Advancing the Care of Children with Renal Diseases

Idiopathic nephrotic syndrome (INS) affects 16 per 100,000 children and is one of the most common acquired childhood kidney diseases. INS often runs a relapsing course in children, even in the children who respond to prednisone therapy. As a result, these children often have a prolonged clinical course. Because of the burden of this condition—augmented by the significant complications associated with INS and its treatments in children—childhood INS remains an intimidating challenge for children, families, and medical professionals.

Remarkably, the present-day approach to childhood INS is still based on a series of foundational studies that are limited in their application to the clinical challenges faced by families and pediatric nephrologists today. These important studies were published between 1970 and 1993 and began with an international collaborative effort sponsored by the International Study of Kidney Disease in Children (ISKDC).

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From 1967 to 1974, 521 children with new-onset INS underwent renal biopsies and standard prednisone treatment. The investigators demonstrated that response to therapy with cessation of abnormal proteinuria within eight weeks of corticosteroid therapy was predictive of minimal change nephrotic syndrome (MCNS) (1). As a result, pediatric nephrologists began to rely on the initial therapeutic response to glucocorticoids to guide subsequent evaluation and therapy for children presenting with INS.

A series of important studies by the Arbeitsgemeinschaft fur Padiatrische Nephrologie also helped define practice management of children with INS (2). While these landmark studies have been critical in our approach to these children, they are now almost 20 years old, and the clinical characteristics and challenges of the children presenting with INS have clearly changed over recent decades. Some examples of the changing nature of INS in children include the increasing recognition of genetic factors that underlie nephrotic syndrome in children, the rising incidence of focal segmental glomerular sclerosis (FSGS) in children with INS, the increasing prevalence of obesity and type II diabetes mellitus that may be exacerbated by standard INS treatments with glucocorticoids, and the importance of family status and treatment compliance in patient outcomes.

In 2008, Gipson and colleagues performed a survey regarding treatment of childhood INS among North American pediatric nephrologists at 10 U.S. centers (3). Great disparities in even the most fundamental aspects of care, such as the management of initial clinical presentations, relapses, and steroid resistance in children with INS were identified among the 30 participating practitioners. In response to these challenges, we participated in a Children’s Nephrotic Syndrome Consensus Conference for North American pediatric nephrologists. The conference was convened to develop updated evidence- and opinion-based recommendations for the evaluation and management of children with INS (4).

In the consensus conference report, only a limited number of treatment recommendations were based on Class 1 evidence. Recommendations related to extent of evaluation, monitoring for complications, and treatment for steroid-dependent and steroid-resistant INS were almost all based on small case series and expert opinion. Thus, in many clinical situations, pediatric nephrologists are dependent on well designed but older randomized trials. These trials have led to continued variations in clinical approach among practicing physicians with little data beyond anecdotal evidence to guide further clinical decision-making for these patients.

Another concern is the paucity of studies in children with INS that address important long-term issues. In the consensus conference report, only a handful of studies involved more than 10 years of follow-up outcomes. A recent report from Kyrieleis (5) addressed long-term steroid responsiveness in children with INS and highlights the value and impact of detailed long-term observational studies in these children. Because the vast majority of children with INS now survive to adulthood, there is a real need for studies of the long-term outcomes (and complications) of our therapies to help define the lifelong consequences of INS and INS treatment in children. For too long, studies of treatment of children with INS have been limited to single centers and short-term perspectives, which inherently preclude insight about important long-term issues.

Careful prospective multicenter observational and interventional studies that address evaluation and treatment and incorporate comprehensive follow-up of children with INS are required to provide the basis for improvements in consistent and effective care. We have designed a prospective evaluation of new incident children with primary nephrotic syndrome in conjunction with the Mid-West Pediatric Nephrology Consortium (MWPNC). In doing so, we hope to begin the systematic evaluation of appropriate approaches for evalulating and treating children with steroid-sensitive and steroid-dependent/resistant nephrotic syndrome.

In our evaluation, we have relied on the methods and lessons of the Children’s Oncology Study Group (COG). COG (www.curesearch.com) began in the United States and is now a worldwide clinical trial cooperative group comprised of investigators from 238 institutions who are supported by the National Cancer Institute to study childhood cancers. COG was formed in 2000 from the merger of four independent cooperative cancer study groups that date back to 1956 in conducting prospective randomized clinical trials to study best treatments, quality of life, and impact of cost on families of children with cancer. We have been particularly struck by these lessons learned from the COG experience:

  • 1) Improved patient outcomes can be derived from sequential comparisons of standard-of-care versus novel treatments in prospective clinical trials. The basis for all improvements is the comparison of new therapies to the existing standard care.

  • 2) Successful studies can be obtained by combining patient results from multiple institutions; this is necessary to overcome the challenges of low patient numbers for most pediatric diseases.

