Commentary From the Section on Pediatric Nephrology

Commentary From the Section on Pediatric Nephrology

The American Academy of Pediatrics (AAP) founded the Section on Nephrology (SONp) in 1977. The mission of the SONp is to improve the health and well-being of infants, children, and adolescents with disorders of the kidneys and urinary tract and hypertension. SONp provides educational information and opportunities for the pediatric medical community, patients, and families; promotes pediatric nephrology as a career among medical students and pediatric residents; provides expert recommendations for AAP programs, policy, and other public materials; and advocates for those who provide and require pediatric nephrology care.

Members of the SONp collaborated on a thematic review of the seminal nephrology articles published in Pediatrics over the last 75 years. We agreed on 3 developmental themes in the evolution of the subspecialty beginning with visionaries who contributed to the following 3 domains: Fluid and Electrolyte Provision in Parenteral Fluid Therapy; Pediatric Kidney Diseases: from Clinical Descriptions to Practice Guidelines; and Renal Replacement Therapy. Pediatric Nephrology today has built on these foundations of knowledge to apply the most sophisticated methods of prevention and treatment to the care of our children with disorders of the kidney.

Special acknowledgment to Robert Chevalier, MD, FAAP; Vikas Dharnidharka, MD, MPH, FAAP; Suzanne Kirkwood, MS; Victoria Norwood, MD, FAAP; and George Schwartz, MD, for their review of and input into the development of these commentaries.

Fluid and Electrolyte Provision in Parenteral Fluid Therapy

Manju Chandra, MD, FAAP¹, Frederick Kaskel, MD, PhD, FAAP, FASN²

Affiliations: ¹New York University Long Island School of Medicine, Mineola, NY; ²Albert Einstein College of Medicine, Bronx, NY, USA

Highlighted Articles From Pediatrics

1. Holliday MA, Segar WE. The maintenance need for water in parenteral fluid therapy. Pediatrics. 1957;19(5):823-832
2. Moritz ML, Ayus JC. Prevention of hospital acquired hyponatremia: a case for using isotonic saline. Pediatrics. 2003;111(2):227-230
3. Feld LG, Neuspiel DL, Byron AF, et al. Clinical practice guideline: maintenance intravenous fluids in children. Pediatrics. 2018;142(6):e20183083
4. Holliday M. Isotonic saline expands extracellular fluid and is inappropriate for maintenance therapy. Pediatrics. 2005;115(1):193-194

In 1957, Holliday and Segar¹ published a simple formula to estimate parenteral maintenance water and electrolyte needs in children based on sound physiologic principles. This formula indexed daily maintenance fluid needs to daily caloric expenditure as a function of a child’s body mass.

The proposed formula estimated caloric expenditure to be 100 kcal/kg for an infant who weighed 3 to 10 kg; 1,000 kcal plus 50 kcal/kg for each kg over 10 kg for a child who weighed between 10 to 20 kg; and 1,500 kcal plus 20 kcal/kg for each kg over 20 kg for a child who weighed >20 kg. The average daily maintenance water requirement was proposed to be 100 mL/100 kcal that allowed for replacement of insensible water loss (40 mL/100 kcal) and for replenishment of obligatory urine water loss (∼60 mL/100 kcal) assuming urinary excretion of an average renal solute load at a concentration of 300 mOsm/L. The authors chose an iso-osmolar urine as an average, because healthy kidneys can excrete urine with a wide range of osmolarity, from 75 to 1,200 mOsm/L. Daily maintenance sodium, potassium, and chloride needs were estimated to be 3, 2, and 2 mEq per 100 kcal, respectively. The authors acknowledged that these specifications may exceed actual minimum requirements because human milk only provides 1 mEq of sodium/100 kcal. In the second paragraph of their conclusion, the authors cautioned, “With respect to the general applicability of the average figures for water intake per 100 calories, it is evident that specific clinical situations dictate alterations,” because they had developed the calculations in consideration of otherwise healthy hospitalized children who were recovering from diarrheal dehydration.

Although clinicians for decades have widely used this formula to estimate maintenance fluid and electrolyte requirements for hospitalized patients, they have at times ignored the authors’ advice to exercise caution and to individualize requirements. As a result, sick patients have developed acute hyponatremia. The hyponatremia occurs both from excessive free water administration and retention as well as a secondary natriuresis induced by expansion of plasma volume. Acute hyponatremia has resulted in brain damage and death in previously well children who were hospitalized for acute illness or elective surgery.

