QTc interval prolongation independently associates with FGF23 and predicts mortality in predialysis CKD.

INTRODUCTION: QTc interval prolongation is increasingly frequent as CKD advances and predicts death in dialysis. However, predictors and mortality-risk in predialysis CKD are understudied. FGF23 induces left ventricular hypertrophy (LVH) which is associated with QTc interval prolongation and death, suggesting a possible pathway from FGF23 to death that entails LVH and QTc prolongation. We looked for links between FGF23 and prolonged QTc intervals mediated by LVH, and for deaths associated with QTc prolongation in a prospective observational cohort of patients with predialysis CKD. METHODS: Participants underwent protocolized baseline and semi-annual FGF23 testing, baseline and study end echocardiograms, and baseline and annual electrocardiograms over three years. RESULTS: 2,254 participants (34.1% female; mean age 68.7 years; mean glomerular filtration rate 41.4 ml/min/m2) enrolled. Baseline LVH (left ventricular mass index >131 g/m2 (>100 g/m2 if female)) was present in 10.8% and prolonged QTc intervals (>=500 ms) in 1.5%. One hundred thirty-eight (6.1%) participants died during the study. In generalized mixed effects regression, each unit increase in the natural log of FGF23 - but not LVH - predicted an odds ratio of 1.76 (1.15, 2.70, p=0.009) for prolonged QTc intervals independently of 15 other covariates. Mediation analysis showed that only 13% of FGF23's total effect on prolonged QTc intervals was mediated by LVH. Patients with prolonged QTc intervals had higher unadjusted (log rank p<0.001) and adjusted (hazard ratio 3.15 (1.38, 7.16, p=0.006)) mortality rates than those with QTc intervals <500 ms. CONCLUSIONS: QTc interval prolongation ≥500 ms was prospectively associated with FGF23 independently of LVH, and with a tripling of mortality-risk in patients with predialysis CKD.

Functional patency rates of arteriovenous fistula of a retrospective cohort study from one of the biggest centers in Canada.

BACKGROUND: The main barriers to arterio-venous fistula (AVF) utilization are primary failure, long maturation duration, and low secondary patency rates. METHODS: In this retrospective cohort study, primary, secondary, functional primary, and functional secondary patency rates were calculated and compared between two age groups (< 75 years and > = 75 years) and between radiocephalic (RC-) and upper arm (UA-) AVFs, and factors determining the duration of functional secondary patency were evaluated. RESULTS: Between 2016 and 2020, 206 predialysis patients whose AVFs had been created previously initiated renal replacement treatment. RC-AVFs comprised 23.3% and were created after favorable analysis of the forearm vasculature. Overall, the primary failure rate was 8.3, and 84.7% started hemodialysis with a functioning AVF. Functional secondary patency rates of primary AVFs were better with RC-AVFs [1,3 and 5 year rates of 95.8, 81.9 and 81.9% versus 83.4, 71.8 and 59.2% for UA-AVFs (log rank p: 0.041)]. There was no difference between the two age groups for any of the AVF outcomes assessed. Among patients whose AVF was abandoned, 40.3% had gone on to have a second fistula created. This was significantly less likely in the older group (p < 0.01). IN CONCLUSION: (1) UA-AVFs were placed more commonly than RC-AVFs; (2) a selection bias existed whereby RC-AVFs were only created after favorable forearm vasculature was demonstrated or suspected; (3) superior functional secondary patency rates were observed with RC-AV's, perhaps stemming from this selection bias; (4) the elderly were more likely to have only one AVF creation attempt.

Associations between echocardiographic findings and prospective changes in residual renal function in patients new to peritoneal dialysis.

Although echocardiograms are often performed when peritoneal dialysis is started, associations between commonly reported findings and prospective changes in renal function remain understudied. Ninety-nine of 101 patients in the Trio Trial had transthoracic echocardiograms within 6 months of dialysis initiation, and measurements of residual renal function every six weeks for up to two years. Generalized mixed modelling linear regression in STATA was used to examine associations between left atrial size, left ventricular hypertrophy, left ventricular ejection fraction, right ventricular systolic pressure, and left valvular calcification with subsequent slopes in renal function. After echocardiography (performed a median of 16 days following peritoneal dialysis initiation) right ventricular systolic pressure was associated with faster, while declining left ventricular ejection fraction and valvular calcification were associated with slower declines in residual renal function. Future studies could be conducted to confirm these findings, and identify pathophysiological mechanisms.