  • 3) An established clinical trial infrastructure must exist to enable repeated clinical trials that can perform sequential comparisons with consistent methods and participation among member centers. There are tremendous advantages to having an existing study group and not having to construct a new study group for each study.

  • 4) Networks and defined study groups can develop relationships that promote collective efforts, dedication to mutual goals, and accountability to projects. Relationships especially matter in collaborative clinical research endeavors.

Under the stewardship of the MWPNC steering committee (Denis Geary, Larry Greenbaum, John Mahan, Tej Mattoo, and William Smoyer), the MWPNC has held a members meeting every six months since 2003 to develop collaborative research projects and present the results of existing and completed MWPNC studies. Member centers elect to sign on to studies of interest, and authorship is offered to all participants who are involved in at least two of three essential study elements: design, execution, and analysis/publication.

At this point the MWPNC has published 11 pediatric nephrology studies in several areas of investigation and has 15 approved studies underway. From an initial group of 20 collaborating centers located in the Midwest, the MWPNC has grown to involve 30 participating centers in the United States and Canada that are centered in, but not limited to, the Midwest. A prospective trial of standardized therapy for children with INS that leads to subsequent testing of alternate strategies and provides patient data and samples that help define complications and outcomes in children with INS is now approved. The study will soon be underway in the MWPNC (www.MWPNC.org).

Study networks in pediatric nephrology have evolved over time to carry out the important work of advancing the care of children with kidney disorders.

The Southwest Pediatric Nephrology Group (SWPNG), founded in 1980, was the first successful North American collaborative pediatric nephrology study group. SWPNG now consists of over 70 participating centers and is still active today; it has published 27 papers since its inception. The SWPNG provided important evidence of the power of collaborative networks in this area.

The North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry was founded in 1987 and has pioneered the process of translating a pediatric nephrology registry into an opportunity for collaborative clinical research. NAPRTCS now includes 110 participating institutions in the United States and Canada and has a distinguished track record of registry descriptive studies that have done much to advance our understanding of clinical issues in children with chronic kidney disease and posttransplant. NAPRTCS has now developed a number of multicenter collaborative trials devoted to these populations.

Other examples of collaborative clinical research networks in pediatric nephrology include the Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry, a study group founded in 2001 that is devoted to advancing care of children who require continuous renal replacement therapy. In addition, study groups devoted to a single, yet many times multifaceted, study have helped move the care of children with kidney disease forward. These include the Prospective Cohort Study of Kidney Disease in Children (CKiD) study, the Novel Therapies for Resistant FSGS (FONT) Study Group, the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Study, and the now completed NIH FSGS trial group. Efforts devoted to providing continuous quality improvement (CQI) models appear to be another useful approach to improve the practice of care but are limited in the ability to generate new evaluation tactics and therapies.

Important lessons can be derived from the COG experience and our experience in pediatric nephrology. We propose that any attempts to test new evaluation strategies and therapies in children with kidney disease should include:

  • 1) the power of relationships to motivate individual practitioners and investigators to work together to address important clinical issues.

  • 2) the need for investigators to be willing to put aside their own cherished patterns of care and beliefs to enroll patients in studies that prove the value of therapies.

  • 3) the absolute value and need to question the established standard of care and/or try to improve our therapies and assess short- and long-term outcomes.

  • 4) the need to consider each patient with a pediatric renal disease as a study patient.

It is only in these ways that we will be able to keep the focus where it belongs: the child with kidney disease. We believe so strongly in the power of the COG-like model that we are attempting to develop this in the MWPNC as an enduring mechanism to conduct and deliver prospective multicenter collaborative studies that will advance the care of childhood INS, as well as other pediatric kidney diseases.

Notes

[1] John Mahan, MD, and William Smoyer, MD, are with the department of pediatric nephrology at Nationwide Children’s Hospital, the Ohio State University College of Medicine, in Columbus.

References

1.

Bergstein JM, Weinberger MH. Hypokalemia, normal blood pressure, and hyperreninemia with hypoaldosteronism. J Pediatr 1981; 98:561–564.

2.

Alternate-day versus intermittent prednisone in frequently relapsing nephrotic syndrome: a report of “Arbeitsgemeinschaft für Pädiatrische Nephrologie.” Lancet 1979; 1:401–403.

3.

Ehrich JHH, Brodehl J. Arbeitsgemeinschaft für Pädiatrische Nephrologie: Long versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Eur J Pediatr 1993; 152:357–361.

4.

MacHardy N, et al. Management patterns of childhood-onset nephritic syndrome. Pediatr Nephrol 2009; 24:2193–2201.

5.

Gipson DS, et al. Management of childhood onset nephrotic syndrome. Pediatr 2009; 124: 747–757.

6.

Kyrieleis HAC, et al. Long-term outcome of biopsy-proven, frequently relapsing minimal-change nephrotic syndrome in children. Clin J Am Soc Nephrol. 2009; 4:1593–1600.