In order to prevent hyponatremia from fluid therapy in sick patients, a key paper by Moritz et al argued to replace hypotonic solutions with isotonic saline as the standard maintenance fluid.² After 15 years of accumulating evidence, the AAP incorporated this recommendation in a 2018 clinical guideline.³

Many sick patients are unable to excrete urine at 300 mOsm/L due to either non-osmotic release of antidiuretic hormone due to nausea, vomiting, anesthesia, pain, or drugs or due to decreased effective intravascular volume secondary to fluid losses or to third spacing into the interstitial fluid compartment. Hence, “maintenance”-free water administration of 60 mL/100 kcal to replace water loss associated with renal solute load excretion assuming an iso-osmolar urine exceeds true needs in sick or postoperative patients who excrete hyperosmolar urine. It is noteworthy that a sick person who has nausea, vomiting, or pain, situations accompanied with non-osmotic ADH release and a low output of concentrated urine, will spontaneously not want to drink much and thus imbibe a lower than the usually calculated “maintenance” fluid volume. However, when a similar sick hospitalized patient receives parenteral fluids, total daily fluids administered may exceed actual needs even when limited to “maintenance” needs.

In a letter to the editor in 2005, Holliday expressed concern that use of 0.9% saline rather than standard 0.25% saline for meeting maintenance fluid needs can result in fluid overload and the development of hypertension. He emphasized that in patients with severe dehydration, septic shock, or burns, initial rapid correction of intravascular volume with infusion of 60-100 mL/kg of 0.9% saline in the first 2 to 4 hours will restore circulation to the kidneys and also turn off extracellular fluid depletion-induced stimulus for ADH release. Afterwards, hypotonic fluids can be infused with a volume tailored to the individual’s requirements to replace insensible water loss and urinary losses.⁴ While isotonic fluids are currently the mainstay of intravenous hydration, the original comment by Holiday and Segar¹ that fluid and electrolyte therapy should be tailored to the specific patient’s needs remains as true today as when they first introduced their formula.

Pediatric Kidney Diseases: From Clinical Descriptions to Practice Guidelines

William A. Primack, MD, FAAP¹, Kevin V. Lemley, MD, PhD²

Affiliations: ¹University of North Carolina Kidney Center, Chapel Hill, NC; ²University of Southern California Keck School of Medicine, Los Angeles, CA

Highlighted Articles From Pediatrics

1. Barness LA, Moll GH, Janeway CA. Nephrotic syndrome I. Natural history of the disease. Pediatrics. 1950;5(3):486-503
2. Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics. 1976;58(2):259-263
3. Hogg RJ, Furth S, Lemley KV, et al. National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, and stratification. Pediatrics. 2003; 111(6):1416-1421
4. Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics. 2017;140(3):e20171904

In this commentary, we highlight 4 publications in Pediatrics that illustrate an evolution from clinical descriptions of disease¹ to quantification of functional kidney measures² to the systematization of evaluation and treatment for pediatric kidney diseases and hypertension.^3,4

In 1950, Barness et al¹ reviewed the natural history of 449 nephritic and nephrotic children cared for at a single hospital from 1926 until 1948, in the eras before and after the introduction of antibiotics, and before the availability of corticosteroids. They observed a 33% mortality rate (mostly from infection) in the 208 patients with pure nephrotic syndrome (lipoid nephrosis) and an approximate 50% mortality (often from kidney failure) in patients with chronic glomerulonephritis. They found that no treatment was clearly effective, although striking and mostly short-term remission of nephrotic syndrome occurred in most children who were therapeutically inoculated with measles virus. Notably, patient mortality rates appeared to fall after the introduction of antibiotic therapies in the early 1940s. They commented, “Few diseases tax the resources of the practitioner so extensively as the nephrotic syndrome. He must be a combination of infectious disease expert, nutritionist, physiologist, and psychiatrist for the patient and, above all, guide, counsellor, and friend to the parents, who have to live, day in and day out, for two or three years with a child who eats poorly and often has periods of irritability or depression, who frequently vomits or has diarrhea, whose appearance may become grotesque at times, and who may become desperately sick with peritonitis and bacteremia at any moment. On the other hand, the satisfaction of seeing a patient restored to normal health and activity after several years of nephrotic edema is well worth the time and patience required.”

