Saudi Journal of Kidney Diseases and Transplantation

: 2005  |  Volume : 16  |  Issue : 3  |  Page : 271--276

Pediatric Obstructive Uropathy: Clinical Trials

James CM Chan1, Jonathan I Scheinman2, Karl S Roth3,  
1 Professor of Pediatrics, University of Vermont and Director of Research, The Barbara Bush Children’s Hospital, Maine Medical Center, Portland, Maine, USA
2 Division of Pediatric Nephrology, University of Kansas, Kansas City, KS, USA
3 Department of Pediatrics, Creighton University, Omaha, NE, USA

Correspondence Address:
James CM Chan
The Barbara Bush Children’s Hospital, Maine Medical Center, 22 Bramhall Street, Portland, Maine 04102-3175


As the powerful tools of molecular biology continue to delineate new concepts of pathogenesis of diseases, new molecular-level therapeutic modalities are certain to emerge. In order to design and execute clinical trials to evaluate outcomes of these new treatment modalities, we will soon need a new supply of investigators with training and experience in clinical research. The slowly-progressive nature of chronic pediatric kidney disease often results in diagnosis being made at a time remote from initial insult, and the inherently slow rate of progression makes changes difficult to measure. Thus, development of molecular markers for both diagnosis and rate of progression will be critical to studies of new therapeutic modalities. We will review general aspects of clinical trials and will use current and past studies as examples to illustrate specific points, especially as these apply to chronic kidney disease associated with obstructive uropathy in children.

How to cite this article:
Chan JC, Scheinman JI, Roth KS. Pediatric Obstructive Uropathy: Clinical Trials.Saudi J Kidney Dis Transpl 2005;16:271-276

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Chan JC, Scheinman JI, Roth KS. Pediatric Obstructive Uropathy: Clinical Trials. Saudi J Kidney Dis Transpl [serial online] 2005 [cited 2021 Jan 20 ];16:271-276
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Major advances in our understanding of obstructive uropathy have been made in recent years by utilizing the tools of molecular biology. We now have a better understanding of how kidney morphogenesis is regulated, [1],[2] the impact of various factors in fetal kidney develop­ment and functions [3],[4] and the multifactorial effects of obstruction on the kidney. [5],[6],[7],[8],[9],[10] Many hypotheses concerning obstructive uropathy are now ready to make the leap from cell cultures [1],[2] and animal models to patients with congenital urinary tract obstruction. All will require clinical trials, designed and performed by highly-trained investigators capable of creating the bridge from the laboratory to the bedside.

A clinical trial is an instrument to test the outcome of therapeutic intervention. Not unlike bench-top research, a clinical trial also starts with a question being asked. A study is then designed to answer the question, utilizing accepted and sometimes innovative methodo­logies. For the clinical trials of the future mentioned above to be successful, measure­ment of biological markers by means not yet developed may be essential; indeed, the markers themselves may not yet have been found. Nonetheless, the fundamental principles of clinical trial design are likely to remain essentially unchanged in the future. The devil is in the detail, and in this case, the details are in the study design.

 Study Design

A clinical trial should be randomized, controlled and blinded whenever possible to increase statistical power. Under certain circumstances, an open label, non-blinded, study design is inevitable. Depending upon the nature of the question being asked, there may be sufficient numbers of patients for single center studies. However, for issues bearing upon most pediatric kidney diseases, due to the small numbers at each center, a multi-center study is the better design.

The causative events in the development of chronic kidney disease often occur remote in time from the onset of clinical symptoms and may even pass unnoticed, making prospective clinical trials difficult, if not impossible. The reason why we think clinical trials are imp­ortant in patients with obstructive uropathy is the risk of progression to end-stage kidney disease, starting from a well-defined point in time since obstruction to urinary flow is easily noted in most cases. However, obstructive uropathy is a heterogonous group of disorders with widely-varying etiologies. To limit hetero­geneity, let us focus on obstructive uropathy caused by posterior urethra valve; this dis­order has the advantage for study of being congenital in nature and typically affects both kidneys more or less equally. Moreover, it is generally diagnosed in utero as a consequence of fetal ultrasound evaluation during routine prenatal care. In studies of over one hundred children, [11][,12],[13],[14] up to 30 percent progresses to end-stage kidney disease, but the follow-up was less than 10 years and often for much shorter [1] periods. In two recent long-term studies, [4],[15] with over 20-years follow-up, more than 70 percent of patients progressed to end-stage kidney disease. [14] Thus, the length of follow-up can make a big difference in the outcome in a slowly progressive kidney disease, such as obstructive uropathy.

