Publications by authors named "Robert P Woroniecki"

24 Publications

  • Page 1 of 1

Cumulative Application of Creatinine and Urine Output Staging Optimizes the Kidney Disease: Improving Global Outcomes Definition and Identifies Increased Mortality Risk in Hospitalized Patients With Acute Kidney Injury.

Crit Care Med 2021 04 28. Epub 2021 Apr 28.

1 Department of Pediatrics, Division of Nephrology, Stanford University, Stanford, CA. 2 Division of Nephrology, Department of Pediatrics, Division of Nephrology, Sidra Medicine, Doha, Qatar. 3 Department of Pediatrics, Division of Critical Care Medicine, Emory University, Atlanta, GA. 4 Department of Pediatrics, Division of Nephrology, University of Colorado School of Medicine, Aurora, CO. 5 Department of Pediatrics, Division of Nephrology, Stony brook Children's Hospital, Stony Brook, NY. 6 Department of Pediatrics, Division of Nephrology, Toronto Hospital for Sick Children, Toronto, ON, Canada.

Objectives: Acute kidney injury is diagnosed according to creatinine and urine output criteria. Traditionally, both are applied, and a severity stage (1-3) is conferred based upon the more severe of the two; information from the other criteria is discarded. Physiologically, however, rising creatinine and oliguria represent two distinct types of renal dysfunction. We hypothesized that using the information from both criteria would more accurately characterize acute kidney injury severity and outcomes.

Design: Prospective cohort study.

Setting: Multicenter, international collaborative of ICUs.

Patients: Three thousand four hundred twenty-nine children and young adults admitted consecutively to ICUs as part of the Assessment of the Worldwide Acute Kidney Injury, Renal Angina and Epidemiology Study.

Measurements And Main Results: The Kidney Disease: Improving Global Outcomes creatinine and urine output acute kidney injury criteria were applied sequentially, and the two stages were summed, generating an Acute Kidney Injury (AKI) Score ranging from 1 to 6. The primary outcome was 28-day mortality; secondary outcomes were time until ICU discharge and nonrecovery from acute kidney injury. Models considered associations with AKI Score, assessing the relationship unadjusted and adjusted for covariates. Twenty-eight-day mortality and nonrecovery from acute kidney injury were modeled using logistic regression. For 28-day ICU discharge, competing risks analysis was performed. Although AKI Scores 1-3 had similar mortality to no Acute Kidney Injury, AKI Scores 4-6 were associated with increased mortality. Relative to No Acute Kidney Injury, AKI Scores 1-6 were less likely to be discharged from the ICU within 28 days. Relative to AKI Score 1, AKI Scores 2-6 were associated with higher risk of nonrecovery. Within the traditional Kidney Disease: Improving Global Outcomes Stage 3 acute kidney injury cohort, when compared with AKI Score 3, AKI Scores 4-6 had increased mortality, AKI Scores 5-6 had prolonged time to ICU discharge, and AKI Score 6 experienced higher nonrecovery rates.

Conclusions: Cumulative application of the creatinine and urine output criteria characterizes renal excretory and fluid homeostatic dysfunction simultaneously. This Acute Kidney Injury score more comprehensively describes the outcome implications of severe acute kidney injury than traditional staging methods.
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http://dx.doi.org/10.1097/CCM.0000000000005073DOI Listing
April 2021

Pediatric Immunization Practices in Nephrotic Syndrome: An Assessment of Provider and Parental Knowledge.

Front Pediatr 2020 5;8:619548. Epub 2021 Feb 5.

Division of Pediatric Nephrology, Department of Pediatrics, University of Michigan, Ann Arbor, MI, United States.

Children with nephrotic syndrome (NS) are at high risk for vaccine-preventable infections due to the immunological effects from the disease and concurrent treatment with immunosuppressive medications. Immunizations in these patients may be deferred due to their immunosuppressive treatment which may increase the risk for vaccine-preventable infections. Immunization practices in children with NS continue to vary among pediatric nephrologists. This raises the question of whether children with NS are receiving the recommended vaccinations at appropriate times. Therefore, it is critical to understand the practices and patient education provided by physicians to patients on the topic of vaccinations. After informed consent, parents/guardians of 153 pediatric patients (<18 years old) diagnosed with NS from 2005 to 2018 and 50 pediatric nephrologists from 11 participating centers completed anonymous surveys to evaluate immunization practices among pediatric nephrologists, assess the vaccine education provided to families of children with NS, assess the parental knowledge of immunization recommendations, and assess predictors of polysaccharide pneumococcal vaccine adherence. The Advisory Committee on Immunization Practices (ACIP) Immunization 2019 Guideline for those with altered immunocompetence was used to determine accuracy of vaccine knowledge and practices. Forty-four percent of providers self-reported adherence to the ACIP guidelines for inactive vaccines and 22% to the guidelines for live vaccines. Thirty-two percent of parents/guardians reported knowledge that aligned with the ACIP guidelines for inactive vaccines and 1% for live vaccines. Subjects residing in the Midwest and provider recommendations for vaccines were positive predictors of vaccine adherence ( < 0.001 and 0.02, respectively). Vaccine recommendation by medical providers is paramount in vaccine adherence among pediatric patients with NS. This study identifies potential educational opportunities for medical subspecialty providers and family caregivers about immunization recommendations for immunosuppressed patients.
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http://dx.doi.org/10.3389/fped.2020.619548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901920PMC
February 2021

