI: 1.50-5.03), Malnutrition Inflammation Score (OR adj: 2.15; 95 % CI: 1.17-3.94), and poorer physical (OR adj: 3.49; 95 % CI: 1.89-6.47) and mental (OR adj: 5.75; 95 % CI: 3.02-10.95) scores. CONCLUSIONS: A graded but non-significant increase in the proportion of PEW patients occurred as appetite became poorer. However, after dichotomization, a positive but marginally significant association was observed between diminished appetite and PEW diagnosis.

Exposure-effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis.

AIMS: The aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis. METHODS: Six blood samples were drawn pre- and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C0 ), maximum concentration (Cmax ) and area under the concentration-time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events. RESULTS: Dose-normalized AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values (95% CI) of total MPA AUC(0,8 h) (21.5 [15.0, 42.0] vs. 11.2 [4.8, 30.0] mg l(-1) h, P= 0.048) and Cmax (11.9 [6.7, 26.3] vs. 6.1 [1.6, 9.2] mg l(-1) , P = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1, 77.5] vs. 18.5 [11.7, 32.7] mg l(-1) h, P = 0.038) and unbound MPA AUC(0,12 h) (751 [214, 830] vs. 227 [151, 389] mg l(-1) h, P = 0.004). Unbound prednisolone AUC(0,24 h) was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242, 1774] vs. 846 [528, 1049] nmol l(-1) h, P = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023). CONCLUSIONS: This study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis.

Persistent hypertension in lupus nephritis and the associated risk factors.

Arterial hypertension (HPT) burden up to two third of systemic lupus erythematosus (SLE) patients and contributes to accelerated atherosclerosis and cardiovascular (CV) risk. We aim to determine the prevalence of HPT among lupus nephritis (LN) patients who were in complete remission (CR) for a minimum of 6 months, with estimated glomerular filtration rate (eGFR) of >60 mL/min/1.73 m(2). This is a cross-sectional study of 64 LN patients who attended Nephrology/SLE Clinic at The National University of Malaysia Medical Centre (UKMMC). Persistent hypertension (blood pressure (BP) ≥140/90 mmHg for at least two occasions), CR for a minimum of 6 months and eGFR of >60 mL/min/1.73 m(2) were identified. Univariate and multivariate analyses were performed to determine the demographic and disease characteristics associated with HPT. Thirty-four of them (53.1 %) were hypertensive. Persistent HPT was associated with disease duration, acute kidney injury and high BP at the onset of LN, longer duration interval to achieve CR, number of relapses and cyclosporine A (CyA) use. There were no associations between histological classes, nephrotic range proteinuria, body mass index and waist circumference with HPT. Factors independently associated with HPT were disease duration OR 1.06 [95 %CI (0.91-1.24)], longer duration interval to achieve CR OR 1.104 [95 %CI (1.02-1.19)], number of relapses OR 2.53 [95 % CI (1.01-6.3)] and CyA use OR 5.3 [95 % CI (1.14-23.9)]. The prevalence of HPT among LN is high despite in remission. Aggressive treatment is important to achieve early CR and to prevent relapses.

Angiotensin-converting enzyme gene polymophism in adult primary focal segmental glomerulosclerosis.

BACKGROUND: Primary focal segmental glomerulosclerosis (FSGS) accounts for a third of biopsy-proven primary glomerulonephritis in Malaysia. Pediatric studies have found the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene to be associated with renal disease progression. The aim of this study was to determine the prevalence of the ACE (I/D) genotypes in adult primary FSGS and its association with renal outcome on follow-up. METHODS: Prospective observational study involving primary FSGS patients was conducted. Biochemical and urine tests at the time of study were compared to the time of the diagnosis and disease progression analyzed. ACE gene polymorphism was identified using polymerase chain reaction amplification technique and categorized into II, ID and DD genotypes. RESULTS: Forty-five patients with a median follow-up of 3.8 years (interquartile range: 1.8 - 5.6) were recruited. The commonest genotype was II (n = 23, 51.1%) followed by ID (n = 19, 42.2%) and DD (n = 3, 6.7%). The baseline characteristics were comparable between the II and non-II groups at diagnosis and at study recruitment except that the median urine protein-creatinine index was significantly lower in the II group compared to the non-II group (0.02 vs. 0.04 g/mmol (P = 0.03). Regardless of genotypes, all parameters of renal outcome improved after treatment. CONCLUSION: The II followed by ID genotypes were the predominant ACE gene alleles in our FSGS. Although the D allele has been reported to have a negative impact on renal outcome, treatment appeared to be more important than genotype in preserving renal function in this cohort.

The effect of calcium with or without calcitriol supplementation on renal function in patients with hypovitaminosis d and chronic kidney disease.

