Mycobacterium tuberculosis peritonitis in peritoneal dialysis patients: A scoping review.

BACKGROUND: The clinical syndrome of Mycobacterium tuberculosis (M. tuberculosis) peritoneal dialysis (PD) peritonitis is poorly understood. Whether local tuberculosis (TB) patterns modify the clinical syndrome, and what factors associate with poor outcomes is also unknown. METHODS: A scoping review identified published cases of TB PD peritonitis. Cases from low- and high-TB burden areas were compared, and cases that did or did not suffer a poor clinical outcome were compared. RESULTS: There were 216 cases identified. Demographics, presentation, diagnosis, treatment and outcomes were described. Significant delays in diagnosis were common (6.1 weeks) and were longer in patients from low-TB burden regions (7.3 vs. 3.7 weeks). In low-TB burden areas, slower diagnostic methods were more commonly used like PD fluid culture (64.3% vs. 32.7%), and treatment was less likely with quinolone antibiotics (6.9% vs. 34.1%). Higher national TB incidence and lower GDP per capita were found in cases that suffered PD catheter removal or death. Diagnostic delays were not longer in cases in which a patient suffered PD catheter removal or death. Cases that suffered death were older (51.9 vs. 45.1 years) and less likely female (37.8% vs. 55.7%). Removal of PD catheter was more common in cases in which a patient died (62.0% vs. 49.1%). CONCLUSIONS: Outcomes in TB PD peritonitis are best predicted by national TB incidence, patient age and sex. Several unique features are identified to alert clinicians to use more rapid diagnostic methods that might enhance outcomes in TB PD peritonitis.

A Scoping Review of Alternative Anticoagulation Strategies for Hemodialysis Patients with a Mechanical Heart Valve.

INTRODUCTION: Patients with end-stage renal disease (ESRD) have high rates of cardiac valvulopathy but can develop contraindications for vitamin K antagonist (VKA) therapy. We explored the evidence for alternative anticoagulation strategies in patients with ESRD with a contraindication for VKA therapy. METHODS: A scoping review was completed, searching MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Conference abstracts from inception to March 30, 2021. The study population was patients with ESRD who were on VKA therapy and developed a contraindication to VKA therapy use. All data regarding studies, patient characteristics, anticoagulation strategy, and clinical outcomes were summarized. RESULTS: Twenty-three articles met inclusion criteria. These articles included 57 patients. Contraindications to VKA therapy included calcific uremic arteriolopathy (CUA) (n = 55) and warfarin-induced skin necrosis (n = 2). All studies were either case reports or case series. There were 10 anticoagulation strategies identified. Continuation of VKA therapy was associated with increased death and decreased rates of CUA resolution (80.0% and 10.0%, respectively), compared to apixaban (24.0% and 70.8%), subcutaneous (SC) low-molecular-weight heparin (LMWH) (14.3%, 85.7%), and SC unfractionated heparin (0.0%, 100.0%). While only 5 patient cases were reported with mechanical heart valves, SC LMWH use has been reported in this context with good outcomes. CONCLUSIONS: In patients with ESRD who develop a contraindication to VKA therapy, several alternative anticoagulation strategies have been reported with superior outcomes to VKA continuation. While outcomes appear superior to continuation of VKA therapy, more data are required before definitive recommendations can be made for the patient with ESRD and a mechanical heart valve.

Untargeted metabolomics reveals N, N, N-trimethyl-L-alanyl-L-proline betaine (TMAP) as a novel biomarker of kidney function.

The diagnosis and prognosis of chronic kidney disease (CKD) currently relies on very few circulating small molecules, which can vary by factors unrelated to kidney function. In end-stage renal disease (ESRD), these same small molecules are used to determine dialysis dose and dialytic clearance. Therefore, we aimed to identify novel plasma biomarkers to estimate kidney function in CKD and dialytic clearance in ESRD. Untargeted metabolomics was performed on plasma samples from patients with a single kidney, non-dialysis CKD, ESRD and healthy controls. For ESRD patients, pre- and post-dialysis plasma samples were obtained from several dialysis modalities. Metabolomics analysis revealed over 400 significantly different features in non-dialysis CKD and ESRD plasma compared to controls while less than 35 features were significantly altered in patients with a single kidney. N,N,N-trimethyl-L-alanyl-L-proline betaine (TMAP, AUROC = 0.815) and pyrocatechol sulfate (AUROC = 0.888) outperformed creatinine (AUROC = 0.745) in accurately identifying patients with a single kidney. Several metabolites accurately predicted ESRD; however, when comparing pre-and post-hemodialysis, TMAP was the most robust biomarker of dialytic clearance for all modalities (AUROC = 0.993). This study describes TMAP as a novel potential biomarker of kidney function and dialytic clearance across several hemodialysis modalities.

