Mark R. Benfield

Fluid Overload and Mortality in Children Receiving Continuous Renal Replacement Therapy: The Prospective Pediatric Continuous Renal Replacement Therapy Registry

BACKGROUND Critically ill children with hemodynamic instability and acute kidney injury often develop fluid overload. Continuous renal replacement therapy (CRRT) has emerged as a favored modality in the management of such children. This study investigated the association between fluid overload and mortality in children receiving CRRT. STUDY DESIGN Prospective observational study. SETTING & PARTICIPANTS 297 children from 13 centers across the United States participating in the Prospective Pediatric CRRT Registry. PREDICTOR Fluid overload from intensive care unit (ICU) admission to CRRT initiation, defined as a percentage equal to (fluid in [L] - fluid out [L])/(ICU admit weight [kg]) x 100%. OUTCOME & MEASUREMENTS The primary outcome was survival to pediatric ICU discharge. Data were collected regarding demographics, CRRT parameters, underlying disease process, and severity of illness. RESULTS 153 patients (51.5%) developed < 10% fluid overload, 51 patients (17.2%) developed 10%-20% fluid overload, and 93 patients (31.3%) developed > or = 20% fluid overload. Patients who developed > or = 20% fluid overload at CRRT initiation had significantly higher mortality (61/93; 65.6%) than those who had 10%-20% fluid overload (22/51; 43.1%) and those with < 10% fluid overload (45/153; 29.4%). The association between degree of fluid overload and mortality remained after adjusting for intergroup differences and severity of illness. The adjusted mortality OR was 1.03 (95% CI, 1.01-1.05), suggesting a 3% increase in mortality for each 1% increase in severity of fluid overload. When fluid overload was dichotomized to > or = 20% and < 20%, patients with > or = 20% fluid overload had an adjusted mortality OR of 8.5 (95% CI, 2.8-25.7). LIMITATIONS This was an observational study; interventions were not standardized. The relationship between fluid overload and mortality remains an association without definitive evidence of causality. CONCLUSIONS Critically ill children who develop greater fluid overload before initiation of CRRT experience higher mortality than those with less fluid overload. Further goal-directed research is required to accurately define optimal fluid overload thresholds for initiation of CRRT.

Demographic Characteristics of Pediatric Continuous Renal Replacement Therapy: A Report of the Prospective Pediatric Continuous Renal Replacement Therapy Registry

BACKGROUND This article reports demographic characteristics and intensive care unit survival for 344 patients from the Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry, a voluntary multicenter observational network. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS Ages were newborn to 25 yr, 58% were male, and weights were 1.3 to 160 kg. Patients spent a median of 2 d in the intensive care unit before CRRT (range 0 to 135). At CRRT initiation, 48% received diuretics and 66% received vasoactive drugs. Mean blood flow was 97.9 ml/min (range 10 to 350 ml/min; median 100 ml/min); mean blood flow per body weight was 5 ml/min per kg (range 0.6 to 53.6 ml/min per kg; median 4.1 ml/min per kg). Days on CRRT were <1 to 83 (mean 9.1; median 6). A total of 56% of circuits had citrate anticoagulation, 37% had heparin, and 7% had no anticoagulation. RESULTS Overall survival was 58%; survival differed across participating centers. Survival was lowest (51%) when CRRT was started for combined fluid overload and electrolyte imbalance. There was better survival in patients with principal diagnoses of drug intoxication (100%), renal disease (84%), tumor lysis syndrome (83%), and inborn errors of metabolism (73%); survival was lowest in liver disease/transplant (31%), pulmonary disease/transplant (45%), and bone marrow transplant (45%). Overall survival was better for children who weighed >10 kg (63 versus 43%; P = 0.001) and for those who were older than 1 yr (62 versus 44%; P = 0.007). CONCLUSIONS CRRT can be used successfully for a wide range of critically ill children. Survival is best for those who have acute, specific abnormalities and lack multiple organ involvement; sicker patients with selected diagnoses may have lower survival. Center differences might suggest opportunities to define best practices with future study.