Hypertension in Childhood Nephrotic Syndrome.

Front Pediatr 2019 16;7:287. Epub 2019 Jul 16.

Pediatric Nephrology and Hypertension, Stony Brook Children's Hospital, Stony Brook, NY, United States.

Arterial hypertension (HTN) is commonly encountered by clinicians treating children with steroid sensitive (SSNS) and steroid resistant nephrotic syndrome (SRNS). Although the prevalence of HTN in SSNS is less documented than in SRNS, recent studies reported high prevalence in both. Studies have estimated the prevalence of HTN in different patient populations with NS to range from 8 to 59.1%. Ambulatory HTN, abnormalities in BP circadian rhythm, and measures of BP variability are prevalent in patients with NS. Multiple mechanisms and co-morbidities contribute to the pathophysiology of HTN in children with NS. Some contributing factors are known to cause acute and episodic elevations in blood pressure such as fluid shifts, sodium retention, and medication side effects (steroids, CNIs). Others are associated with chronic and more sustained HTN such as renal fibrosis, decreased GFR, and progression of chronic kidney disease. Children with NS are more likely to suffer from other cardiovascular disease risk factors, such as obesity, increased measures of arterial stiffness [increased carotid intima-media thickness (cIMT), endothelial dysfunction, increased pulse wave velocity (PWV)], impaired glucose metabolism, dyslipidemia, left ventricular hypertrophy (LVH), left ventricular dysfunction, and atherosclerosis. Those risk factors have been associated with premature death in adults. In this review on HTN in patients with NS, we will discuss the epidemiology and pathophysiology of hypertension in patients with NS, as well as management aspects of HTN in children with NS.
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http://dx.doi.org/10.3389/fped.2019.00287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646680PMC
July 2019

Editorial: Nephrotic Syndrome in Pediatric Patients.

Front Pediatr 2017 3;5:167. Epub 2017 Aug 3.

Division of Pediatric Nephrology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, New York, NY, United States.

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http://dx.doi.org/10.3389/fped.2017.00167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540939PMC
August 2017

Left Ventricular Hypertrophy in Pediatric Hypertension: A Mini Review.

Front Pediatr 2017 11;5:101. Epub 2017 May 11.

Division of Pediatric Nephrology and Hypertension, Stony Brook Children's Hospital, School of Medicine, Stony Brook, NY, USA.

Adults with arterial hypertension (HTN) have stroke, myocardial infarction, end-stage renal disease (ESRD), or die at higher rates than those without. In children, HTN leads to target organ damage, which includes kidney, brain, eye, blood vessels, and heart, which precedes "hard outcomes" observed in adults. Left ventricular hypertrophy (LVH) or an anatomic and pathologic increase in left ventricular mass (LVM) in response to the HTN is a pediatric surrogate marker for HTN-induced morbidity and mortality in adults. This mini review discusses current definitions, clinically relevant methods of LVM measurements and normalization methods, its epidemiology, management, and issue of reversibility in children with HTN. Pediatric definition of LVH and abnormal LVM is not uniformed. With multiple definitions, prevalence of pediatric HTN-induced LVH is difficult to ascertain. In addition while in adults cardiac magnetic resonance imaging is considered "the gold standard" for LVM and LVH determination, pediatric data are limited to "special populations": ESRD, transplant, and obese children. We summarize available data on pediatric LVH treatment and reversibility and offer future directions in addressing LVH in children with HTN.
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http://dx.doi.org/10.3389/fped.2017.00101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425592PMC
May 2017

Renal and Cardiovascular Morbidities Associated with Status among African-American and Non-African-American Children with Focal Segmental Glomerulosclerosis.

Front Pediatr 2016 17;4:122. Epub 2016 Nov 17.

Pediatric Nephrology, Children's Hospital at Montefiore , Bronx, NY , USA.

Background And Objectives: African-American (AA) children with focal segmental glomerulosclerosis (FSGS) have later onset disease that progresses more rapidly than in non-AA children. It is unclear how genotypes contribute to kidney disease risk, progression, and cardiovascular morbidity in children.