Once studies had shown the efficacy of ACTH and later prednisone in the treatment of corticosteroid-sensitive nephrosis (minimal change nephrotic syndrome), patient outcomes improved dramatically, and emphasis turned to the study and treatment of chronic kidney disease (CKD). Following the progression of CKD required the accurate estimation of kidney function. In 1976, Schwartz et al² correlated serum creatinine values with the gold standards for determining glomerular filtration rate (GFR), urinary creatinine clearance or inulin clearance, and also developed a simple formula to estimate GFR (eGFR) based on measured patient height and serum creatinine. Use of an updated version of the Schwartz formula is now standard practice in pediatrics. This has allowed clinicians to identify CKD early and to follow serial measurements of eGFR to assess functional progression of disease, as well as to guide dosing of medications in patients with kidney dysfunction.

In 2003, Hogg et al reported the National Kidney Foundation Clinical Practice Guidelines for evaluation and care of children with CKD³ based on a systematic review and analysis of the literature. The goal of these guidelines was to provide “practical guidance for the evaluation of kidney function by healthcare providers who encounter children and adolescents in their practices,” to allow early identification of CKD in children to optimize their care, for example by addressing treatable co-morbid conditions such as hypertension or hyperlipidemia. This seminal publication defined the 5 stages of progressive CKD, based in part on the Schwartz equation, and outlined a standardized clinical diagnostic approach (action plan) for each stage. The presence of CKD depends on evidence of kidney damage (eg, quantitative proteinuria) or a decreased level of kidney function, as indicated by eGFR. CKD is broadly defined in children 2 years or older as an eGFR <60 mL/min/1.73 m² body surface area for 3 months or more (K/DOQI stage 3), or other signs of kidney damage, such as abnormal ultrasound imaging, abnormal proteinuria, or hypertension. The publication describes 6 specific guidelines, including how to determine the stage of CKD, how to estimate GFR, and how to assess proteinuria and other markers of CKD. Knowledge of the CKD stage may also help practitioners focus on dosage adjustment or avoidance of specific medications, as well as on appropriate referral to a specialty center for patients at increased risk of progression to end-stage kidney failure. The appropriate approaches are further distinguished between children who “appear to be free of any risk factors for CKD” and those who are at increased risk of CKD by virtue of a history of diabetes or a family or personal history of kidney disease.

Barness noted that hypertension could be a manifestation of CKD.¹ In 2017, Flynn et al published clinical practice guidelines for the evaluation and management for hypertension in children and adolescents.⁴ These guidelines updated the 2004 pediatric hypertension guidelines that also were published in Pediatrics. The goal of the guidelines, which the American Heart Association endorses, is to “foster a patient- and family-centered approach to care, reduce unnecessary and costly medical interventions, improve patient diagnoses and outcomes, support implementation, and provide direction for future research.” Importantly, the normative blood pressure tables are now based on values measured in children of normal weight rather than in all children, because an increasing proportion of children that are overweight or obese have abnormal elevated blood pressures. These guidelines provide a simplified screening table, suitable for use in general pediatric clinics, to expedite the identification of children with elevated blood pressures, who are (often repeatedly) overlooked at clinic visits. The guidelines recommend screening blood pressure measurements only at the time of preventive care visits (for patients without risk factors), streamline the initial evaluation and management of abnormal blood pressures (eg, depending on patient BMI), and expand the role for ambulatory blood pressure monitoring. In total, the guidelines provide 30 key action statements and 27 additional recommendations.

Renal Replacement Therapy

Richard N. Fine, MD, FAAP¹, Douglas M. Silverstein, MD, FAAP²

Affiliations: ¹Renaissance School of Medicine at Stony Brook University, Stony Brook NY, USA; University of Southern California Keck School of Medicine, Los Angeles, CA; ²United States Food and Drug Administration, Silver Spring, MD

Highlighted Articles From Pediatrics

1. Korsch BM, Fine RN, Negrete VF. Noncompliance in children with renal transplants. Pediatrics. 1978;61(6):872-876
2. Lynfield R, Herrin JT, Rubin RH. Varicella in pediatric renal transplant recipients. Pediatrics. 1992;90(2):216-220
3. Broyer M, Tete MJ, Gagnadoux MF, Rouzioux C. Varicella and zoster in children after kidney transplantation: long-term results of vaccination. Pediatrics. 1997;99(1):35-39
4. Goldstein SL, Currier H, Graf JM, Cosio CC, Brewer ED, Sachdeva R. Outcome in children receiving continuous venovenous hemofiltration. Pediatrics. 2001;107(6):1309-1312

Several seminal articles have described therapy and complications of various forms of pediatric renal replacement therapy (RRT), including dialysis and transplantation. The articles below highlight strategies to overcome some of the major challenges in providing adequate dialysis and managing infection in children receiving RRT.