Associations of Calcium from Food Sources Versus Phosphate Binders with Serum Calcium and FGF23 in Hemodialysis Patients.

BACKGROUND: Dysregulated serum calcium and FGF23 are associated with increased mortality and morbidity rates in patients receiving hemodialysis. Preliminary data suggest serum calcium regulates FGF23 secretion independently of serum phosphate, parathyroid hormone, and 25-OH vitamin D. It is unclear to what extent dietary and prescription sources of calcium influence calcium and FGF23 levels, and whether they confound this relationship. In this cross-sectional analysis of a multi-ethnic cohort of prevalent hemodialysis patients, association of dietary calcium and prescribed calcium were examined against serum calcium and FGF23. Bi- and multivariable linear regression was used for all analyses. RESULTS: 81 patients (mean age 58 years, dialysis vintage 2 years, 51 men) participated. Dietary calcium was inversely associated with FGF23 (p = 0.04) however association of FGF23 with prescribed calcium did not reach statistical significance (0.08). In multivariable models, dietary calcium and prescribed calcium were associated in opposing directions with serum calcium (prescribed calcium; ß-coefficient = -0.35, p = 0.005 versus dietary calcium; ß-coefficient = 0.35, p = 0.03). FGF23 was independently associated with serum calcium (p = 0.007). CONCLUSIONS: We found differing, sometimes opposing, associations between serum calcium and FGF23 levels when considering prescribed versus dietary sources of calcium. Serum calcium and FGF23 were strongly correlated regardless of possible confounders examined in this hemodialysis cohort. Dietary calcium was associated with higher serum calcium and lower FGF23 concentrations, while prescribed calcium was only inversely associated with serum calcium. Further studies are required to confirm these associations and determine causality.

The Trio Trial - A Randomized Controlled Clinical Trial Evaluating the Effect of a Biocompatible Peritoneal Dialysis Solution on Residual Renal Function.

UNLABELLED: ♦ BACKGROUND AND OBJECTIVE: Residual renal function (RRF) correlates with mortality and morbidity rates in patients receiving peritoneal dialysis (PD). We examined the effect of a biocompatible PD solution (Gambrosol Trio; Gambro Lundia AB, Lund, Sweden) with lower concentrations of glucose degradation products on rates of decline in RRF. ♦ DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Incident patients at 2 centers in Canada and 1 in Hong Kong were randomized (by minimization) in an open-label parallel group trial to receive Gambrosol Trio or standard PD solution (Dianeal; Baxter Healthcare, Mississauga, Canada) for 2 years. Primary outcome was slope of RRF. Secondary outcomes were urine volumes, fluid and nutrition indices, PD and membrane characteristics, peritonitis rates, adverse events, and PD technique survival. ♦ RESULTS: Residual renal function declined by 0.132 mL/minute/1.73 m(2)/month in 51 patients allocated to biocompatible, and 0.174 mL/minute/1.73 m(2)/month in 50 patients allocated to standard PD solution (difference 0.042 mL/minute/1.73 m(2)/month, p = 0.001). Urine volume, body mass index, normalized protein catabolic rates, and fat mass were higher; total body water, peritoneal ultrafiltration, and D/P creatinine did not differ; and serum phosphate, rates of icodextrin, and automated cycler use were lower with Gambrosol Trio use. There were more peritonitis events with Gambrosol Trio use, while PD technique survival did not differ between groups. ♦ CONCLUSIONS: The use of the biocompatible PD solution Gambrosol Trio was associated with slower rates of decline in RRF, fluid and nutrition benefits, and increased peritonitis rates. TRIAL NUMBER: ISRCTN26252543.

MgCaCO3 versus CaCO3 in peritoneal dialysis patients--a cross-over pilot trial.