Effect of CKD and dialysis modality on exposure to drugs cleared by nonrenal mechanisms.

BACKGROUND: Patients with kidney disease frequently experience adverse effects from medication exposure, even when drugs are cleared by nonrenal pathways. Although many studies suggest that nonrenal drug clearance is decreased in chronic kidney disease (CKD), there remains a paucity of in vivo studies in patients with varying degrees of decreased kidney function and those comparing the impact of dialysis modality (eg, hemodialysis [HD] and peritoneal dialysis [PD]). STUDY DESIGN: We performed in vivo clinical pharmacokinetic studies of midazolam, a nonrenally cleared specific probe for CYP3A4, and fexofenadine, a nonspecific probe for hepatic and intestinal transporters. SETTING & PARTICIPANTS: Healthy controls (n=8), patients with non-dialysis-dependent (NDD)-CKD (n=8), and patients receiving HD (n=10) or PD (n=8). OUTCOMES: Exposure to midazolam and fexofenadine were quantified using area under the curve (AUC). Comprehensive pharmacokinetic parameters also were calculated for both probes. RESULTS: Midazolam AUC was significantly higher in the HD group (382.8 h·ng/mL) than in the healthy-control (63.0 h·ng/mL; P<0.001), NDD-CKD (84.5 h·ng/mL; P=0.002), and PD (47.4 h·ng/mL; P<0.001) groups. Fexofenadine AUC was significantly higher in each of the NDD-CKD (2,950 h·ng/mL; P=0.003), HD (2,327 h·ng/mL; P=0.01), and PD (2,095 h·ng/mL; P=0.04) groups compared with healthy controls (1,008 h·ng/mL). LIMITATIONS: Small study groups had different proportions of diabetic patients, early stages of CKD not available. CONCLUSIONS: Our data suggest that selection of dialysis modality is a major determinant of exposure to the CYP3A4 probe midazolam. Exposure to the intestinal and hepatic transporter probe fexofenadine is altered in patients with NDD-CKD and PD and HD patients. Thus, drug development and licensing of nonrenally cleared drugs should include evaluation in these 3 patient groups, with these results included in approved product information labeling. This reinforces the critical need for more in vivo studies of humans that evaluate the exposure to drugs cleared by these pathways.

The choice of dialysate sodium is influenced by hemodialysis frequency and duration: what should it be and for what modality?

Cardiovascular disease is the leading cause of mortality in hemodialysis patients. A chronic state of volume and pressure overload contributes, and central to this is the net sodium balance over the course of a hemodialysis. Of recent interest is the contribution of the dialysate sodium concentration (Dial-Na+) to clinical outcomes. Abundant evidence confirms that in thrice-weekly conventional hemodialysis, higher Dial-Na+ associates with increased intradialytic weight gain, blood pressure, and cardiovascular morbidity and mortality. On the other hand, low Dial-Na+ associates with intradialytic hypotension in the same patient population. However, the effect of Dial-Na+ in short hours daily hemodialysis (SHD; often referred to as "quotidian" dialysis), or nocturnal dialysis (FHND) is less well studied. Increased frequency and duration of exposure to a diffusive sodium gradient modulate the way in which DPNa+ alters interdialytic weight gain, predialysis blood pressure, and intradialytic change in blood pressure. Furthermore, increased dialysis frequency appears to decrease the predialysis plasma sodium setpoint (SP), which is considered stable in conventional thrice-weekly patients. This review discusses criteria to determine optimal Dial-Na+ in conventional, SHD and FHND patients, and identifies areas for future research.

What is single needle cannulation hemodialysis: is it adequate?

BACKGROUND: It is important to know the relative clearances obtained when using single-needle versus double-needle cannulation techniques. METHOD: Twelve hemodialysis treatments were conducted using a machine that is capable of single-needle as well as double-needle cannulation. Single-needle and double-needle blood flow rates, as well as urea clearance, were compared. RESULTS: The measured blood flow rates were 368 ± 11 ml/min, 294 ± 4 ml/min, 200 ± 0 ml/min, and 100 ± 0 ml/min during double-needle hemodialysis and were 201 ± 10.9 ml/min, 173 ± 44.9 ml/min, 103 ± 4.1 ml/min, and 45 ± 4.9 ml/min during single-needle hemodialysis. The hemodialysis urea clearances at similar blood flow rate (approximately 200 ml/min) were 167 ± 4 ml/min and 161 ± 9 ml/min (paired t test; p > 0.05), respectively. CONCLUSION: The measured blood flow rates and urea clearances during single-needle hemodialysis were approximately half of the measured blood flow rate during double-needle hemodialysis, and should be used in selected settings.