Design Setting Participants And Measurements: We examined the prevalence of genotypes and associated cardiovascular phenotypes among children with FSGS in the Chronic Kidney Disease in Children (CKiD) study; an ongoing multicenter prospective cohort study of children aged 1-16 years with mild to moderate kidney disease.

Results: A total of 140 AA children in the CKiD study were genotyped. High risk (HR) genotypes were present in 24% of AA children (33/140) and were associated with FSGS,  < 0.001. FSGS was the most common cause of glomerular disease in children with HR (89%; 25/28). Of 32 AA children with FSGS, 25 (78%) had HR . Compared to children with low risk and FSGS (comprising 36 non-AA and 7 AA), children with HR developed FSGS at a later age, 12.0 (IQR: 9.5, 12.5) vs. 5.5 (2.5, 11.5) years,  = 0.004, had a higher prevalence of uncontrolled hypertension (52 vs. 33%,  = 0.13), left ventricular hypertrophy (LVH) (53 vs. 12%,  < 0.01), C-reactive protein > 3 mg/l (33 vs. 15%,  = 0.12), and obesity (48 vs. 19%,  = 0.01). There were no differences in glomerular filtration rate, hemoglobin, iPTH, or calcium-phosphate product.

Conclusion: AA children with HR genotype and FSGS have increase prevalence of obesity and LVH despite a later age of FSGS onset, while adjusting for socioeconomic status. Treatment of obesity may be an important component of chronic kidney disease and LVH management in this population.
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http://dx.doi.org/10.3389/fped.2016.00122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110572PMC
November 2016

Krüppel-Like Factor 15 Mediates Glucocorticoid-Induced Restoration of Podocyte Differentiation Markers.

J Am Soc Nephrol 2017 Jan 10;28(1):166-184. Epub 2016 Jun 10.

Department of Pharmacology and Systems Therapeutics and.

Podocyte injury is the inciting event in primary glomerulopathies, such as minimal change disease and primary FSGS, and glucocorticoids remain the initial and often, the primary treatment of choice for these glomerulopathies. Because inflammation is not readily apparent in these diseases, understanding the direct effects of glucocorticoids on the podocyte, independent of the immunomodulatory effects, may lead to the identification of targets downstream of glucocorticoids that minimize toxicity without compromising efficacy. Several studies showed that treatment with glucocorticoids restores podocyte differentiation markers and normal ultrastructure and improves cell survival in murine podocytes. We previously determined that Krüppel-like factor 15 (KLF15), a kidney-enriched zinc finger transcription factor, is required for restoring podocyte differentiation markers in mice and human podocytes under cell stress. Here, we show that in vitro treatment with dexamethasone induced a rapid increase of KLF15 expression in human and murine podocytes and enhanced the affinity of glucocorticoid receptor binding to the promoter region of KLF15 In three independent proteinuric murine models, podocyte-specific loss of Klf15 abrogated dexamethasone-induced podocyte recovery. Furthermore, knockdown of KLF15 reduced cell survival and destabilized the actin cytoskeleton in differentiated human podocytes. Conversely, overexpression of KLF15 stabilized the actin cytoskeleton under cell stress in human podocytes. Finally, the level of KLF15 expression in the podocytes and glomeruli from human biopsy specimens correlated with glucocorticoid responsiveness in 35 patients with minimal change disease or primary FSGS. Thus, these studies identify the critical role of KLF15 in mediating the salutary effects of glucocorticoids in the podocyte.
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http://dx.doi.org/10.1681/ASN.2015060672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198263PMC
January 2017

APOL1-associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts.

Nephrol Dial Transplant 2017 Jun;32(6):983-990

Division of Pediatric Nephrology, University of Michigan School of Medicine, Ann Arbor, MI, USA.

Background: Individuals of African ancestry harboring two variant alleles within apolipoprotein L1 ( APOL1 ) are classified with a high-risk (HR) genotype. Adults with an HR genotype have increased risk of focal segmental glomerulosclerosis and chronic kidney disease compared with those with a low-risk (LR) genotype (0 or 1 variants). The role of APOL1 risk genotypes in children with glomerular disease is less well known.

Methods: This study characterized 104 African-American children with a glomerular disease by APOL1 genotype in two cohorts: the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE).

Results: Among these subjects, 46% had an HR genotype with a similar age at cohort enrollment. For APOL1 HR children, the median age of disease onset was older (CKiD: 4.5 versus 11.5 years for LR versus HR; NEPTUNE: 11 versus 14 years for LR versus HR, respectively) and preterm birth was more common [CKiD: 27 versus 4%; NEPTUNE: 26 versus 12%; combined odds ratio 4.6 (95% confidence interval: 1.4, 15.5)]. Within studies, HR children had lower initial estimated glomerular filtration rate (eGFR) (CKiD: 53 versus 69 mL/min/1.73 m 2 ; NEPTUNE: 74 versus 94 mL/min/1.73 m 2 ). Longitudinal eGFR decline was faster among HR children versus LR (CKiD: -18 versus -8% per year; NEPTUNE: -13 versus -3% per year).

