Research Activities

The faculty of the Division of Pediatric Nephrology at the University of Miami School of Medicine are involved in a broad range of both clinical and basic science research activities. Over the past two decades, the pediatric nephrology program has been internationally recognized for its contributions to research in the field. Basic laboratory research has addressed many problems paralleled in the clinical arena by using experimental animal models. These include subtotal renal ablation in weaning rats to study the effects of chronic renal insufficiency and puromycin induced nephrotic syndrome. Recently, we have developed a model for chronic partial unilateral ureteral obstruction in young animals to study renal tubular abnormalities.

Clinical research has focused largely on our unique and expanding population of patients from our multi-ethnic and inter-racial community. The prevalence of HIV nephropathy in children in South Florida is unparalleled in the country. The large dialysis population has allowed extensive studies in End Stage Renal Disease. Collaboration with University of Miami colleagues to study specific renal diseases has fostered a close liaison with pediatric infectious disease, neonatology, pediatric urology, nuclear medicine, and renal/pediatric pathology, as well as pediatric intensive care medicine. Multicenter collaborative trials include the ongoing North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), Growth Failure in Renal Disease (GFRD - NIH Funded Study), and Steroid Resistant Nephrotic Syndrome - Focal Segmental Glomerular Sclerosis Trial, which is in the working phase for RFA submission with our center as the core.

The following is a partial summary of the research currently being conducted. Every project is conducted with the effort of each member of the faculty, and many are in collaboration with faculty from other divisions in the Departments of Pediatrics, Urology, Radiology, Transplant Services, and Pathology.

A Multicenter Study to Evaluate the Pharmacokinetics, Dose-Response, Efficacy,and Safety of Benazepril in Pediatric Subjects

KIDS-BP Trial
(KInetics Dose response Safety of Benazepril in Pediatrics)

Carolyn Abitbol, M.D., and Terry Cano, R.N.

The primary objective of this study is to evaluate the efficacy and dose-response relationship of benazepril in children aged 6 to 16 years with hypertension and to determine the pharmacokinetics of benazepril tablets in children aged 6 to 16 years with hypertension. The secondary objective of this study is to determine the safety and tolerability of both short and chronic administration of benazepril in hypertensive children aged 6 to 16 years. ACE inhibitors have become primary agents for pharmacologic therapy of hypertension because they reduce blood pressure and have a favorable hemodynamic profile. The ACE inhibitors block the formation of angiotensin II, a potent vasoconstrictor, and of aldosterone, which causes salt and water retention. They also increase levels of the vasodilator substances bradykinin and prostaglandin E2. Evidence suggests that these agents are safe and efficacious in adolescents and children, although data in infants is limited. Although ACEI are widely used in clinical practice to treat children with hypertension, there are few prospective controlled trials of their use in children. This study in hypertensive children explores the dose-response relationship, efficacy, safety, and tolerability of benazepril over a wide dosing range.

Funded and monitored by Novartis Pharmaceuticals and Scirex Corporation.

The NESP Study

Gastón Zilleruelo, M.D., and Terry Cano, R.N.

The NESP study is an open-label, randomized, non-inferiority study of the new product Novel Erythropoiesis Stimulating Protein (NESP) and Recombinant Human Erythropoietin (r-HuEPO) for the treatment of anemia in pediatric patients with chronic renal insufficiency or end stage renal disease (ESRD) receiving dialysis.

Funded and monitored by Amgen Pharmaceuticals.

Multi-center Evaluation of Chronic Renal Insufficiency in Children: The MECRIC Study

Gastón Zilleruelo, M.D., Director of the Southeast Region

This is a multi-center consortium of Pediatric Nephrology Centers who are responding to the National Institutes of Health Request for Proposal RFA 01-005, calling for a study of the progression of renal disease in children. Approximately 1000 patients of different ages, genders, and ethnicities, with chronic renal insufficiency, from 18-20 regional centers will be recruited. The specific aims include careful, frequent measurement of glomerular and tubular function and multiple clinical and biochemical markers that influence progression of renal disease. Constitutional markers such as obesity, protein intake, hyperlipidemia, and hypertension will be followed. Genetic factors such as gene polymorphisms, transforming growth factor, and tumor necrosis factor will be analyzed. Urinary indices such as total protein, microalbumin, and podocyte protein biomarkers will be assayed. This is an important collaborative effort that will impact the practice of pediatric nephrology nationally.

Effect Of Angiotensin T1 (AT1) Receptor Blockers In Children With Nephrotic Range Proteinuria

Jayanthi Chandar, M.D.

An important part of treating kidney disease is to conserve renal function and to prevent progression of the disease. During the past decade, angiotensin converting enzyme (ACE) inhibitors have been shown in adults to control hypertension, decrease proteinuria, and significantly delay the progression of renal disease. In recent years, researchers have developed selective AT1 receptor blockers, that do not have some of the undesirable side effects of ACE inhibitors. To date there has been no published literature on the efficacy of this type of drug in children. The aim of this project is to study the effect of the Angiotensin II receptor blocker, candesartan cilexetil, on the urinary excretion of protein in children with nephrotic range proteinuria and determine if it alters the selectivity of the proteinuria. The efficacy and safety of the drug will be studied.