In recently published data, [14] posterior urethral valve obstruction was released shortly after birth, and the previously elevated serum creatinine returned to steady nadir levels. Long term follow-up showed that there was unrelenting progression in the majority of these patients. Doubling of the serum creatinine occurred at 3.95 years [Figure 1] and doubling occurred again at 7.95 years. In studies in adults, the doubling of serum creatinine can provide an acceptable endpoint. However, in pediatrics, due to growth related changes in serum creatinine, its use as an endpoint cannot be easily addressed, especially in those less than two years of age.

The heterogeneity of presentation and severity of a disease in the patient population and access to an adequately-sized study population will determine which study design is acceptable. Pediatric studies are characterized by the challenges inherent in the broad norms of growth and development in the rapid growth periods of infancy and adolescence. In view of the fact that the pediatric kidney disease population is small, we are often faced with a suboptimal number of study subjects and inadequate length of follow-up. We are some­times criticized for unrealistic estimates and lack of pilot/ feasibility data, which, however, must necessarily be based upon these small numbers and limited extended follow-up. However, unless the National Institutes of Health fund pediatric studies, we will not be able to nurture and mentor new investigators so that they can gain experience in clinical trials and eventually, provide answers to the many unanswered questions about clinical pediatric kidney disease.

 Entry, Exclusion and Exit Criteria

For purposes of illustrating this aspect of clinical study design, let us consider the experience of a multi-center clinical trial in developing and controlling entry, exclusion and exit criteria to achieve the study end­point. [16] We asked the question whether treat­ment of renal osteodystrophy with 1, 25 dihydroxyvitamin D was associated with an accelerated rate of deterioration of kidney function in children with chronic kidney insufficiency as suggested by data in adult patients. [16] Because the number of patients with this disorder was not sufficient at any individual pediatric center to provide valid generalization, a multi-center study design was adopted. The entry criteria were:{1} patients with chronic kidney insufficiency as docu­mented by glomerular filtration rates between 20 and 70 ml per minute by 1.73m 2 , {2} eligible subjects were between 2 and 10 years of age, to avoid the rapid growth periods of infancy and adolescence, and {3} the documentation of at least one elevated plasma parathyroid hormone during the 6-month control period. The patients were then randomized to the blinded protocol of 1, 25-dihydroxyvitamn D {calcitriol} versus dihydrotachysterol. We excluded any patients with nephrotic syndrome, any condition requiring the use of steroids, vitamin D and other agents that may affect growth. As a result, 71% of our patients with chronic kidney insufficiency had obstructive uropathy and 20% had kidney dysplasia.

 Primary and Secondary End-Points

Our data [Figure 2] demonstrated that calci­triol treatment was likely to be associated with a three-fold increased risk of deterio­ration of kidney function, compared to dihydro­tachysterol treatment. [16] We were able to arrive at the primary end- point by careful control of the entry and exclusion criteria. Patients who exited the study for reasons of dialysis or kidney transplantation continued to be followed up but their data were separately analyzed.

At the beginning of the study and follow­up visits, we gathered additional data to achieve secondary end-points. As a result, we were able in terms of linear growth, anthropometrical parameters and parathyroid hormone suppre­ssion, to demonstrate that calcitriol was no different from dihydrotachysterol. Further­more, Boineau et al [17] demonstrated that when the Glomerular filtration rate was better than 10 ml per minute per 1.73m 2 ; none required erythropoietin or blood transfusions. Using the carefully collected dietary data, Foreman et al [18] demonstrated that the caloric intake was 80 + 23% of the recommended dietary allowance and the protein intake was signi­ficantly elevated at 153 + 53% of the recom­mended dietary allowance. These circumstances may have an impact on the growth and kidney hyperfiltration, respectively, of these subjects. Finally, Trachtman et al [19] demonstrated that the calcium intake in these patients was 74% of the recommended dietary allowance with implications relevant to blood pressure.