Conclusions: Children with an HR genotype in CKiD and NEPTUNE seem to have a more aggressive form of glomerular disease, in part due to a higher prevalence of focal segmental glomerulosclerosis. These consistent findings across independent cohorts suggest a common natural history for children with APOL1 -associated glomerular disease. Further study is needed to determine the generalizability of these findings.
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http://dx.doi.org/10.1093/ndt/gfw061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837652PMC
June 2017

Assessment of Left Ventricular Mass and Hypertrophy by Cardiovascular Magnetic Resonance Imaging in Pediatric Hypertension.

J Clin Hypertens (Greenwich) 2016 10 14;18(10):976-981. Epub 2016 Mar 14.

Division of Pediatric Nephrology and Hypertension, Stony Brook Children's Hospital, Stony Brook, NY, USA.

Cardiovascular magnetic resonance (CMR) imaging in adults is considered the gold standard for assessment of left ventricular mass (LVM) and left ventricular hypertrophy (LVH). The authors aimed to evaluate agreement of LVM measurements and LVH determination between echocardiography (ECHO) and CMR imaging in children with hypertension (HTN) confirmed by 24-hour ambulatory blood pressure monitoring (ABPM). The children (n=22) underwent contemporaneous ECHO, CMR imaging, and ABPM. Patients had a mean body mass index of 30.9±7.5 (kg/m ), and 81.8% had severe HTN. LVM measured by ECHO was 189.6±62.1 g and by CMR imaging was 164.6±44.7 g (P<.0001). Bland-Altman analysis revealed significant variability between ECHO and CMR imaging in the measurement of LVM. Interobserver error was higher with ECHO than with CMR imaging. ECHO had high sensitivity and low specificity in LVH determination. In conclusion, ECHO overestimates LVM and is less accurate in measuring LVM as compared with CMR imaging in children with HTN. Further prospective study using CMR imaging to assess LVM in children is warranted.
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http://dx.doi.org/10.1111/jch.12808DOI Listing
October 2016

Rituximab in post-transplant pediatric recurrent focal segmental glomerulosclerosis.

Pediatr Nephrol 2013 Feb 4;28(2):333-8. Epub 2012 Oct 4.

Weill Cornell Medical College, Helmsley Towers 3, Box 176, New York, NY 10021, USA.

Background: Focal segmental glomerulosclerosis (FSGS) recurs in 20-40 % of allografts. Plasmapheresis (TPE) has been one of the mainstays of treatment with variable results. Rituximab (RTX), a monoclonal antibody to the protein CD20, is being used for treatment of recurrent FSGS (recFSGS) but pediatric experience is limited.

Methods: We conducted a retrospective review of eight patients with recFSGS, treated with RTX (1-4 doses) after having minimal response to TPE. Complete response was defined as a decrease in urine protein creatinine ratio (Up/c) to less than 0.2 and partial response was a decrease in Up/c ratio by 50 % of baseline and in the sub-nephrotic range (U p/c <2).

Results: Complete response was seen in two of eight patients, and partial response was seen in four of eight patients. Two patients had no response. At last follow-up, all the partial responders had sub-nephrotic range proteinuria (Up/c ratios ranging from 0.29 to 1.6). Delayed response, up to 9 months post-RTX, was also seen in some of the patients. Significant complications such as rituximab-associated lung injury (RALI), acute tubular necrosis, and central nervous system(CNS) malignancy were also observed in our case series.

Conclusions: Rituximab can be used with caution as a treatment for recFSGS. Efficacy is variable from none to complete response. Even partial reduction in proteinuria is of benefit in prolonging the life of the allograft. Long-term, multicenter studies are needed to prove its sustained efficacy in those who respond and to monitor for serious adverse effects.
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http://dx.doi.org/10.1007/s00467-012-2314-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3541458PMC
February 2013

Recurrent focal segmental glomerulosclerosis in renal allograft recipients: role of human leukocyte antigen mismatching and other clinical variables.

Int J Nephrol 2011 15;2011:506805. Epub 2011 Jun 15.

Department of Pediatric Nephrology, Albert Einstein College of Medicine, Bronx, NY 10467, USA.

