The effect of increased frequency of hemodialysis on serum cystatin C and ß2-microglobulin concentrations: A secondary analysis of the frequent hemodialysis network (FHN) trial.

INTRODUCTION: Small molecular weight toxin clearance is the main method of assessment of hemodialysis efficiency. Middle molecules including cystatin C (CysC) and Beta-2 microglobulin (ß2-M) are understudied. We hypothesized that lowering of predialysis CysC and ß2-M serum concentrations would be affected by switching to more frequent hemodialysis. METHODS: Predialysis CysC and ß2-M serum concentrations were measured from serum samples of the Frequent Hemodialysis Network (FHN) Daily and Nocturnal Trials. The differences between predialysis concentrations at baseline (while on conventional thrice weekly dialysis) and those after 12-months of study (on more frequent dialysis) were compared separately by trial (Nocturnal, Daily). We tested the associations between predialysis serum CysC and ß2-M concentrations and outcomes. FINDINGS: Forty-nine percent and 52% of the patients from the FHN Daily and Nocturnal Trials respectively were included in this ancillary study. Predialysis serum CysC concentrations remained unchanged after intensifying hemodialysis dose by either modality. There was significant lowering of the serum ß2-M concentrations in the frequent Daily Trial hemodialysis group at 12 months in all patients and in patients without residual renal function at baseline (-3.8 ± 12.62 µg/mL, P = 0.004; -5.9 ± 12.99 µg/mL, P = 0.02, respectively). There were no significant differences between the baseline and the 12-months predialysis ß2-M serum concentrations in the two control groups (Daily 3× and Nocturnal 3× groups). No association between the changes in the two biomarkers between baseline and 12-months and in changes in left ventricular mass, physical-health composite scores, hospitalization rate, and death were found. The numbers of hospitalizations and deaths were small. DISCUSSION: ß2-M may be a better biomarker of dialysis dose than CysC. Reduction in the concentration of potentially toxic long-lived proteins of the size of ß-2M is one potential long-term benefit of more intensive dialysis that may be explored.

A cross-sectional study measuring vanadium and chromium levels in paediatric patients with CKD.

OBJECTIVES: Although many secondary effects of high levels of vanadium (V) and chromium (Cr) overlap with symptoms seen in paediatric patients with chronic kidney disease (CKD), their plasma V and Cr levels are understudied. DESIGN: Ancillary cross-sectional study to a prospective, longitudinal, randomised controlled trial. SETTING: Children's Hospital of Western Ontario, London Health Sciences Centre, London, Ontario, Canada. PARTICIPANTS: 36 children and adolescents 4-18 years of age with CKD. INTERVENTIONS: 1-6 trace element measurements per patient. Cystatin C (CysC) estimated glomerular filtration rate (eGFR) was calculated using the Filler formula. Plasma V and Cr levels were measured using high-resolution sector field inductively coupled mass spectrometry. Anthropomorphic data and blood parameters were collected from our electronic chart programme. Water Cr and V data were obtained from the Ontario Water (Stream) Quality Monitoring Network. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes: plasma Cr and V. SECONDARY OUTCOMES: age, season, CysC, CysC eGFR, and Cr and V levels in environmental water. RESULTS: The median (IQR) eGFR was 51 mL/min/1.73 m2 (35, 75). The median V level was 0.12 µg/L (0.09, 0.18), which was significantly greater than the 97.5th percentile of the reference interval of 0.088 µg/L; 32 patients had at least one set of V levels above the published reference interval. The median Cr level was 0.43 µg/L (0.36, 0.54), which was also significantly greater than the established reference interval; 34 had at least one set of Cr levels above the published reference interval. V and Cr levels were moderately correlated. Only some patients had high environmental exposure. CONCLUSIONS: Our study suggests that paediatric patients with CKD have elevated plasma levels of V and Cr. This may be the result of both environmental exposure and a low eGFR. It may be necessary to monitor V and Cr levels in patients with an eGFR <30 mL/min/1.73 m2. TRIAL REGISTRATION NUMBER: NCT02126293; HC#172241.

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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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.

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.

Plasma exchange for kidney disease: what is the best evidence?