Funded by the Kidney Foundation of South Florida.

Detection Of Renal Disease By Screening Urine Analysis

Jayanthi Chandar, M.D.

Over the years, medical professionals have questioned the need and usefulness of routine urine analysis in healthy pediatric patients without symptoms. A basic urine dipstick tests pH, specific gravity, protein, blood, glucose, nitrites, and leukocytes. Established practice is referral to a nephrologist when blood and protein are persistently found in the urine. However, the etiology of these abnormalities may be benign or indicate more serious disease. Anecdotal experience in our institution suggests that routine urine analysis is important in detecting significant renal/genito-urinary disease. This study is designed to determine the prevalence of renal disease in patients referred to a large tertiary care pediatric nephrology service with microhematuria and proteinuria found on routine screening urine analysis by the primary care physician. The etiology, natural history, risk factors for significant renal disease, treatment, and outcome of children who initially manifested with asymptomatic microhematuria and proteinuria will be studied.

Funded by the Kidney Foundation of South Florida.

Angiotensin Blockade Prevents Local and Systemic Abnormality in Unilateral Ureteral Obstruction (UUO) & Young Rat Model of Partial Ureteral Obstruction (UUO) by Psoas Wrap

Carolyn Abitbol, M.D., Ashraf Beharrie, M.D. (ped nephrology fellow), & Julie Franc-Guimond, M.D. (ped urology fellow)

Unilateral ureteral obstruction (UUO) in infants and young animals has been associated with the development of systemic metabolic alterations and some degree of renal insufficiency. The renin-angiotensin system has been implicated as a mediator of both local and systemic injury in the pathogenesis of this disease. Our study is designed to examine the impact of angiotensin blockade on the metabolic and local tissue pathology created by UUO in a young rat model.

Funded by the Kidney Foundation of South Florida.

Continuous Overnight Catheter Drainage (COCD)

Brenda Montané, M.D., and Carolyn Abitbol, M.D.

Progression to end stage renal disease (ESRD) in children with obstructive uropathy and dysfunctional bladder emptying is common despite appropriate surgical and medical management. Patients with neurogenic and/or dysfunctional bladder emptying require intermittent catheterization (IC) as a maneuver to prevent urinary retention, which may lead to high intravesical pressure and progressive deterioration in renal function. Polyuria commonly develops in these patients and may overwelm the bladder capacity/compliance, especially overnight. Our purpose is to determine the effect of providing optimal decompression of the collecting system by continuous overnight catheter drainage (COCD) on the progression of renal disease.

Osteodystrophy & Bone Mineral Density

Domingo Leal, M.D. (fellow), with Gaston Zilleruelo, M.D.

Reliable, non-invasive methods to diagnose renal ostrodystrophy (ROD) in young patients on dialysis are needed. This study compares absorptiometric bone mineral density (BMD) of the lumbar spine (L2-L4) with biochemical markers of bone remodeling: (osteocalcin (OC), alkaline phosphatase (AP), bone-specific alkaline phosphatase (BAP), carboxy-terminal propeptide of type I collagen (PICP), carboxy-terminal telopeptide of type I collagen (ICTP) and parathyroid hormone (PTH). Nutritional status was assessed by calculating body mass index (BMI=weight/height2 in kg/m2). BMD and BMI are expressed as z-scores for the reference population which was matched for age and gender. Bone disease is characterized as high-turnover (HTBD) with PTH > 200 pg/ml and BAP > 20 U/L versus low-turnover (LTBD) with PTH < 200 pg/ml and BAP < 20 U/L, respectively. Within these definitions, bone markers are studied to help define and monitor bone disease activity for further refinement towards treatment applications.

Oligonephropathy of Prematurity

Carolyn Abitbol, M.D., and Jayanthi Chandar, M.D.

Epidemiological and laboratory studies suggest that interruptions in nephronogenesis related to intrauterine malnutrition, prematurity, or growth inhibiting medications such as angiotensin converting enzyme (ACE) inhibitors result in abruption of nephron induction and a decrease in the total number of nephrons. This entity is appropriately termed “oligonephronia” – or “too few nephrons”. Adult studies suggest that people born at less than 2500 grams (especially women) will have a greater tendency to suffer hypertension and renal insufficiency in later life. Our center is unique in having a tertiary care nursery that has successfully preserved significant numbers of very low birth weight infants (<1200 grams) for over 15 years. We have now identified a large cohort of infants who manifest some degree of oligonephropathy including proteinuria and insidious progression to end stage renal disease (ESRD). This prospective database begins to identify important clinical parameters that should lead to a better understanding of pathogenesis and potential treatment interventions for preservation of renal function in an important and growing component of our population.

Funding requests are being processed from the Maternal and Child Health Bureau (MCHB) and the March of Dimes Foundation.