BACKGROUND: Despite adverse effects such as constipation, vascular calcification, and hypercalcemia, calcium-based salts are relatively affordable and effective phosphate binders that remain in widespread use in the dialysis population. We conducted a pilot study examining whether the use of a combined magnesium/calcium-based binder was as effective as calcium carbonate at lowering serum phosphate levels in peritoneal dialysis (PD) patients. METHODS: This was a cross-over, investigator-masked pilot study in which prevalent PD patients received calcium carbonate alone (200 mg calcium per tablet) or calcium magnesium carbonate (100 mg calcium, 85 mg magnesium per tablet). Primary outcome was serum phosphate level at 3 months. Analysis was as per protocol. RESULTS: Twenty patients were recruited, 17 completed the study. Mean starting dose was 11.35 ± 7.04 pills per day of MgCaCO3 and 9.00 ± 4.97 pills per day of CaCO3. Mean phosphate levels fell from 2.13 mmol/L to 2.01 mmol/L (95% confidence interval (CI): 1.76 - 2.30, p = 0.361) in the MgCaCO3 group, and 1.81 mmol/L (95% CI: 1.56 - 2.0, p = 0.026) in the CaCO3 alone group. Six (35%) patients taking MgCaCO3 and 9 (54%) taking CaCO3 alone achieved Kidney Disease Outcomes Quality Initiative (KDOQI) serum phosphate targets at 3 months. Diarrhea developed in 9 patients taking MgCaCO3 and 3 taking CaCO3. Serum magnesium exceeded 1.4 mmol/L in 5 patients taking MgCaCO3 while serum calcium exceeded 2.65 mmol/L in 3 patients receiving CaCO3. When compared to the initial dose, the prescribed dose at 3 months was reduced by 44% (to 6.41 tablets/day) in the MgCaCO3 group and by 8% (to 8.24 pills per day) in the CaCO3 alone group. CONCLUSION: Compared with CaCO3 alone, the preparation and dose of MgCaCO3 used in this pilot study was no better at lowering serum phosphate levels in PD patients, and was associated with more dose-limiting side effects.

Risk factors and consequences of hyperaluminemia in a peritoneal dialysis cohort.

BACKGROUND: Widespread Al toxicity is unusual today. In 2005, Canadian peritoneal dialysis (PD) centers reported widespread hyperaluminemia in patients using dialysates from one specific manufacturer. Our objectives were to evaluate risk factors related to Al accumulation and to assess its clinical consequences in patients from 2 centers. METHODS: A retrospective closed cohort study was conducted in patients treated with PD in May 2005. A multivariate linear regression model was constructed to identify variables associated with a higher serum Al level in the exposed group at the moment of solution change. Using appropriate statistical methods, anemia and bone metabolism parameters were compared between the exposed and unexposed groups. Time to first peritonitis was estimated by the Kaplan-Meier method. RESULTS: The study cohort included 87 Al-exposed patients and 95 unexposed patients. In the exposed group, serum Al at the moment of solution change was influenced by the length of exposure to Al-containing dialysates and by PD creatinine clearance; serum Al was inversely correlated with renal creatinine clearance. No consequences of Al accumulation were observed. No difference was observed in the time to first peritonitis between patients who switched manufacturers and those who remained with the original manufacturer. CONCLUSIONS: Our results suggest that hyperaluminemia is directly related to the length and extent of exposure to Al-containing dialysates; residual renal function is protective against Al accumulation. Because the problem was detected rapidly, no clinical consequences of hyperaluminemia were observed in the study cohort.

Variability in CKD stage in outpatients followed in two large renal clinics.

OBJECTIVE: Chronic kidney disease (CKD) is staged by glomerular filtration rate (GFR). CKD stages sometimes vary between routine office visits, and it is unknown if this impacts renal and patient survival separately from a cross-sectional CKD stage value. We quantified and categorized CKD stage variability in a large group of outpatients and correlated this with clinical and demographic features and with renal and patient survival. METHODS: All estimated GFRs were staged in the first observation period. CKD stages were then categorized as static, improving, worsening, or fluctuating. Logistic regression analysis was performed to identify clinical variables associated with CKD stage variability. Death and dialysis progression rates were then collected and analyzed using Cox proportional regression. RESULTS: During a 1.1-year observation period, 1,262 patients (mean age 71.25 years) had a mean 5 eGFR's. CKD stages were static in 60.4%, worsened in 14.4%, improved in 7.4%, and fluctuated in 17.2% of patients. Secondary analysis revealed heavy proteinuria and East Asian ethnicity to be negatively, and diabetes mellitus and previous acute kidney injury to be positively associated with improving CKD stages. Cox proportional regression of 902 patients analyzed 2.3 years later revealed a negative association with improving CKD stage and subsequent need for dialysis. CONCLUSIONS: CKD stage changed in 40% of 1,262 elderly patients when determined 5 times in just over 1 year. Improving CKD stage was the only variability pattern significantly associated with any of the clinical outcomes when assessed 2.3 years later, being unlikely to be linked with subsequent need for dialysis.

Aluminum toxicokinetics in peritoneal dialysis patients.

