Hepato-splanchnic circulatory stress: An important effect of hemodialysis.

The gastro-intestinal tract is being increasingly recognized as the site of key pathophysiological processes in the hemodialysis patient. Intestinal dysbiosis, increased intraluminal toxin production, and increased intestinal permeability are commonly observed processes which contribute to the pathogenesis of cardiovascular disease and thus elevated mortality. The acute circulatory effects of dialysis itself may contribute significantly to the development of gastrointestinal dysfunction as a result of both local and distant effects. Additionally, the liver, a relatively unknown entity in this process, has a substantial role as a functional barrier between the portal and systemic circulation and in the metabolism of pathogenic gut-derived uremic toxins. Here we summarize the evidence for acute gastro-intestinal and hepatic effects of hemodialysis and identify gaps in knowledge to date which require further study.

Effect of ultrafiltration during hemodialysis on hepatic and total-body water: an observational study.

BACKGROUND: The hepatic circulation is involved in adaptive systemic responses to circulatory stress. However, it is vulnerable to both chronic hypervolemia and cardiac dysfunction. The influence of hemodialysis (HD) and ultrafiltration (UF) upon liver water content has been understudied. We conducted a detailed pilot study to characterize the effects of HD upon liver water content and stiffness, referenced to peripheral fluid mobilization and total body water. METHODS: We studied 14 established HD patients without liver disease. Magnetic resonance imaging (MRI) together with ultrasound-based elastography and bioimpedance assessment were employed to measure hepatic water content and stiffness, body composition, and water content in the calf pre- and post-HD. RESULTS: Mean UF volume was 8.13 ± 4.4 mL/kg/hr. Fluid removal was accompanied with effective mobilization of peripheral water (measured with MRI within the thigh) from 0.85 ± 0.21 g/mL to 0.83 ± 0.18 g/mL, and reduction in total body water (38.9 ± 9.4 L to 37.4 ± 8.6 L). However, directly-measured liver water content did not decrease (0.57 ± 0.1 mL/g to 0.79 ± 0.3 m L/g). Liver water content and IVC diameter were inversely proportional (r = - 0.57, p = 0.03), a relationship which persisted after dialysis. CONCLUSIONS: In contrast to the reduced total body water content, liver water content did not decrease post-HD, consistent with a diversion of blood to the hepatic circulation, in those with signs of greater circulatory stress. This novel observation suggests that there is a unique hepatic response to HD with UF and that the liver may play a more important role in intradialytic hypotension and fluid shifts than currently appreciated.

High prevalence of elevated molybdenum levels in pediatric CKD patients. A cross-sectional and longitudinal study
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AIMS: Many of the secondary effects of high levels of molybdenum (Mo) overlap with symptoms commonly seen in pediatric patients with chronic kidney disease (CKD). We measured plasma Mo levels and examined the relationship between Mo levels and kidney function. MATERIALS AND METHODS: The study was carried out at the London Health Sciences Centre in London, Ontario, Canada with 36 children and adolescents 4 - 18 years of age with CKD. There were 1 - 6 trace element measurements (Mo and copper (Cu)) per patient. We studied the proportion of patients with abnormal trace element levels and the relationship between trace element levels and estimated glomerular filtration rate (eGFR), calculated using the Filler formula. Plasma Mo and Cu levels were measured using High Resolution Sector Field Inductively Coupled Mass Spectrometry. Anthropomorphic data and blood parameters were collected from our electronic chart program. RESULTS: Median eGFR was 51 mL/min/1.73m2 (35, 75). Median Mo level was 2.00 µg/L (1.40, 2.88). 20 patients had at least one set of Mo levels above the published reference interval in either unit, and the results of 46% of the tests were above the interval. There was a strong negative correlation between the Mo levels and the eGFR (Spearman's r = -0.627, p < 0.0001). CONCLUSIONS: Our study suggests that pediatric patients with CKD have elevated plasma levels of Mo, which may cause secondary effects commonly associated with CKD. The elevated Mo levels in our center's catchment area may cause an accumulation of this trace element in patients with impaired renal function.
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Plasmapheresis for the treatment of kidney diseases.

The purpose of this review is to examine the evidence supporting the application of plasma exchange in renal disease. Our review focuses on the following 6 most common renal indications for plasma exchange based on 2014 registry data from the Canadian Apheresis Group: (i) thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome; (ii) renal transplantation, (iii) anti-neutrophil cytoplasm antibodies-associated vasculitis, (iv) cryoglobulinemia, (v) focal segmental glomerulosclerosis, and (vi) Goodpasture syndrome. The rarity of these diseases and their rapid, often fatal course mean that randomized controlled studies of plasma exchange are rarely conducted. Although evidence from an adequately powered randomized controlled trial supports the use of plasma exchange to treat thrombotic thrombocytopenic purpura, the use of plasma exchange to treat other renal diseases is only supported by observational and mechanistic studies. Larger well-designed trials are needed to clarify the potential role of plasma exchange in renal disease. Growing international collaboration will improve the quality of future studies in this area.