Recurrence of focal segmental glomerulosclerosis (FSGS) after renal transplantation impacts long-term graft survival and limits access to transplantation. We hypothesized that HLA donor/recipient matching could be used as a surrogate marker of recurrence. In a retrospective study of 42 pediatric and 77 adult subjects with primary FSGS, transplanted from 1990 to 2007 at a single center, we analyzed the degree of donor/recipient HLA compatibility and other clinical variables associated with FSGS recurrence. There were total of 131 allografts for primary FSGS (11 subjects were transplanted twice, and 1 had a third allograft) with 20 cases of FSGS recurrence (17 children) in the primary allograft, and two children who had FSGS recurrence in the second allograft. Fifty-two subjects (40%) were African American, and 66 (50%) Caucasians. Recurrent FSGS and controls were not different for age at transplant, gender, donor source, acute/chronic rejection episodes, and HLA matches. Recurrent FSGS was not associated with HLA mismatches; power equals 83%. Immunosuppressive regimen had no effect on recurrence of FSGS, P = .75. Recurrent FSGS is not associated with HLA mismatching, acute cellular or vascular rejection, and occurs primarily in the pediatric population.
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http://dx.doi.org/10.4061/2011/506805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3132668PMC
July 2011

Hypertension, chronic kidney disease, and renal pathology in a child with hermansky-pudlak syndrome.

Int J Nephrol 2011 5;2011:324916. Epub 2011 Jul 5.

Pediatric Nephrology, The Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY 10467, USA.

We report a child with Hermansky-Pudlak Syndrome (HPS) and chronic kidney disease (stage II) with histological diagnosis of focal segmental glomerulosclerosis (FSGS). A 15-year-old male of Puerto Rico ancestry with history of HPS, hypertension (HTN), asthma, obesity, and chronic kidney disease (CKD) stage II presented with new-onset proteinuria without edema. His blood pressure had been controlled, serum creatinine had been 0.9-1.4 mg/dL, and first morning urine protein/creatinine ratio (UPC) ranged from 0.2 to 0.38. Due to persistent nonorthostatic proteinuria with CKD, renal biopsy was performed and FSGS (not otherwise specified) with chronic diffuse tubulopathy (tubular cytoplasmic droplets) and acute tubular injury was reported. Ceroid-like material is known to infiltrate tissues (i.e., lungs, colon, and kidney) in HPS, but the reason for the renal insufficiency is unknown. Nonspecific kidney disease and in one adult case IgA nephropathy with ANCA-positive glomerulonephritis have previously been reported in patients with Hermansky-Pudlak syndrome. To our knowledge, we report the first pediatric renal pathology case of HPS associated with CKD. This paper discusses presentation and management of renal disease in HPS.
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http://dx.doi.org/10.4061/2011/324916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3132663PMC
July 2011

Progression of glomerular and tubular disease in pediatrics.

Semin Nephrol 2009 Jul;29(4):412-24

Division of Nephrology, Department of Pediatrics, Albert Einstein College of Medicine, The Children's Hospital at Montefiore, 3326 Bainbridge Ave., Bronx, NY 10467, USA.

Chronic kidney disease may be stimulated by many different etiologies, but its progression involves a common, yet complex, series of events that lead to the replacement of normal tissue with scar. These events include altered physiology within the kidney leading to abnormal hemodynamics, chronic hypoxia, inflammation, cellular dysfunction, and activation of fibrogenic biochemical pathways. The end result is the replacement of normal structures with extracellular matrix. Treatments presently are focused on delaying or preventing such progression, and are largely nonspecific. In pediatrics, such therapy is complicated further by pathophysiological issues that render children a unique population.
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http://dx.doi.org/10.1016/j.semnephrol.2009.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380145PMC
July 2009

Laser capture microdissection of kidney tissue.

Methods Mol Biol 2009 ;466:73-82

Department of Pediatrics, The Children's Hospital at Montefiore, Albert Einstein College of Medicine, New York, NY, USA.

Kidney tissue laser capture microdissection (LCM) is of great clinical relevance since genome wide studies on total kidney messenger RNA (mRNA) potentially miss important factors involved in the pathogenesis of the disease in glomeruli and tubules. This technique is readily applicable to study mRNA from isolated glomeruli and tubules of human kidney biopsy material. In this chapter we present a "cook-book" practical approach of utilizing LCM in combination with RNA isolation technique in downstream applications in nephrology.
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http://dx.doi.org/10.1007/978-1-59745-352-3_6DOI Listing
February 2009

Increased prevalence of renal and urinary tract anomalies in children with congenital hypothyroidism.

J Pediatr 2009 Feb 27;154(2):263-6. Epub 2008 Sep 27.

Division of Pediatric Nephrology, The Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY 10467, USA.

Objective: We investigated the prevalence of congenital renal and urologic anomalies in children with congenital hypothyroidism to determine whether further renal and urologic investigations would be of benefit.

Study Design: Prevalence of congenital hypothyroidism was obtained from the New York State Congenital Malformation Registry. The occurrence of urinary tract anomalies were calculated for children with congenital hypothyroidism and compared to children without congenital hypothyroidism. In addition we obtained congenital hypothyroidism data from New York State newborn screening, and the cases were matched to Congenital Malformation Registry.