CONTEXT: Despite the risk of aluminum (Al) toxicity in dialysis patients, little is known about its toxicokinetics (TK) in this population. A national contamination of dialysate solutions with Al provided the opportunity to study Al TK in peritoneal dialysis (PD) patients and to better understand the influence of covariates on its disposition. METHODS: Al levels in serum and dialysate as well as other laboratory values were collected prospectively from 83 PD patients after correction of Al contamination. Population TK analyses were conducted with NONMEM VI using standard model discrimination criteria. Covariate analyses were also performed using stepwise forward regression followed by backward deletion. RESULTS: After correction of Al exposure, serum levels declined in a biphasic manner, which was captured by the TK model. The TK of Al were best described by a 2-compartment model with linear elimination. Total creatinine clearance was a significant covariate for total clearance (CL). Mean parameter estimates for volume of central compartment (V1), CL, volume of peripheral compartment (V2), volume of distribution at steady-state (Vss), and intercompartmental clearance (Q) were 168 L, 8.99 L/day, 12 000 L, 12 168 L, and 4.93 L/day, respectively. Inter-individual variability for CL and V2 were 22.6 and 51.1%, respectively. Al distributional half-life was 8.5 days, while the terminal elimination half-life was 7.2 years. This model confirms that the large Vss reflects the widespread distribution of Al in bone, lungs, liver, and other tissues. CONCLUSION: This study describes the first population Al TK model in a large group of PD patients, which includes a covariate effect. The model confirms the extensive half-life and tissue distribution of Al in a dialysis-dependent population.

Peritoneal dialysis in the nursing home.

UNLABELLED: The mean age of patients with end-stage renal disease increases steadily. The elderly on dialysis have significant comorbidity and require extra attention to meet their dialysis, dietary, and social needs, and some may need to be treated at a long-term care facility such as a nursing home (NH). Providing dialysis and caring for elderly patients in a nursing home (NH) presents a number of challenges. Few data are available in the literature about elderly patients on peritoneal dialysis (PD) in an NH. This paper describes our experience of starting and maintaining a peritoneal dialysis program in three community-based nursing homes. RESULTS: During the period 2004-2008, after the nursing home personnel had received appropriate training, we established a PD program in three community-based nursing homes and admitted 38 patients on peritoneal dialysis. We educated 112 NH staff over the three-year period. Mean age of the patients at entry was 77.3 + or - 8.5(18.4%) were male. The main causes of end-stage renal disease were diabetes mellitus (DM) 21 (55.8%) and hypertension 13 (34.2%). Comorbid conditions included DM (27, 71.1%), hypertension (26, 68.4%), coronary artery disease (18.5%), chronic heart failure (11, 28.9%), cerebrovascular event (12, 31.6%), and cancer(3, 7.9%). The average total time on chronic peritoneal dialysis was 36.5 + or - 29.8 months, (median 31, range: 1-110 months) of which the average time in the NH program, as of the time of this report, was 18.4 + or - 13.1 months (median 15.5, range: 1-45 months). During the study period, 16 (42.1%) of the patients died, 2 (5.3%) transferred to HD, 2 (5.3%) stopped treatment, and 18 (47.4%) are still in the program. Actuarial patient survival from entry into the NH program was 89.5% at six months, 60.5% at 12 months, 39.5% at 24 months and 13.2% at 36 months. Patient survival from initiation of chronic dialysis was 89.5% at six months, 76.3% at 12 months, 63.1% at 24 months, and 39.5% at 36 months. We observed 28 episodes of peritonitis with a rate of one episode every 40.3 treatment-months. Two PD catheters had to be replaced, giving a rate of one in every 362.5 patient months. CONCLUSION: Our results with elderly patients in a nursing home show an excellent patient and technique survival and a low peritonitis rate. With appropriate training of the NH nursing staff, peritoneal dialysis could be performed successfully in these nursing homes. Successful peritoneal dialysis in a nursing home requires a close collaboration between the nursing home staff and PD dialysis unit.

Improvement in eGFR in patients with chronic kidney disease attending a nephrology clinic.