Can the new CKD-EPI BTP-B2M formula be applied in children?

Although measuring creatinine to determine kidney function is currently the clinical standard, new markers such as beta-trace protein (BTP) and beta-2-microglobulin (B2M) are being investigated in an effort to measure glomerular filtration rate more accurately. In their recent publication, Inker et al. (Am J Kidney Dis 2015; 67:40-48) explored the use of these two relatively new markers in combination with some commonly available clinical characteristics in a large cohort of adults with chronic kidney disease. Their research led them to develop three formulae using BTP, B2M, and a combination of the two. The combined formula is particularly attractive as it removes all gender bias, which applies to both serum creatinine and cystatin C. Using data from a cohort of 127 pediatric patients from our center, we sought to determine whether these formulae would be equally as effective in children as in adults. Unfortunately, we found that the formulae cannot be applied to the pediatric population.

Euvolemia in hemodialysis patients: a potentially dangerous goal?

Dialysis patients have high mortality rate and the leading cause of death is cardiovascular disease. Uremic cardiomyopathy differs from that due to conventional atherosclerosis, where cardiovascular changes result in ineffective circulation and lead to tissue ischemia. Modern dialysis has significant limitations with fluid management probably the most challenging. Current evidence suggests that both volume overload and aggressive fluid removal can induce circulatory stress and multi-organ injury. Furthermore, we do not have accurate volume assessment tools. As a result, targeting euvolemia might result in more harm than benefit with conventional hemodialysis therapy. Therefore, it might be time to consider a degree of permissive over-hydration until we have better tools to both determine ideal weight and improve current renal replacement therapy so that the process of achieving it is not so fraught with the current dangers.

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 the intrapatient variability of mycophenolic acid trough levels?

TDM of MPA, the active compound of MMF, is rarely used despite its substantial intra- and interpatient variability. Little is known about the utility of long-term MPA TDM. Data are expressed as mean (one standard deviation). All available data from 27 renal transplant recipients (mean age at transplantation: 7.7 [5.0] yr) with an average follow-up of 9.3 (4.6) yr were analyzed. MPA levels were measured using the EMIT. GFR was measured using cystatin C and eGFR was calculated using the Filler formula. Intrapatient CV of the trough level was calculated as the ratio of the mean divided by one standard deviation. Mean cystatin C eGFR was 56.9 (24.4) mL/min/1.73 m(2) . There was a weak but significant correlation between the MPA trough level and the AUC (Spearman r = 0.6592, p < 0.0001). A total of 1964 MPA trough levels (73 [45]/patient) were measured, as compared to 3462 Tac trough levels (144 [71]/patient). The average MPA trough level was 3.01 (1.26) mg/L and the average trough Tac level was 7.3 (1.8) ng/mL. Intrapatient CV was statistically higher (p = 0.00093) for MPA at 0.68 (0.29) when compared to Tac with a CV of 0.46 (0.12). CV did not correlate with eGFR. Intrapatient MPA trough level CV is significantly higher than for Tac, while CV for both MPA and Tac was high. MPA trough level monitoring may be a feasible monitoring option to improve patient exposure and possibly outcomes.

Similar MPA exposure on modified release and regular tacrolimus.

Concomitant immunosuppression may affect the mycophenolate mofetil exposure. Astellas developed a once-daily modified release formulation of tacrolimus (TacMR) with the potential to reduce the likelihood of nonadherence. It is unknown whether mycophenolic acid (MPA) area under the concentration-time curve (AUC) differs between the 2 tacrolimus (Tac) formulations. In a 2-by-2 crossover design, 20 stable renal transplant recipients on twice-daily Tac either continued their usual Tac therapy (n = 10, group 1) or switched to TacMR for a 12-week period (n = 10, group 2), after which the patients crossed over to the other formulation for another 12-week period. Pharmacokinetic profiles using limited sampling strategies were obtained before randomization (visit 1), and at 12 (visit 2) and 24 weeks (visit 3) at steady state. MPA AUC was calculated using the Pawinski formula. When analyzing visits on Tac, TacMR, and back on Tac combined, the MPA AUC for all 20 patients at baseline was 42.24 (16.98), 37.18 (13.75), and 40.09 (16.69) mg·h·L(-1), respectively, which was not statistically significant using repeated measures (P = 0.1327, R(2) = 0.1109). We conclude that MPA pharmacokinetic profiles are not altered when converting patients from Tac to TacMR.