Therapeutic plasma exchange (TPE) has been used as adjunctive therapy for various kidney diseases dating back to the 1970s. In many cases, support for TPE was on mechanistic grounds given the potential to remove unwanted large molecular-weight substances such as autoantibodies, immune complexes, myeloma light chains, and cryoglobulins. More recently, growing evidence from randomized controlled trials, meta-analyses, and prospective studies has provided insights into more rational use of this therapy. This report describes the role of TPE for the 6 most common kidney indications in the 2013 Canadian Apheresis Group (CAG) registry and the evidence that underpins current recommendations and practice. These kidney indications include thrombotic microangiopathy, antiglomerular basement membrane disease, anti-neutrophil cytoplasmic antibody-associated vasculitis, cryoglobulinemia, recurrence of focal and segmental glomerulosclerosis in the kidney allograft, and kidney transplantation.

N-acetylcysteine rescue protocol for nephrotoxicity in children caused by ifosfamide.

Nephrotoxicity is a serious side effect associated with ifosfamide use. It can affect up to 30% of children who are treated with this chemotherapeutic drug, and treatment may necessitate lifelong supplementations, renal dialysis, renal transplant, and in severe cases may result in death. The antioxidant n-acetylcysteine is a promising strategy for mitigating this renal toxicity. It is currently used in children for acetaminophen overdose in the 21-hour IV protocol, a dose which has also been suggested to provide renal protection against ifosfamide. Of significance, both in vitro and in vivo studies suggest n-acetylcysteine does not interfere with the antitumor actions of ifosfamide. Most importantly, n-acetylcysteine has successfully protected against ifosfamide-induced nephrotoxicity in both cell and rodent models, as well as in several paediatric cases, suggesting it should be evaluated as a treatment option for children on ifosfamide who present with renal dysfunction. The purpose of this paper is to outline strategies and recommendations for treating patients at risk or suffering from nephrotoxicity during ifosfamide therapy. These recommendations may be used when deciding who to treat, how and when to treat, as well as several considerations when exact recommendations cannot be met. They have been created to increase both the quality of care and quality of life of paediatric oncology patients.

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.

Performance of the creatinine-based and the cystatin C-based glomerular filtration rate (GFR) estimating equations in a heterogenous sample of patients referred for nuclear GFR testing.

Cystatin C may be a more accurate marker of the glomerular filtration rate (GFR) than creatinine. We evaluated the performance of the creatinine-based abbreviated modification of diet in renal disease (MDRD), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, and 6 cystatin C-based equations in estimating GFR (eGFR) in a heterogeneous sample of patients. Measured GFR (mGFR) was obtained from the plasma clearance of 99mtechnetium Diethylenetriaminepentaacetic acid in 42 adult patients referred for nuclear GFR testing (January to March 2008). We evaluated the bias, precision, and accuracy of the abbreviated MDRD, CKD-EPI, Filler, Grubb, Hoek, Larsson, Le Bricon, and Rule eGFR equations. Participants had a mean mGFR of 70.9 mL/min/1.73 m2 (range: 22-125 mL/min/1.73 m2), a median age of 57 years (interquartile range: 45, 66), were 62% male, and were 38% liver transplant recipients. Correlation coefficients between eGFRs and mGFR ranged from 0.65 to 0.87 (each P<0.001). The cystatin C-based Hoek equation had the best overall performance with a low bias (-1.4 mL/min/1.73 m2), good precision (13.3 mL/min/1.73 m2), and greatest accuracy, with 93% of values within 30% of mGFR. Although the CKD-EPI equation had the lowest bias (-0.6 mL/min/1.73 m2), it had poor precision (20.7 mL/min/1.73 m2) and low accuracy, with only 69% of values within 30% of mGFR. The Hoek equation remained accurate and had the least bias when patients were grouped according to the history of liver transplantation and the mGFR above or below 60 mL/min/1.73 m2. In this heterogeneous sample, the cystatin C-based Hoek equation performed the best overall, regardless of mGFR level or history of liver transplantation.

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.

Cystatin C reduction ratio depends on normalized blood liters processed and fluid removal during hemodialysis.