BACKGROUND: Hypovitaminosis D (serum 25-OHD < 30 ng/mL) is common in patients with chronic kidney disease (CKD). Vitamin D is believed to involve in the regulation of renin-angiotensin system and may be renoprotective. OBJECTIVES: To compare the effects of calcium with or without calcitriol on renal function in patients with CKD. PATIENTS AND METHODS: A prospective randomized trial was performed involving patients with stages 2-4 CKD and hypovitaminosis D. Baseline demographics data were taken at baseline. Patients were randomized equally into oral calcitriol plus calcium carbonate (calcitriol group) or calcium carbonate alone (non-calcitriol group). Serum levels of 25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D3 (1,25-(OH)2D), creatinine, calcium and urine protein creatinine index (uPCI) were measured at 6 and 12 weeks. RESULTS: Fifty (21 Female: 29 Male) patients with CKD with a median age of 53 (22-65) years were recruited. Their median MDRD eGFR (modification of diet in renal disease, estimation of glomerular filtration rate) was 36.0 (15-89) mL/min/1.73 m(2) with the CKD stage 2 (n = 8, 16%), stage 3 (n = 29, 58%), and stage 4 (n = 13, 26%) respectively. In both study groups serum 25-OHD levels were increased at 12 weeks (P = 0.001), in contrast to serum 1,25-(OH)2D levels which remained unchanged (P > 0.05), serum creatinine and uPCI were also remained unchanged until the end of study (P > 0.05 each). Patients with diabetes had higher serum creatinine (P = 0.01) and lower serum 1,25-(OH)2D (P = 0.02) at baseline. Regardless of the diabetics status, the serum 25-OHD was increased, and 1,25-(OH)2D remained unchanged at 12 weeks in both study groups. At 12 weeks, serum creatinine was decreased in patients with diabetes in the noncalcitriol group (P = 0.03) compared to stabilization of creatinine in the calcitriol group (P > 0.05). Serum calcium was increased, though it was still within the normal range in the calcitriol group (P < 0.001); whereas, in the noncalcitriol group, there was an initial reduction but increased back to baseline (P = 0.007). Urine PCI remained unchanged in both groups. CONCLUSIONS: We have demonstrated that calcitriol supplementation did not offer any additional benefit to reduce 25-OHD and 1,25-(OH)2D levels over calcium carbonate alone in patients with CKD in this short term study. Overall renal function remained unchanged. However, we found that calcitriol at 0.5 mg daily plus calcium carbonate 500 mg daily could be reno-protective in diabetic nephropathy regardless of their serum 25-OHD levels.

Assessment of fluid status in CAPD patients using the body composition monitor.

AIMS AND OBJECTIVES: To assess the degree of overhydration in our peritoneal dialysis patients and to examine the factors contributing to overhydration. BACKGROUND: Volume control is critical for the success of peritoneal dialysis, but dry weight has been difficult to ascertain accurately. Chronic fluid overload and hypertension are among the leading causes of mortality in dialysis patients. DESIGN: A cross-sectional observational study. METHODS: The body composition monitor (Fresenius Medical Care, Bad Homburg, Germany) is a bioimpedance spectroscopy device that has been validated for the assessment of overhydration. We used this body composition monitor device on all patients on continuous ambulatory peritoneal dialysis at our institution who met the inclusion criteria to assess their degree of overhydration. RESULTS: Thirty four (17 men, 17 women; mean age 44·5 ± 14·2 years) of a 45 continuous ambulatory peritoneal dialysis patients were enrolled. The mean overhydration was 2·4 ± 2·4 l. Fifty per cent of the patients were ≥2 l overhydrated. Overhydration correlated with male gender, low serum albumin, increasing number of antihypertensive agents and duration of dialysis. There was no difference in overhydration between diabetic and non-diabetic patients. Men were more overhydrated than women, had lower Kt/V and were older. Although, there was no difference in blood pressure between the genders, men had a trend towards a higher usage of antihypertensive agents. CONCLUSION: Our study demonstrates that overhydration is common in peritoneal dialysis patients. Blood pressure should ideally be controlled with adherence to dry weight and low salt intake rather than adding antihypertensive agents even in the absence of clinical oedema. RELEVANCE TO CLINICAL PRACTICE: Body composition monitor is a simple, reliable and inexpensive tool that can be routinely used in the outpatient clinic setting or home visit to adjust the dry weight and avoid chronic fluid overload in between nephrologists review.

Systemic lupus erythematosus with a non functioning pituitary macroadenoma.

BACKGROUND: Malignancies are more common in patients with systemic lupus erythematosus (SLE) than the general population. SLE patients are recognized to have higher prolactin levels. However, there are very few reported cases of SLE with pituitary adenomas. CASE REPORT: We report the second case of a pituitary adenoma in a patient with underlying SLE. A 51 year old lady presented with blurred vision and magnetic resonance imaging of the brain demonstrated a pituitary macroadenoma with mildly elevated serum prolactin levels. The diagnosis of a non functioning pituitary macroadenoma was confirmed histologically. The diagnosis of SLE was made on the basis of thrombocytopenia, antinuclear antibodies, anti double stranded DNA antibodies and lupus nephritis (confirmed on renal biopsy). The patient initially received medical therapy with carbegoline, followed by transsphenoidal neurosurgery for the pituitary macroadenoma. SLE with lupus nephritis was treated with steroids and low dose intravenous cyclophosphamide. CONCLUSIONS: Hyperprolactinaemia is prevalent in twenty to thirty percent of SLE patients but it is rarely due to a prolactinoma. The source of excessive circulating prolactin in SLE patients has not been fully determined.