Nocturnal home hemodialysis associates with improvement of electrocardiographic features linked to sudden cardiac death.

Sudden cardiac death (SCD) remains the leading cause of death in hemodialysis patients. We performed a retrospective electrocardiograph (ECG) and chart review to determine whether hemodialysis modality, frequency, or duration could predict change in ECG parameters associated with SCD. Frequent nocturnal hemodialysis was associated with an improvement in Tpeak to Tend within 365 days (83.8-71.8 ms, p = 0.005) and past 365 days of dialysis initiation (85.9-77.1 ms, p = 0.005) and improvement in QRS amplitude variation within 365 days (0.0583-0.0297, p = 0.025) and past 365 days of dialysis initiation (0.0546-0.0332, p = 0.029). Compared with intermittent conventional hemodialysis, more frequent nocturnal (15/25 vs. 3/14, p = 0.04) and intermittent nocturnal hemodialysis (INHD) (6/8 vs. 3/14, p = 0.03) patients decreased Tpeak to Tend. More short-hours daily than INHD patients increased T-wave amplitude variation (16/25 vs. 1/8, p = 0.02). These improvements occurred before changes in Cornell or Sokolow-Lyon electrocardiographic left ventricular mass. Thus, it appears that hemodialysis modalities of longer duration are associated with improvements in electrocardiographic parameters associated with SCD. Prospective trials are required to determine whether dialysis prescription reduces SCD, cardiovascular morbidity, and mortality in hemodialysis patients.

Warfarin use in hemodialysis patients with atrial fibrillation: decisions based on uncertainty.

BACKGROUND: Warfarin prescribing patterns for hemodialysis patients with atrial fibrillation vary widely amongst nephrologists. This may be due to a paucity of guiding evidence, but also due to concerns of increased risks of warfarin use in this population. The literature lacks clarity on the balance of warfarin therapy between prevention of thrombotic strokes and the increased risks of bleeding in hemodialysis patients with atrial fibrillation. METHODS: We performed a survey of Canadian Nephrologists, assessing warfarin prescribing practice, and measured the certainty in making these choices. RESULTS: Respondents were consistently uncertain about warfarin use for atrial fibrillation. This uncertainty increased with a history of falls or starting hemodialysis, even when a high CHADS2 or CHA2DS2VASc score was present. The majority of respondents agreed that clinical equipoise existed about the use of oral anticoagulation in hemodialysis patients with atrial fibrillation (72.2%) and that the results of a randomized controlled trial would be relevant to their practice (98.2%). CONCLUSIONS: A randomized controlled trial of warfarin use in hemodialysis patients with atrial fibrillation would clarify the risks and benefits of warfarin use in this population.

Plasma sodium setpoint: is it constant or changed by hemodialysis prescription?

Stability of predialysis sodium "setpoint" has not been validated in quotidian dialysis patients. We performed a retrospective review of our home hemodialysis program, to determine the effect of transitioning from conventional thrice weekly to home hemodialysis modalities differing in dialysis duration and frequency (n = 87). Mean sodium setpoint remained constant in patients who went home on intermittent hemodialysis, but decreased by 100 days in frequent nocturnal home hemodialysis (FNHD) (140.5-137.1 mM, p = 0.001) and short hours daily hemodialysis (SHD) (140.2-138.7 mM, p = 0.019) patients with a pretransition setpoint greater than dialysate sodium of 140 mM. Slope of predialysis sodium concentration within the first 100 days post-transition (M100) was less than zero in SHD (95% confidence interval [CI], -0.0081 to -0.0351 mM/day) and FNHD (95% CI, -0.0209 to -0.0695 mM/day) patients who started with a pretransition setpoint greater than dialysate sodium concentration of 140 mM. Change in sodium setpoint (SP) was predicted by dialysis frequency and the difference between dialysate sodium concentration and the pretransition predialysis sodium concentration (R = 35.4%, adjusted R = 33.8%, p < 0.001). Thus, personalizing dialysate sodium concentrations may be associated with a decrease in SP, which is independently associated with increased mortality. Further research is required to determine whether intentional increases in the SP could improve cardiovascular and all-cause mortality.