Results: Analysis of Congenital Malformation Registry data showed 980 children with congenital hypothyroidism and 3 661 585 children without congenital hypothyroidism born in New York State (1992-2005). Children with congenital hypothyroidism have a significantly increased risk of congenital renal and urological anomalies with the odds ratio (OR) of 13.2 (10.6-16.5). The other significantly increased defects in congenital hypothyroidism were cardiac, gastrointestinal, and skeletal. Analysis of matched data confirmed an increase of congenital renal and urologic anomalies with OR of 4.8 (3.7-6.3).

Conclusions: Children with congenital hypothyroidism have an increased prevalence of congenital renal and urologic anomalies. We suggest that these children should be evaluated for the presence of congenital renal and urologic anomalies with renal ultrasonography, and that further studies of common genes involved in thyroid and kidney development are warranted.
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http://dx.doi.org/10.1016/j.jpeds.2008.08.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749842PMC
February 2009

Outcome of dialysis in children with human immunodeficiency virus infection.

Pediatr Nephrol 2009 Jan 23;24(1):171-5. Epub 2008 Sep 23.

Division of Pediatric Nephrology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.

Human immunodeficiency virus (HIV) infection accounts for an unknown percentage of children with end-stage kidney disease (ESKD). Our objective was to compare the outcome of renal replacement therapy (RRT) in subjects with ESKD due to HIV and other diagnoses and to examine the prevalence of ESKD due to HIV. We analyzed Kt/V, morbidity, mortality, echocardiography, nutritional, and transplant status in 12 dialysis patients with HIV and 32 without HIV followed at our center between February 2002 and February 2007. Body mass index (BMI) was lower and Kt/V higher in HIV than in non-HIV patients. Shortening fraction was significantly lower in HIV patients. There were six deaths in the HIV group and one in the non-HIV group over the study period. Hemodialysis (HD) is the prevalent mode of RRT in HIV in urban settings, and its adequacy as measured by Kt/V was higher in HIV patients than in non-HIV patients. Decreased BMI and cardiovascular disease may be associated with increased mortality in children with HIV on RRT.
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http://dx.doi.org/10.1007/s00467-008-0976-xDOI Listing
January 2009

The role of osteopontin in the development of albuminuria.

J Am Soc Nephrol 2008 May;19(5):884-90

Division of Nephrology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

Several gene array studies have suggested that osteopontin (Opn) expression strongly correlates with albuminuria and glomerular disease. Urinary Opn concentration and kidney Opn immunoreactivity were found to be increased in patients with steroid-sensitive nephrotic syndrome. In addition, renal Opn mRNA was increased in the Ins2(Akita) mouse model of type 1 diabetic nephropathy, in the LPS-induced albuminuria model, and in glomeruli of puromycin aminonucleotide-induced nephrotic rats. Opn knockout mice did not develop albuminuria in response to LPS injection, and Opn knockout mice were protected from diabetes-induced albuminuria and mesangial expansion. In the glomerulus, Opn immunostaining was increased specifically in podocytes. Treatment of podocytes with recombinant Opn activated the NF-kappaB pathway, increased expression of urokinase plasminogen activator and matrix metalloproteinases 2 and 9, and increased podocyte motility. Taken together, these results indicate that Opn plays an important role in the development of albuminuria, possibly by modulating podocyte signaling and motility.
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http://dx.doi.org/10.1681/ASN.2007040486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386721PMC
May 2008

Urinary cytokines and steroid responsiveness in idiopathic nephrotic syndrome of childhood.

Am J Nephrol 2008 3;28(1):83-90. Epub 2007 Oct 3.

Pediatric Nephrology, The Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY 10467, USA.

Background/aim: Steroid-resistant nephrotic syndrome (SRNS) has been associated with activation of TGF-beta(1) and progression to chronic kidney disease. Steroid-sensitive nephrotic syndrome (SSNS) has been associated with activation of T-cells and favorable outcome. Our objective was to distinguish SRNS from SSNS and focal segmental glomerulosclerosis (FSGS) from minimal change disease (MCD) on the basis of urinary cytokine profile.

Method: We used a high-throughput cytokine array. ICAM-1 and TGF-beta(1) in urine and kidney tissue were evaluated by ELISA and immunohistochemistry (IHC), respectively.