Changing trends in pediatric transplantation: 2001 Annual Report of the North American Pediatric Renal Transplant Cooperative Study

Abstract:  The North American Pediatric Renal Transplant Cooperative Study has collected clinical information on children undergoing a renal transplantation since 1987. This cooperative group now includes over 150 participating medical centers in the United States, Canada, Mexico, and Costa Rica. This report covers the years from 1987 through 2001 and includes data on 7545 renal transplants in 6878 patients. This report demonstrates changing trends in many areas of pediatric transplantation including increasing numbers of African American and Hispanic children receiving transplantation, remarkable improvements in the rate of acute rejection, rejection reversal, and short‐ and long‐term allograft survival. In the most recent cohorts of patients, we now see that 1‐yr allograft survival is no different in cadaver donor compared to living donor recipients and in infants compared to all other age groups. However, this analysis also reveals areas of continued challenges including inferior outcomes in African American and adolescent populations, chronic rejection, and the adverse effects of immunosuppression.

The 1997 Annual Renal Transplantation in Children Report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)

Abstract: This report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), covering the years 1987–96 (January 15, 1997), analyzed data on 4898 patients who received 5362 transplants. Over the 10 yr of the study, 21.3% of the patients were under the age of 6 yr. Of the disorders that lead to end‐stage renal disease (ESRD), structural and developmental anomalies of aplasia, dysplasia, and obstructive uropathy accounted for over 1500 patients. Despite the potential therapies for focal segmental glomerulosclerosis (FSGS), there has been little change in its incidence and this lesion continues to be the most common cause of renal failure and transplantation among acquired diseases. Eighty‐nine per cent of patients with a functioning graft continue to receive cyclosporin A (CsA) 5 yr post‐transplantation, and 84% of patients continue to receive azathioprine (AZA), whereas 26% of patients receive alternate‐day steroid therapy at 4 yr post‐transplant. Thirty‐seven per cent of the living donor (LD) recipients and 47% of cadaver donor (CD) recipients were treated with the polyclonal T‐cell antibody ATG/ALG for induction, and the monoclonal T‐cell antibody, OKT3, was utilized for induction in 12% of LD patients and in 19% of CD patients. Twenty‐five per cent of the 5362 transplants (1333) have failed over the 10‐yr period. Graft survival is 90% at 1 yr and 74% at 6 yr for LD kidneys, and is 80% at 1 yr and 58% at 6 yr for CD patients. The most common cause for graft failure (30%) is chronic rejection. For recipients of LD grafts, relative risk (RR) factors for graft survival are African–American race (RR = 2.1, p<0.001) and greater than five prior transfusions (RR = 1.6, p<0.001). Prophylactic anti‐T‐cell antibody reduces the risk of graft failure (RR = 0.76, p=0.009). For recipients of cadaver kidneys, risk factors are: recipient age < 2 yr (RR = 2, p<0.001), donor age < 6 yr (RR = 1.3, p=0.005), and absence of induction T‐cell antibody (RR = 1.31, p<0.001).

Pediatric hemofiltration: Normocarb dialysate solution with citrate anticoagulation

Abstract Fourteen children, newborn to 17 years of age, underwent continuous veno-venous hemofiltration with dialysis (CVVHD), using a new FDA-approved bicarbonate-based calcium-free dialysis solution (Normocarb) in combination with citrate anticoagulation. Dialysis prescription included use of the PRISMA system (Gambro, Lakewood, Colo., USA), with ACD-A (Baxter, Deerfield, Ill., USA) for anticoagulation and Normocarb (Dialysis Solution, Richmond Hills, Ontario, Canada) for dialysate. Diagnosis included 11 children with sepsis and 3 children with tumor lysis syndrome. Mean weight was 31.6±4.7 kg (range 3.7–62 kg) and average length of therapy was 11.4±3.7 days (range 6 h to 67 days). Length of circuit patency was 71.3±7.2 h (range 6 h to 127 h), which was influenced in part by a decision to change circuits at 72 h as per manufacturer’s recommendation. No bleeding occurred. This protocol utilizes industry-manufactured CVVHD machinery with both thermic and ultrafiltration control, with an effective anticoagulation protocol, and industry-produced bicarbonate dialysate. The use of industry machinery and solutions allows for consistent industrial quality assurance standards. This potentially may decrease the cost of therapy and minimize the risk of pharmacy errors that can occur with pharmacy-made dialysis solutions.