Frequent nocturnal hemodialysis associates with improvement of prolonged QTc intervals.

BACKGROUND/AIMS: Sudden cardiac death remains the leading cause of death in hemodialysis (HD) patients. Prolongation of QTc intervals (as measured by the tangent method) increases sudden cardiac death risk in populations without kidney disease. METHODS: We performed a retrospective electrocardiograph (ECG) and chart review of HD patients. Our objectives were (1) to establish the effect of one of four different dialysis modalities on interdialytic QTc intervals, (2) to determine the effect of dialysis frequency and time on QTc interval and on the prevalence of borderline or prolonged QTc intervals, and (3) to determine if changes in QTc interval were simultaneous to changes in electrocardiographic left ventricular mass. RESULTS: Frequent nocturnal HD was associated with a decrease in QTc interval for all patients (from 436.5 to 421.3 ms, p = 0.0187) and for patients who initiated dialysis with prolonged QTc (468.2 to 438.2 ms, p = 0.0134). This change happened before changes in left ventricular mass were evident. Dialysis duration predicted a decrease in QTc better than dialysis frequency (R(2) 6.50 vs. 3.00%, p = 0.023 vs. 0.102). Prevalence of borderline or prolonged QTc increased in patients dialyzed <4 h/session (12/39 to 22/39, p = 0.039). CONCLUSIONS: Frequent nocturnal HD may be the ideal modality to initiate HD in end-stage kidney disease patients with prolonged QTc.

Modifiable variables affecting interdialytic weight gain include dialysis time, frequency, and dialysate sodium.

Interdialytic weight gain (IDWG) is associated with hypertension, left ventricular hypertrophy, and all-cause mortality. Dialysate sodium concentration may cause diffusion gradients with plasma sodium and influence subsequent IDWG. Dialysis time and frequency may also influence the outcomes of this Na(+) gradient; these have been overlooked. Our objective was to identify modifiable factors influencing IDWG. We performed a retrospective multivariable regression analyses of data from 86 home hemodialysis patients treated by hemodialysis modalities differing in frequency and session duration to determine factors involved that predict IDWG. Age, diabetic status, and residual renal function did not correlate with IDWG in the univariable analysis. However, using a combination of backwards selection and Akaike information criterion to build our model, we created an equation that predicted IDWG on the basis of serum albumin, age, patient sex, dialysis frequency, and the diffusive balance of sodium, represented by the product of the duration of dialysis and the patient plasma to dialysate Na(+) gradient. This equation was internally validated using bootstrapping, and externally validated in a temporally distinct patient population. We have created an equation to predict IDWG on the basis of independent factors readily available before a dialysis session. The modifiable factors include dialysis time and frequency, and dialysate sodium. Patient sex, age, and serum albumin are also correlated with IDWG. Further work is required to establish how improvements in IDWG influence cardiovascular and other clinical outcomes.

Pre to post-dialysis plasma sodium change better predicts clinical outcomes than dialysate to plasma sodium gradient in quotidian hemodialysis.

Sodium balance across a hemodialysis treatment influences interdialytic weight gain (IDWG), pre-dialysis blood pressure, and the occurrence of intradialytic hypotension, which associate with patient morbidity and mortality. In thrice weekly conventional hemodialysis patients, the dialysate sodium minus pre-dialysis plasma sodium concentration (δDPNa+) and the post-dialysis minus pre-dialysis plasma sodium (δPNa+) are surrogates of sodium balance, and are associated with both cardiovascular and all-cause mortality. However, whether δDPNa+ or δPNa+ better predicts clinical outcomes in quotidian dialysis is unknown. We performed a retrospective analysis of clinical and demographic data from the Southwestern Ontario Regional Home Hemodialysis program, of all patients since 1985. In frequent nocturnal hemodialysis, δPNa+ was superior to δDPNa+ in predicting IDWG (R(2)=0.223 vs. 0.020, P=0.002 vs. 0.76), intradialytic change in systolic (R(2)=0.100 vs. 0.002, P=0.02 vs. 0.16) and diastolic (R(2)=0.066 vs. 0.019, P=0.02 vs. 0.06) blood pressure, and ultrafiltration rate (R(2)=0.296 vs. 0.036, P=0.001 vs. 0.52). In short hours daily hemodialysis, δDPNa+ was better than δPNa+ in predicting intradialytic change in diastolic blood pressure (R(2)=0.101 vs. 0.003, P=0.02 vs. 0.13). However, δPNa+ was better than δDPNa+ in predicting IDWG (R(2)=0.105 vs. 0.019, P=0.04 vs. 0.68) and pre-dialysis systolic blood pressure (R(2)=0.103 vs. 0.007, P=0.02 vs. 0.82). We also found that the intradialytic blood pressure fall was greater in frequent nocturnal hemodialysis patients than in short hours daily patients, when exposed to a dialysate to plasma sodium gradient. These results provide a basis for design of prospective trials in quotidian dialysis modalities, to determine the effect of sodium balance on cardiovascular outcome.