Combination Mycophenolate and Angiotensin Blockade in the Treatment of Steroid Resistant Nephrotic Syndrome

Brenda Montané, M.D., and Gastón Zilleruelo, M.D.

Management of steroid resistant and frequently relapsing Nephrotic Syndrome (NS) of childhood poses a dilemma in attempting to balance toxicity of medications against unknown longterm prognosis. Recent experimental studies suggest that mycophenolate mofetil (MMF) and angiotensin blockade (AB) may be useful in preventing the progression of the lesions of focal glomerular sclerosis (FGS). Our recent experience with the use of MMF and AB in steroid resistant NS has offered extensive insight into the benefits of this treatment. Prior to the initiation of MMF and AB, all patients were placed into partial remission with high dose intravenous corticosteroid therapy (15 mg/kg/week for six to eight weeks), so that the proteinuria was < 1 g/m2/d and serum albumin was > 2 g/dL. Angiotensin converting enzyme inhibitors (ACE-I) and/or angiotensin II receptor blockers (A2RB) were begun when serum albumin was ³ 2.0 g/dL and serum creatinine was normal for age or stable at baseline. All patients have shown response to this treatment regimen by normalization or > 50% reduction in proteinuria. No patients have shown deterioration in renal function. All patients have had resolution of edema for greater than 12 months. Our experience supports the use of MMF and AB as a late treatment of NS when other conventional treatments have failed and/or have induced toxicity.

Cardiomyopathy in Children Receiving Hemodialysis

Washaree Seeherunvong, M.D., and Gastón Zilleruelo, M.D.

Left ventricular hypertrophy is a major predictive factor of high mortality in adults with end stage renal disease (ESRD). Information on the incidence and character of cardiomyopathy in pediatric hemodialysis patients is limited. We have studied the prevalence of cardiomyopathy, type of left ventricular hypertrophy (LVH), and risk factors related to LVH in children receiving chronic hemodialysis. All subjects are studied by M Mode and 2-D Doppler ECHO. LVH is indexed to age, height and body surface area (BSA). Concentric LVH was LV hypertrophy with thickened wall and small to normal cavity volume. Dilated LVH was defined as LV cavity > 95th percentile prediction as above. Overall prevalence of LVH detected by ECHO has been > 80% , but the prevalence of LVH at initiation of hemodialysis is only approximately 50%. Therefore, we have found a high prevalence of cardiomyopathy in pediatric hemodialysis patients. The development of LVH appears to continue after chronic hemodialysis. The major factors contributing to LVH appear to be related to both hypertension and anemia. The early detection of cardiomyopathy by screening ECHO before starting hemodialysis and during maintenance on hemodialysis is recommended. Moreover, aggressive treatment of hypertension and correction of anemia seem indicated. A further study on the long term prognosis of pediatric hemodialysis patients with cardiomyopathy is imperative.

Angiotensin Blockade as an Adjuvant in the Treatment of Posttransplant Recurrence of Focal Segmental Glomerulosclerosis in Children

Gastón Zilleruelo, M.D., and Hans Hubsch, M.D. (fellow)

Recurrence of focal segmental glomerulosclerosis (FSGS) post-renal transplant ranges from 25–90% in various centers and is a common cause of allograft loss and increased morbidity from the nephrotic syndrome (NS). Recent attempts to control proteinuria and preserve allograft function with aggressive and expensive plasma exchange treatments including plasmapheresis (PP) and/or immunoadsorption (IA) have met with limited success. The potential benefits of low dose angiotensin blockade (AB) in the management of steroid resistant nephrotic syndrome in children prior to transplantation suggested its use as an adjuvant therapy post-transplant. During the past 15 years many centers have experienced a recurrence of FSGS in excess of 90% of patients with this primary disease. In our more recent three year experience the use of AB as maintenance therapy following PP and/or IA in recurrence of FSGS appears to be worthwhile. From the onset of recurrence of the NS, proteinuria decreases on the average of 90±6% while serum albumin increased by 30±21% to normal values. Our limited experience supports the safety and efficacy of low dose maintenance angiotensin blockade in the management of recurrent FSGS with hope for longterm preservation of renal allograft function.

C-Reactive Protein (CRP) as a Marker for Infection/Inflammatory Illness in Young Dialysis Patients

Maria Fatima Gesteira, M.D. (fellow), and Carolyn Abitbol, M.D.

A common problem in young dialysis patients is the lack of markers to help differentiate life-threatening infections from less serious viral or bacterial infections early in the illness. The differential diagnosis of common situations that require early intervention in the young dialysis population include line infection, associated or not with bacteremia, peritonitis, pancreatitis, and viral and bacterial infections. The objective of this study is to evaluate the sensitivity of C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in the diagnosis and management of infections or inflammatory illnesses in children with end stage renal disease (ESRD) on chronic dialysis. It is designed as a prospective study to determine if these two acute phase reactants are reliable indicators of infections in young dialysis patients.