Results: Age, gender, race, body mass index, and glomerular filtration rate were similar among groups. There were no statistically significant differences between SRNS (n = 12) and SSNS (n = 12) in regard to the presence of hypertension, treatment with ACE inhibitors, and renal histology. Arrays detected a 1- to 5.5-fold increase in urinary cytokine expression in subjects with idiopathic nephrotic syndrome (INS) as compared to controls. Using ELISA, urinary excretion of ICAM-1 was significantly higher in INS subjects than in controls (control group, n = 12; p = 0.005), but it did not differentiate SRNS from SSNS, or FSGS from MCD. IHC failed to reveal differences in renal tissue expression of ICAM-1 among controls, SRNS and SSNS. There were no significant differences among controls, and patients with SRNS and SSNS in the urinary excretion of TGF-beta(1) (p = 0.21). However, urinary TGF-beta(1) levels were significantly higher in FSGS than in MCD (p = 0.03), and IHC showed increased immunoreactivity in FSGS.

Conclusion: Our data indicate that urinary TGF-beta(1) was able to differentiate between FSGS and MCD but was not a biomarker of steroid responsiveness.
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http://dx.doi.org/10.1159/000109396DOI Listing
December 2007

Genetics of focal segmental glomerulosclerosis.

Pediatr Nephrol 2007 May 9;22(5):638-44. Epub 2007 Mar 9.

Albert Einstein College of Medicine, Bronx, NY, USA.

The recent advances in understanding the pathophysiology of focal segmental glomerulosclerosis (FSGS) and molecular function of glomerular filtration barrier come directly from genetic linkage and positional cloning studies. The exact role and function of the newly discovered genes and proteins are being investigated by in vitro and in vivo mechanistic studies. Those genes and proteins interactions seem to change susceptibility to kidney disease progression. Better understanding of their exact role in the development of FSGS may influence future therapies and outcomes in this complex disease.
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http://dx.doi.org/10.1007/s00467-007-0445-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2467504PMC
May 2007

Association of steroid and cyclosporin resistance in focal segmental glomerulosclerosis.

Pediatr Nephrol 2007 Jun 10;22(6):834-9. Epub 2007 Feb 10.

Pediatric Nephrology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY 10467, USA.

Given the variable response of steroid-resistant nephrotic syndrome (SRNS) to treatment with cyclosporin (CsA), it may be inappropriate to expose all SR patients to additional immunosuppression. How to determine from which patients to withhold CsA is unclear. We tested the hypothesis that in patients with primary focal segmental glomerulosclerosis (FSGS), steroid resistance predicts CsA resistance. We studied 16 children with steroid-dependent (SD) or steroid-resistant (SR) histologically confirmed primary FSGS treated with CsA with no prior exposure to other immunosuppressive medications. All had received at least 4 weeks of daily prednisone, followed by addition of CsA aiming at trough levels of 200 ng/ml. Of the 16 patients, nine (56%) were SR, of whom seven (78%) were CsA resistant and two (22%) were CsA responsive. Seven patients (44%) were SD; all of them (100%) were CsA responsive (P = 0.003, Fisher's exact test). SR patients had faster deterioration of glomerular filtration rate (GFR) over a median follow-up of 21 months (P = 0.06). These data demonstrate that in primary FSGS, steroid resistance may predict CsA resistance. Genetic testing for known mutations associated with resistance to immunosuppression may be advisable before treatment of SR-FSGS patients with cyclosporin. Prospective studies should be conducted to explore this hypothesis.
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http://dx.doi.org/10.1007/s00467-006-0413-yDOI Listing
June 2007

Urinary proteome of steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome of childhood.

Am J Nephrol 2006 7;26(3):258-67. Epub 2006 Jun 7.

Section of Pediatric Nephrology, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10467, USA.

The response to steroid therapy is used to characterize the idiopathic nephrotic syndrome (INS) of childhood as either steroid-sensitive (SSNS) or steroid-resistant (SRNS), a classification with a better prognostic capability than renal biopsy. The majority (approximately 80%) of INS is due to minimal change disease but the percentage of focal and segmental glomerulosclerosis is increasing. We applied a new technological platform to examine the urine proteome to determine if different urinary protein excretion profiles could differentiate patients with SSNS from those with SRNS. Twenty-five patients with INS and 17 control patients were studied. Mid-stream urines were analyzed using surface enhanced laser desorption and ionization mass spectrometry(SELDI-MS). Data were analyzed using multiple bioinformatic techniques. Patient classification was performed using Biomarker Pattern Software and a generalized form of Adaboost and predictive models were generated using a supervised algorithm with cross-validation. Urinary proteomic data distinguished INS patients from control patients, irrespective of steroid response, with a sensitivity of 92.3%, specificity of 93.7%, positive predictive value of 96% and a negative predictive value of 88.2%. Classification of patients as SSNS or SRNS was 100%. A protein of mass 4,144 daltons was identified as the single most important classifier in distinguishing SSNS from SRNS. SELDI-MS combined with bioinformatics can identify different proteomic patterns in INS. Characterization of the proteins of interest identified by this proteomic approach with prospective clinical validation may yield a valuable clinical tool for the non-invasive prediction of treatment response and prognosis.
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http://dx.doi.org/10.1159/000093814DOI Listing
November 2006

Glomerular expression of transforming growth factor-beta (TGF-beta) isoforms in mice lacking CD2-associated protein.