Should patients with advanced chronic kidney disease and atrial fibrillation receive chronic anticoagulation?

Atrial fibrillation is prevalent in dialysis patients. Both ischaemic and haemorrhagic stroke are common in patients on dialysis with atrial fibrillation. In the general population, warfarin is highly effective for prophylaxis of ischaemic stroke, and though warfarin use likely increases the risk of intracranial haemorrhage, the absolute increase in risk is small. In the general population, absolute and relative increases in major extracranial bleeding from warfarin use are also both modest. In patients on dialysis, the effectiveness of warfarin as a prophylaxis for ischaemic stroke and its effects on intracranial or extracranial bleeding have not been assessed in randomized trials. Cohort studies vary greatly in their estimates of the magnitude of the increased risk of bleeding from warfarin use. A single cohort study found rates of intracranial haemorrhage in patients on dialysis with atrial fibrillation to be in an order of magnitude that is greater than those in the general population with atrial fibrillation, and that intracranial haemorrhage more than doubled in association with warfarin use. Basic, translational and limited clinical observations also implicate warfarin in the pathogenesis of vascular calcification, which is likely on the causal pathway to patient-important vascular outcomes. Finally, the effect of warfarin on ischaemic stroke in three recent large observational studies has been in the direction of harm, no benefit, and modest, non-statistically significant benefit, respectively. We believe that no clear recommendation can be made between three alternative approaches. It is acceptable to withhold or discontinue warfarin in patients on dialysis, to offer anticoagulants to all dialysis patients without a contraindication whose congestive heart failure, hypertension, age, diabetes and previous stroke or transient ischaemic attack (CHADS(2)) score >1 or 2 and to discuss and individualize prophylaxis on a patient-by-patient basis. Randomized trials of new agents are needed in this area.

Evaluation of an electronic warfarin nomogram for anticoagulation of hemodialysis patients.

BACKGROUND: Warfarin nomograms to guide dosing have been shown to improve control of the international normalized ratio (INR) in the general outpatient setting. However, the effectiveness of these nomograms in hemodialysis patients is unknown. We evaluated the effectiveness of anticoagulation using an electronic warfarin nomogram administered by nurses in outpatient hemodialysis patients, compared to physician directed therapy. METHODS: Hemodialysis patients at any of the six outpatient clinics in Calgary, Alberta, treated with warfarin anticoagulation were included. Two five-month time periods were compared: prior to and post implementation of the nomogram. The primary endpoint was adequacy of anticoagulation (proportion of INR measurements within range ± 0.5 units). RESULTS: Overall, 67 patients were included in the pre- and 55 in the post-period (with 40 patients in both periods). Using generalized linear mixed models, the adequacy of INR control was similar in both periods for all range INR levels: in detail, range INR 1.5 to 2.5 (pre 93.6% (95% CI: 88.6% - 96.5%); post 95.6% (95% CI: 89.4% - 98.3%); p = 0.95); INR 2.0 to 3.0 (pre 82.2% (95% CI: 77.9% - 85.8%); post 77.4% (95% CI: 72.0% - 82.0%); p = 0.20); and, INR 2.5 to 3.5 (pre 84.3% (95% CI: 59.4% - 95.1%); post 66.8% (95% CI: 39.9% - 86.0%); p = 0.29). The mean number of INR measurements per patient decreased significantly between the pre- (30.5, 95% CI: 27.0 - 34.0) and post- (22.3, 95% CI: 18.4 - 26.1) (p = 0.003) period. There were 3 bleeding events in each of the periods. CONCLUSIONS: An electronic warfarin anticoagulation nomogram administered by nurses achieved INR control similar to that of physician directed therapy among hemodialysis patients in an outpatient setting, with a significant reduction in frequency of testing. Future controlled trials are required to confirm the efficacy of this nomogram.