Metabolic Abnormalities, Cardiovascular Disease Risk Factors, and GFR Decline in Children with Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Metabolic abnormalities and cardiovascular disease (CVD) risk factors have rarely been systematically assessed in children with chronic kidney disease (CKD). We examined the prevalence of various CKD sequelae across the GFR spectrum. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Data were used from 586 children participating in the Chronic Kidney Disease in Children (CKiD) study (United States and Canada) with GFR measured by iohexol plasma disappearance. Laboratory values and CVD risk factors were compared across GFR categories and with an age-, gender-, and race-matched community sample. RESULTS CKiD participants were 62% male, 66% Caucasian, 23% African American, and 15% Hispanic with a median age of 11 years and a median GFR of 44 ml/min per 1.73 m(2). Compared with those with a GFR ≥ 50 ml/min per 1.73 m(2), having a GFR < 30 ml/min per 1.73 m(2) was associated with a three-fold higher risk of acidosis and growth failure and a four- to five-fold higher risk of anemia and elevated potassium and phosphate. Median GFR change was -4.3 ml/min per 1.73 m(2) and -1.5 ml/min per 1.73 m(2) per year in children with glomerular and nonglomerular diagnoses, respectively. Despite medication and access to nephrology care, uncontrolled systolic hypertension was present in 14%, and 16% had left ventricular hypertrophy. Children with CKD frequently were also shorter and had lower birth weight, on average, compared with norms. CONCLUSIONS Growth failure, metabolic abnormalities, and CVD risk factors are present at GFR >50 ml/min per 1.73 m(2) in children with CKD and, despite therapy, increase in prevalence two- to four-fold with decreasing GFR.

Complete Steroid Avoidance Is Effective and Safe in Children With Renal Transplants: A Multicenter Randomized Trial With Three‐Year Follow‐Up

To determine whether steroid avoidance in pediatric kidney transplantation is safe and efficacious, a randomized, multicenter trial was performed in 12 pediatric kidney transplant centers. One hundred thirty children receiving primary kidney transplants were randomized to steroid‐free (SF) or steroid‐based (SB) immunosuppression, with concomitant tacrolimus, mycophenolate and standard dose daclizumab (SB group) or extended dose daclizumab (SF group). Follow‐up was 3 years posttransplant. Standardized height Z‐score change after 3 years follow‐up was –0.99 ± 2.20 in SF versus –0.93 ± 1.11 in SB; p = 0.825. In subgroup analysis, recipients under 5 years of age showed improved linear growth with SF compared to SB treatment (change in standardized height Z‐score at 3 years –0.43 ± 1.15 vs. –1.07 ± 1.14; p = 0.019). There were no differences in the rates of biopsy‐proven acute rejection at 3 years after transplantation (16.7% in SF vs. 17.1% in SB; p = 0.94). Patient survival was 100% in both arms; graft survival was 95% in the SF and 90% in the SB arms (p = 0.30) at 3 years follow‐up. Over the 3 year follow‐up period, the SF group showed lower systolic BP (p = 0.017) and lower cholesterol levels (p = 0.034). In conclusion, complete steroid avoidance is safe and effective in unsensitized children receiving primary kidney transplants.

Safety of kidney biopsy in pediatric transplantation: a report of the Controlled Clinical Trials in Pediatric Transplantation Trial of Induction Therapy Study Group.