Tandem hemodialysis and plasma exchange.

The combination of hemodialysis and plasma exchange as one tandem procedure was first described in 1999 by Siami et al. (ASAIO J 45:229-233), but larger pediatric case series were not described until 2012. Even in adults, there are only limited case series. If performed in sequence, up to 8 h of treatment time may be required. With the use of the tandem procedure in stable patients, the same procedures can be completed during the same time as a routine hemodialysis, which is more convenient for patients and may reduce healthcare costs. Little is known about the utilization of the combination of hemodialysis and plasma exchange in children. The purpose of this review is to summarize the adult and scarce pediatric experience. The results of a survey carried out by the authors using the Internet listserver "PedNeph" to obtain an overview of the current practice patterns of pediatric nephrologists are also presented.

The (99m)Tc-DTPA urinary clearance method may be preferable to the plasma disappearance method for assessing glomerular filtration rate in diabetic nephropathy.

BACKGROUND: Isotopic glomerular filtration rate (iGFR) measurement is comparable to the inulin method. In this study, we compared urinary and plasma iGFR methodologies in patients with diabetic nephropathy. METHODS: A total of 147 patients from 3 sites in the Diabetic Intervention with Vitamins to Improve Nephropathy (DIVINe) trial provided 213 sets of urine and blood collections, at baseline, 18 and 36 months. RESULTS: The mean (with standard deviation) plasma iGFR of 60.7 (24.9) ml/min/1.73 m(2) compared to urinary iGFR of 52.0 (28.0) ml/min/1.73 m(2) was statistically significant (p value <0.001). Although plasma and urinary iGFRs were highly related (R(2) = 0.86), plasma iGFR increasingly overestimated urinary iGFRs at lower GFRs. In contrast to the cross-sectional analyses, the two measures of iGFR were weakly related (R(2) = 0.32) in regard to patients' change over 18 months of follow-up. CONCLUSION: Plasma iGFR may not be a suitable method for accurately measuring GFR in patients with advancing degrees of chronic kidney disease from diabetic nephropathy.

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.

Association between water intake, chronic kidney disease, and cardiovascular disease: a cross-sectional analysis of NHANES data.

BACKGROUND: Evidence from animal and human studies suggests a protective effect of higher water intake on kidney function and cardiovascular disease (CVD). Here the associations between water intake, chronic kidney disease (CKD) and CVD were examined in the general population. METHODS: We conducted a cross-sectional analysis of the 2005-2006 National Health and Nutrition Examination Survey. Non-pregnant adults with an estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m(2) who were not taking diuretics were included. Total water intake from foods and beverages was categorized as low (<2.0 l/day), moderate (2.0-4.3 l/day) and high (>4.3 l/day). We examined associations between low total water intake and CKD (eGFR 30-60 ml/min/1.73 m(2)) and self-reported CVD. RESULTS: Of 3,427 adults (mean age 46 (range 20-84); mean eGFR 95 ml/min/1.73 m(2) (range 30-161)), 13% had CKD and 18% had CVD. CKD was higher among those with the lowest (<2.0 l/day) vs. highest total water intake (>4.3 l/day) (adjusted odds ratio (OR) 2.52; 95% confidence interval (CI) 0.91-6.96). When stratified by intake of (1) plain water and (2) other beverages, CKD was associated with low intake of plain water: adjusted OR 2.36 (95% CI 1.10-5.06), but not other beverages: adjusted OR 0.87 (95% CI 0.30-2.50). There was no association between low water intake and CVD (adjusted OR 0.76; 95% CI 0.37-1.59). CONCLUSIONS: Our results provide additional evidence suggesting a potentially protective effect of higher total water intake, particularly plain water, on the kidney.

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.

The usefulness of cystatin C and related formulae in pediatrics.

Serum creatinine does not share the properties of an ideal marker of glomerular filtration rate (GFR) like inulin, but continues to be the most widely used endogenous marker of GFR. In the search of a better biomarker of GFR, the small molecular weight protein cystatin C has been introduced with features more similar to that of inulin, such as constant production and no non-renal elimination. However,it has not enjoyed widespread use despite its significantly improved diagnostic performance in the detection of impaired GFR and its independence of body composition. A variety of formulae based on either cystatin C or creatinine or both have been developed to estimate GFR. We summarize the currently used methods of GFR measurement, their limitations and analytical errors. The review also summarizes the history, features and the feasibility of cystatin C measurements as well as the most widely used formulae for the estimation of GFR in children. The diagnostic performance of the cystatin C derived eGFR formulae at various levels of GFR is also discussed. An eGFR formula derived from pooled studies analyzing both creatinine and cystatin C, and using a biology-based mathematical approach maybe advantageous.