In 1978, Korsch et al published a seminal article in Pediatrics that documented non-adherence among children who received renal allografts during the initial 10 years of the dialysis and transplant program at Children’s Hospital of Los Angeles.¹ Systematic follow-up was available on 80 patients who had complete follow-up for 1 year; 14 of the 80 (17.5%) recipients were non-adherent. Clinicians suspected non-adherence on observation of diminution in cushingoid features, unexplained weight loss, and changes in graft function and confirmed during conferences with a member of the psychosocial support team. With one exception, all of the non-adherent recipients were adolescents (>12 years of age) at the time of transplantation. The devastating consequences of non-adherent behavior with the immunosuppressive medications were significant; 6/14 allografts were lost and 8/14 had irreversible loss of allograft function. The clinical teams made assiduous efforts to identify patient personality traits and family characteristics that predisposed to non-adherent behavior compared to those of adherent recipients. Unfortunately, the authors were unable to delineate a clear explanation for the observed non-adherent behavior.

In 1992, Lynfield et al described the incidence and outcome of primary varicella infection in 83 children who had received a renal allograft between January 1979 and November 1991; 8 of 83 developed cutaneous (8) or visceral (4) manifestations of primary varicella.² Despite treatment with intravenous acyclovir and discontinuation of azathioprine, 2 patients died from disseminated primary varicella. The authors suggested that neither VZIG nor intravenous acyclovir offers complete protection against severe varicella in pediatric immunocompromised organ transplant recipients and suggested that vaccination to the varicella virus in susceptible transplant candidates, preferably prior to transplantation, could avoid the devastating consequences described. Other evidence (Feldman et al, Pediatr Res, 2020) shows that vaccination rates among solid organ transplant recipients, including children, are low, possibly due, in part, to vaccine hesitancy, which may increase the challenges to adequate protection after transplantation. These suggestions are of utmost relevance in the setting of the SARS-CoV-2 pandemic and the resurgence of other highly contagious infections.

In 1997, Broyer et al addressed the suggestions of Lynfield et al by describing the impact of varicella vaccination among 704 transplant recipients who received a renal allograft between 1973 and 1994 at the Hospital Necker-Enfants Malades in Paris, France.³ Starting in 1980, all potential recipients received the varicella vaccine prior to transplantation. After vaccination, 62% had detectable varicella/zoster antibodies at 1 year and 42% at 10 years. The incidence of varicella was significantly lower (26/212, or 12%) in those immunized than in those who were not or in those who had no history of varicella (22/49, or 45%). When varicella occurred post-transplantation, it was significantly less severe in the vaccinated recipients. There were 3 deaths among the naïve recipients and none among those vaccinated. The authors considered it unsafe to administer the attenuated live vaccine to recipients receiving immunosuppressive medications, although data at the time of the report in patients with leukemia did not justify the concern. The authors concluded that varicella vaccination in potential recipients prior to renal transplantation has the potential to modify the severity of disease if it occurs following transplantation and to forestall its devastating consequences.

Studies have demonstrated that mortality in children who are treated with continuous venovenous hemofiltration (CVVH) is higher in patients who have >10% fluid overload (FO), who are on pressor therapy, and who have a high severity of illness (as assessed by PRISM scores). Goldstein et al⁴ reported on outcomes of 21 children (mean age, 8.8 years; mean weight, 28.3 kg) with acute kidney injury (AKI) who required either CVVH alone or with dialysis (D). The major contribution of this study was the inclusion of PRISM scores to control for outcomes in CVVH. Forty-three percent of the children survived. Mean PRISM score at CVVH initiation was 15.4±8.9. Patient weight, age, PRISM score at CVVH/D initiation, maximum pressor number, estimated renal function at CVVH/D initiation, and change in mean airway pressure did not differ between survivors and non-survivors. The degree of FO at CVVH/D initiation was significantly lower in survivors. The authors concluded that the pattern of early multi-organ system failure and death, minimal relative cost of CVVH/D provision, and potential for improved outcome with initiation of CVVH/D at lesser degrees of FO supported early initiation of CVVH/D in critically ill children with AKI. The impact of this report that has changed practice to initiate timely initiation of continuous renal replacement therapy for fluid overload cannot be overestimated.