BACKGROUND: The adverse effects arising from late referral to a nephrologist of patients with chronic kidney disease (CKD) are well known. Retrospectively we examined the initial characteristics of patients referred in various stages of CKD to our nephrology division and tried to identify potential baseline factors associated with subsequent changes in estimated glomerular filtration rate (eGFR). PATIENTS AND METHODS: Between September 1997 and June 2006 1,443 patients (909 male, 534 female) with CKD, with eGFRs ranging from 15 to 89 ml/min, were referred to our nephrology division and categorized using the National Kidney Foundation classification for CKD based on eGFR. The slope of eGFR change (ml/min-1/1.73/m2-1/year-1) was determined by linear regression analysis and the patients were divided into five groups: (1) significantly progressive slope (deterioration) (more negative than -5 ml/min/year); (2) mildly progressive slope (>-5 to -1 to +1 to or=+5). RESULTS: At the first nephrology referral, 5.8% of the patients were on CKD stage 2 (eGFR: 90-60 ml/m), 46.7% on CKD stage 3 (eGFR: 59-30 ml/m), and 47.5% on CKD stage 4 (eGFR: 29-15 ml/m) CKD. Significantly improved slope was detected in 48.2% of CKD stage 2 patients, 29.3% of CKD stage 3 patients, and only 14.7% of CKD stage 4 patients (P<0.05). Being in stage 4 or stage 3 versus being in stage 2 significantly reduced the likelihood of an improved slope in logistic regression analysis whereas age, gender, presence of hypertension, and diabetes mellitus did not reach the level of significance. CONCLUSION: Referral to a nephrology clinic can lead not only to arrest of progression of CKD but also to regression/improvement. Early referral is a positive predictive factor for improvement in eGFR, which emphasizes the importance of such referral. The previously held idea that, once established, CKD progresses invariably is not valid anymore.

Generalized seizure and toxic epidermal necrolysis following levofloxacin exposure.

OBJECTIVE: To report the case of a ciprofloxacin-allergic patient who developed a generalized tonic-clonic seizure and toxic epidermal necrolysis (TEN) following a single dose of levofloxacin. CASE SUMMARY: An 87-year-old white woman was admitted to the hospital following a transient episode of unresponsiveness that had been accompanied by flailing of her limbs. Approximately 4 hours earlier, she had developed a pruritic rash on her trunk and limbs, and 3 hours before this had taken a first dose of levofloxacin. The fluoroquinolone had been prescribed for treatment of an upper respiratory tract infection. She had developed a skin rash approximately 3 years earlier following ciprofloxacin prescribed for a urinary tract infection. On admission, the patient had a normal neurologic examination. She was mildly hypomagnesemic (serum magnesium 1.7 mg/dL), with no other electrolyte imbalances present. Skin biopsy confirmed TEN. The lesions progressed to involve 30% of the body surface area and were managed with polymyxin B and gramicidin cream. Levofloxacin was discontinued on admission, and no anticonvulsants were prescribed. The woman remained seizure-free at discharge one week later. DISCUSSION: Generalized tonic-clonic seizures are a rare complication of levofloxacin therapy. TEN following levofloxacin use has, to our knowledge, as of March 28, 2005, been previously reported only once. The seizure and TEN were probably induced by levofloxacin as corroborated by the Naranjo probability scale. We believe that the previous adverse dermatologic reaction to ciprofloxacin sensitized our patient to levofloxacin. CONCLUSIONS: These rare adverse reactions to levofloxacin, involving disparate organ systems, can occur simultaneously. A previous dematologic adverse reaction to a fluoroquinolone can sensitize a patient to more severe adverse reactions (with onset after only a single dose of the subsequent fluoroquinolone). Further fluoroquinolone use should be avoided in such patients.

Suppression of human melanoma metastasis by the metastasis suppressor gene, BRMS1.

We recently identified a novel metastasis suppressor gene, BRMS1, in breast cancer. Since the BRMS1 gene maps to chromosome 11q13.1-q13.2 and since chromosome 11q defects have been described in various stages of human melanoma progression, we hypothesized that BRMS1 may function as a tumor or metastasis suppressor in melanomas as well. Quantitative real-time RT-PCR revealed that BRMS1 mRNA expression was high in melanocytes, considerably reduced in early melanoma-derived cell lines, and barely detectable in advanced/metastatic cell lines. Stable transfectants of BRMS1 in the human melanoma cell lines MelJuSo and C8161.9 did not alter the tumorigenicity of either cell line, but significantly suppressed metastasis compared to vector-only transfectants. Orthotopic tumors continued to express BRMS1, but expression was lost in lung metastases. In vitro morphology, growth rate, and histology of BRMS1 transfectants were similar to controls. BRMS1 transfectants were less invasive in a collagen sandwich assay and had restored homotypic gap junctional intercellular communication (GJIC). Thus, BRMS1 functions as a metastasis suppressor in more than one tumor type (i.e., breast carcinoma and cutaneous melanoma) by modifying several metastasis-associated phenotypes.