Ustekinumab associated thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder. Plasma exchange therapy has been shown to significantly reduce mortality in patients with TTP. Here, we report a case of TTP associated with ustekinumab therapy after a period of 2-3 years. Ustekinumab, a monoclonal antibody that inhibits interleukin 12 and interleukin 23, is one of the newer treatments for psoriasis. Although our patient experienced a prolonged course of TTP requiring 1 month of daily plasma exchange therapy, he recovered and remains in remission after 6 months.

Treatment of Homozygous Familial Hypercholesterolemia With Evinacumab.

Patients with homozygous familial hypercholesterolemia (HoFH) have extremely elevated levels of low-density lipoprotein cholesterol (LDL-C), with premature atherosclerosis and aortic valve disease. Available drug treatments are inadequate, and even with serial apheresis, HoFH patients rarely achieve acceptable LDL-C levels. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 that lowers LDL-C via a novel receptor-independent mechanism. We describe an Ontario patient with HoFH who for 17 months has been treated with monthly infusions of evinacumab added to pre-existing statin, ezetimibe, and evolocumab therapy. Evinacumab in this HoFH patient was associated with markedly improved LDL-C levels and decreased frequency of apheresis.

Les patients atteints d'hypercholestérolémie familiale homozygote (HFH) présentent des taux extrêmement élevés de cholestérol à li-poprotéines de faible densité (C-LDL) avec une athérosclérose prématurée et une valvulopathie aortique. Les traitements médicamenteux disponibles sont inadéquats et, même avec un traitement par aphérèses en série, on obtient rarement des taux acceptables de C-LDL chez les patients atteints d'HFH. L'évinacumab, un anticorps monoclonal dirigé contre la protéine 3 de type angiopoïétine, réduit le taux de C-LDL par un nouveau mécanisme indépendant du récepteur. Nous décrivons le cas d'un patient ontarien atteint d'HFH traité par l'évinacumab pendant 17 mois à raison d'une perfusion mensuelle administrée en complément d'un traitement préexistant par une statine, l'ézétimibe et l'évolocumab. L'évinacumab a été associé chez ce patient à une amélioration marquée des taux de C-LDL et à une diminution de la fréquence des aphérèses.

Steroid-resistant acute allograft rejection in renal transplantation.

Steroid-resistant rejection after pediatric renal transplantation forms a rare but severe complication with a guarded prognosis particularly if this occurs late after transplantation. There is a paucity of data on how to manage these challenging rejection episodes, particularly in the pediatric literature. Mohan Shenoy et al. published a case series of 15 patients who were treated with anti-thymocyte globulin for steroid-resistant acute allograft rejection over a 15-year period in a single center in this issue of Pediatric Nephrology. While the results for the early rejection group were encouraging, the results in the eight patients with late rejection episodes after transplantation were unfavorable and afflicted with a high incidence of side-effects. Important diagnostic tools such as C4d staining of the renal transplant biopsy and the measurement of donor-specific antibodies were underutilized. The editorial reviews the importance of the differentiation between humoral and cellular rejection and the challenges of treating late antibody-mediated acute rejection in these patients. A multi-center approach is required to establish a registry of these events and ideally prospective randomized interventions should be designed to provide some evidence base for the management of this challenging complication after pediatric renal transplantation.

Residual renal function assessment with cystatin C.

Su Jin Kim and coworkers from Korea published an important study on the relationship of residual renal function (RRF) and cystatin in pediatric peritoneal dialysis (PD) patients in this issue of Pediatric Nephrology, both in anuric patients and patients with RRF. Based on a lack of correlation between cystatin C and standard small solute-based dialysis adequacy parameters such as Kt/Vurea but a significant correlation with RRF, the authors concluded that cystatin C may be a good tool to monitor RRF. The editorial reviews the available literature in adults, the different handing between urea and cystatin C, and the determinants of cystatin C clearance in dialysis patients. In adults, cystatin C levels are determined predominantly by RRF, but not exclusively. In anephric hemodialysis and PD patients, there is a correlation with standard weekly Kt/Vurea. Cystatin C levels will also depend on ultrafiltration. Despite these factors that affect cystatin C levels beyond RRF, cystatin C is a useful parameter for monitoring PD patients that may be more closely related to long-term outcomes than small solute adequacy parameters.