BACKGROUND AND OBJECTIVES: A negative correlation between the weekly standard Kt/V (urea) and serum cystatin C level (CysC) in functionally anephric dialysis patients has been previously demonstrated. Our objective was to measure the per dialysis CysC reduction ratio (CCRR) and to compare it with other indices of dialytic functions. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a pilot cross-sectional study of 15 functionally anephric patients on conventional high-flux high-efficiency hemodialysis three times per week, CysC levels were drawn pre-, mid-, and postdialysis over 1 week. CCRR was compared with single-pool Kt/V (Sp Kt/V) using urea kinetic modeling, urea reduction ratio (URR), creatinine reduction ratio (CRR), normalized liters processed (LP/kg), and ultrafiltration volume (UF). Normally distributed data (Shapiro-Wilks test) were described as mean±SD, otherwise as median and interquartile range. RESULTS: The mean pre- and post-CysC levels were 6.0±1.0 and 4.7±1.1 mg/L. The Sp Kt/V and Std Kt/V were 1.5±0.2 and 2.6. The URR, CRR, and CCRR were 70.2%±9.0%, 64.5%±8.2%, and 26.1%±11.8%, respectively. There was no correlation between the CCRR, and the Sp Kt/V, URR, and CRR, whereas CCRR correlated with LP/kg and UF. Multiple regression analysis with these two parameters provided a model that explained 81% of the variance. CONCLUSIONS: Our data suggest that normalized liters processed and ultrafiltration volume explain most of the variance of CCRR. Therefore, CCRR may be an excellent method to monitor dialysis efficiency of low molecular weight proteins.

Hyperfiltration affects accuracy of creatinine eGFR measurement.

BACKGROUND AND OBJECTIVES: Surrogate markers such as creatinine, cystatin C (CysC), and beta trace protein (BTP) have been used to estimate GFR (eGFR). The accuracy of eGFR may be altered with hyperfiltration and differences in filtration fraction (FF). It is hypothesized that the accuracy of creatinine for eGFR may be affected by hyperfiltration and different effective renal plasma flow (ERPF). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 127 pediatric patients with various renal diseases underwent simultaneous measurements of GFR using 51Cr-EDTA renal scan and ERPF (131I-hippurate clearance) to calculate the FF (FF=GFR/ERPF). The eGFRs were calculated using the commonly used Schwartz (creatinine), Filler (CysC), and Benlamri (BTP) formulas. Agreement of the eGFRs with the measured isotope GFRs was assessed by Bland-Altman plots. Correlation analysis was performed using nonparametric tests to compare FF with eGFR-GFR. RESULTS: The 127 children at a median age (with 25th percentile, 75th percentile) of 11.9 (8.5, 14.9) years had a mean 51Cr EDTA-GFR of 100.6±32.1 ml/min per 1.73 m2 and a median 131I-hippurate clearance (ERPF) of 588 (398,739) ml/min per 1.73 m2. Mean FF was 17.7±4.5% with no correlation between the FF and the error (eGFR-GFR) for CysC and BTP eGFR, whereas there was a significant negative correlation between the error for Schwartz eGFR and FF. CONCLUSIONS: There is a significant negative correlation between the error for the Schwartz eGFR and the FF. CysC and BTP are not affected by differences in FF.

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.

Progress in pediatric kidney transplantation.

This review summarizes the focus shift from ischemia-reperfusion injury and avoidance of rejection to long-term outcome after pediatric renal transplantation over the past decade. Although there has been excellent 1-year graft and patient survival, low rejection rates can be achieved with modern immunosuppression after pediatric renal transplantation, and patient survival is improved substantially in comparison with dialysis, pediatric renal transplant recipients experience a high prevalence of infections, malignancies, medication side effects, nonadherence, and, most importantly, cardiovascular morbidity and mortality. Additional challenges occur because of a high prevalence of obesity after transplantation and vascular calcifications. There is also in an underappreciation of chronic kidney disease (CKD) in transplant recipients. The etiology of CKD is multifactorial and can affect graft and patient survival. The rigors of treatment for CKD are less compared with CKD in nontransplant recipients. Almost all immunosuppressive drugs are implicated with a risk of hypertension, hyperlipidemia, and diabetogenicity, all of which contribute to cardiovascular morbidity. Corticosteroids exhibit the most substantial risk and also stunt growth. Effective new treatment protocols such as the recent European Tacrolimus and WIthdrawal of STeroids (TWIST) study with rapid steroid withdrawal after 5 days provide promising results without increasing the rejection risk. The shift in focus on long-term complications allows for improved graft outcome. Side effects of immunosuppressive medications require continued attention to further improve long-term outcomes.