Pediatr Nephrol 2006 Mar 31;21(3):333-8. Epub 2005 Dec 31.

Section of Pediatric Nephrology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY 10467, USA.

Mice lacking CD2-associated protein (CD2AP-/-) develop glomerular lesions resembling human focal segmental glomerulosclerosis (FSGS) between 3-4 weeks of age and die approximately 2 weeks later from massive proteinuria and renal failure. The mechanisms involved in the glomerular injury in this model are unclear. In this study, we used laser capture microdissection (LCM) and real-time PCR, and examined expression of TGF-ss isoforms in CD2AP-/- mice at the level of isolated glomeruli. Total RNA yield from cryosections of 30 glomeruli was 10.71 ng (SD, 5.45) in CD2AP+/+ group (n =7), and 4.20 ng (SD, 2.04) in CD2AP-/- group (n =8), p =0.008. Expression of TGF-ss1 mRNA was increased 1.5-fold in the whole kidney (p =0.030), and twofold in isolated CD2AP-/- glomeruli (p =0.026). Whole kidney mRNA of TGF-ss receptor I (RI) and II (RII) was not different in CD2AP-/- and CD2AP+/+ animals, but it was increased in CD2AP-/- glomerular samples by 4.38-fold (p =0.001) and 11.37-fold (p =0.0163), respectively. By using LCM we confirmed increased glomerular expression levels of TGF-ss isoforms previously described by our group in glomeruli isolated by sieving in CD2AP KO mice and underscored the importance of local factors in the development of glomerulosclerosis.
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http://dx.doi.org/10.1007/s00467-005-2102-7DOI Listing
March 2006

Ventricular arrhythmia following short-acting nifedipine administration.

Pediatr Nephrol 2005 Jul 7;20(7):1000-2. Epub 2005 May 7.

Division of Pediatric Nephrology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.

Short-acting nifedipine is still advocated for use in children with severe hypertension, but is no longer recommended for use in adults because of adverse effects from rapid blood pressure reduction. A 19 year-old adolescent with symptomatic, severe hypertension (blood pressure 180/120) received 10 mg of short-acting nifedipine sublingually for blood pressure reduction. Within minutes after the dose, the patient complained of palpitations. Tachycardia (heart rate 100 beats per minute) and bigeminy were noted on the cardiac monitor. The bigeminy resolved but premature ventricular contractions were noted for the duration of her hospital stay. We hypothesize that reflex sympathetic activation following an abrupt drop in blood pressure may cause arrhythmias because of elevated catecholamine levels. Given this, it may be more appropriate to treat severe hypertension in children with intravenous antihypertensive agents that can be titrated to produce controlled reductions in blood pressure.
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http://dx.doi.org/10.1007/s00467-005-1854-4DOI Listing
July 2005

How are hypertensive children evaluated and managed? A survey of North American pediatric nephrologists.

Pediatr Nephrol 2005 Jun 5;20(6):791-7. Epub 2005 Apr 5.

Division of Pediatric Nephrology, Montefiore Medical Center, Bronx, NY 10467, USA.

To assess how children with hypertension are currently evaluated and managed, we surveyed 438 North American pediatric nephrologists on how they measure blood pressure (BP), BP goals used in pharmacologically treated patients, and antihypertensive drug choices. 190 replies were received (43% response rate), and 185 were analyzable. Oscillometric and aneroid sphygmomanometers were the most commonly used devices for office BP measurement (74.8% of respondents). Ambulatory blood pressure monitoring was used by 63% of respondents. Goal BP in pharmacologically treated patients was set at the 95th percentile by 39% of respondents, and at the 90th percentile by 59%. Only 37% used a different goal BP in children with hypertension and renal disease; of these, 85% used a lower goal and 15% a higher goal. For hypertensive children with diabetes, 47% used a different goal; 99% lower and 1% higher. Whereas angiotensin-converting enzyme inhibitors (ACEI) and calcium-channel blockers (CCB) were chosen by similar proportions of respondents as initial agents for treatment of primary hypertension, most (84%) chose ACEI as their initial agent for hypertension in children with renal disease. Although most pediatric nephrologists treat hypertensive children to a BP goal below the 90th percentile, most do not use lower goals for patients with renal disease or diabetes, in contrast with current recommendations for treatment of adults with these conditions. These findings highlight the need for further studies to determine whether recommendations for treatment of hypertension in adults should be followed in children.
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http://dx.doi.org/10.1007/s00467-004-1804-6DOI Listing
June 2005