 Patient Compliance

Experience in another clinical trial will illu­strate a point about patient compliance. [20] Experimental data suggested that oxidative stress was involved in the pathogenesis of IgA nephropathy [21],[22],[23] Data in experimental IgA nephropathy showed that treatment with an antioxidant, such as vitamin E, ameliorated the process of on-going injury and progression of this kidney disease. [21],[22],[23] Because there was no commonly accepted effective therapy for IgA nephropathy, [24] we reasoned that an antioxidant might have a role in reversing kidney injury and progression.

We conducted a pilot study, in which children with biopsy-proven IgA nephropathy were randomly assigned to either vitamin E or placebo treatment arms. [20] Our preliminary data demonstrated a significant reduction in proteinuria in the treatment group. Patient compliance was independently verified by the significantly higher plasma vitamin E concen­tration in the treatment group versus the placebo group. It was convenient that we had such an easily measurable parameter to independently verify patient compliance. Pre­sently, with the advances in molecular biology, the search and utilization of molecular markers to estimate progression of disease would be especially valuable in a slowly progressive disease such as IgA nephropathy. In this con­dition, one out of four patients would progress to end-stage kidney disease over 25 years. [24] The roles of genes in the predisposition for specific kidney disease and therapeutic modi­fication of such genes are also important subjects to be addressed in clinical trials in the future, potentially providing insight into the rate of progression and the response to therapy.

 Administrative Organization

While there can be little doubt that clinical studies are engendered in the spirit of advancing medical knowledge for the benefit of all, protection of the subjects of the research from unintended harm is of paramount importance. While it is not the only reason, alone this would be sufficient justification to assure that all clinical trial protocols must be approved by the Institutional Review Board (IRB) at each of the clinical centers. The IRB-approved consent form should be signed by the parents or legal guardian and, when appropriate, by the child. Such consent forms should be sent to the Data Coordinating Center before rando­mization.

The Advisory Committee should be inde­pendently funded and responsible for oversight on patient safety, communicating to all clinical centers any adverse effects reported by a single site and recommending appropriate steps. It can also be very helpful in policy changes and their implementation at all clinical centers. Members of the Advisory Committee must have the stature to generate trust and respect for the decisions and recommendations issued by this body. Thus, the choice for membership on this Committee is exceedingly important to the ultimate success of a multi-center endeavor.

 Unsettled Issues

In any clinical study, measurement of bio­logical parameters is of paramount importance to gauge changes. The accuracy of such measurements varies tremendously, depending upon the parameter(s) in question. A unique feature of kidney disease studies is the fact that progression can be quantitated by measure­ment of glomerular filtration rate. [25] On the other hand, as a measurement of aggregate unit function, relatively large changes must occur before a difference can be seen in sequential measurements. Inulin clearance is the 'gold standard' but its cost in time and effort are major issues. Measurements of glo­merular filtration rates by radio-nucleotide and non-nucleotide techniques are practical, but the repeated blood sampling will need special consideration in children less than two years of age, because of the smaller blood volumes in such children. The total radiation in nucleotide glomerular filtration rate measure­ment is equal to the daily, street level, back­ground radiation. [25] Despite this fact, it may still be difficult to convince some parents in giving consent. Serum creatinine values and creatinine clearances are easy to do, but changes associated with growth cannot be easily addressed.


In conclusion, the key to formulation of a clinical trial must be distilled to address the following four components:

The importance of the question askedThe impact on the health of the patients and medical practice in the futureThe strength of the preliminary data in providing justification for the studyThe recognition of potential pitfalls and the utilization of alternative tactics to over­ come problems


Supported by National Institutes of Health grants: DK50419, DK07761. The author thanks Patricia Walker for secretarial support.


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