BACKGROUND Historically, young children undergoing renal transplantation have lower allograft survival than adults, and potential causes of this are being addressed by the North American Pediatric Renal Transplant Cooperative Study through the National Institutes of Health-sponsored study Cooperative Clinical Trials in Pediatric Transplantation. Included in this study is evaluation of surveillance renal biopsies (SB) and clinically indicated biopsies (CB). Few data exist in children to identify the risk involved with renal transplant biopsies. METHODS Questionnaires were mailed to 21 participating centers asking for descriptions of adverse events associated with kidney biopsies, with choices limited to none, gross hematuria, perinephric hematoma, and other. Further clinical details were obtained from review of medical records of all patients with reported adverse events. Data were collected from 19 centers on 126 patients. RESULTS Eighty-six patients had undergone 212 biopsies (75 SB and 137 CB). Nine biopsy-related adverse events were reported (4.2%): three SB (4.0%) and six CB (4.4%). Gross hematuria was reported in six patients (2.8%): two SB (2.7%) and four CB (2.9%). A perinephric hematoma was reported in one patient. Two patients with intraperitoneal kidneys developed significant bleeding after biopsy and required transfusions and surgical exploration. No patient lost kidney function or required nephrectomy after biopsy. No difference was noted in adverse events between SB at day 5 or 12 versus CB. CONCLUSION Evaluation of transplanted kidney tissue may provide important information for the care of the transplantation patient. This analysis suggests that transplanted kidney biopsies can be performed with minimal risks in pediatric patients.

Treatment of IgA nephropathy in children: efficacy of alternate-day oral prednisone

We have previously reported our experience with the use of alternate-day prednisone in the treatment of 6 patients with IgA nephropathy who have clinical or pathological risk factors for disease progression. We have now treated a total of 13 patients and followed them from 4 to 10 years. Patients received an alternate-morning dose of prednisone for 2–4 years. Dosage began at 60 mg/m2 for 3 month, was reduced to 30 mg/m2 by 1 year and 15 mg/m2 by 2 years. At last observation, urinary protein excretion was normal in 12 patients and no patient had hematuria. Twelve patients had normal estimated glomerular filtration rate (GFR) and one had renal insufficiency (GFR=38 ml/min per 1.73 m2). A renal biopsy was performed in 11 patients after 2 years of treatment. Activity score decreased from 5.2 to 4.3 (P=0.03) and chronicity score increased from 2.2 to 2.8 (P=0.12). There were no complications of treatment. When compared with a historical group, the treated patients had a significant improvement in urinalysis (P<0.00001) and preservation of normal GFR (P=0.03). We conclude that alternate-day prednisone therapy may benefit patients with IgA nephropathy. A large prospective controlled trial is needed.

The effect of vascular access location and size on circuit survival in pediatric continuous renal replacement therapy: a report from the PPCRRT registry.

Purpose Well-functioning vascular access is essential for the provision of adequate CRRT However, few data exist to describe the effect of catheter size or location on CRRT performance in the pediatric population. Methods Data for vascular access site, size, and location, as well as type of anticoagulant used and patient demographic data were gathered from the ppCRRT registry. Kaplan-Meier curves were generated and then analyzed by log-rank test or Cox Proportional Hazards model. Results Access diameter was found to significantly affect circuit survival. None of the 5 French catheters lasted longer than 20 hours. Seven and 9 French, but not 8 French, catheters fared worse than larger diameter catheters (p=0.002). Circuits associated with internal jugular access survived longer than subclavian or femoral access associated circuits (p<0.05). Circuit survival was also found to be favorably associated with the CVVHD modality (p<0.001). Conclusions Functional CRRT circuit survival in children is favored by larger catheter diameter, internal jugular vein insertion site and CVVHD. For patients requiring catheter diameters less than 10 French, CRRT circuit survival might be optimized if internal jugular vein insertion is feasible. Conversely, when a vascular access site other than the internal jugular vein is most prudent, consideration should be given to using the largest diameter catheter appropriate for the size of the child. The CVVHD modality was associated with longer circuit survival, but the mechanism by which this occurs is unclear.