Publications by authors named "Amit Dagan"

19 Publications

  • Page 1 of 1

[PRIMARY HYPERTENSION IN CHILDREN AND ADOLESCENTS].

Harefuah 2021 Apr;160(4):260-265

The Institute of Nephrology, Schneider Children's Medical Center, Petah Tikva, Israel.

Introduction: The prevalence of pediatric primary hypertension (HTN) has increased in the past few decades, most probably related to the increased prevalence of overweight/obesity in this population. According to various estimates 3.5-5% of children and adolescents have HTN. Children and especially adolescents with HTN are at an increased risk for HTN in early adulthood, and for early subclinical cardiovascular morbidity. Therefore, screening for and treatment of pediatric HTN is highly recommended, especially in high risk populations, such as overweight children. In the past few years, new guidelines for the diagnosis, evaluation and treatment of pediatric HTN were published by both the European Society of Hypertension and the American Academy of Pediatrics. The following review will discuss central aspects of the epidemiology, risk factors, definitions, and initial clinical approach of primary HTN in children and adolescents.
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April 2021

Is the prognosis of congenital single functioning kidney benign? A population-based study.

Pediatr Nephrol 2021 Feb 22. Epub 2021 Feb 22.

Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: We investigated the risk of kidney injury among adolescents with and without a congenital single functioning kidney (SFK).

Methods: This retrospective study is based on a medical evaluation database of 17-year-old Israeli conscripts, born during 1989-1999. Those with congenital SFK diagnosis, verified by a pediatric nephrologist's review of the original military medical committee classifications, were compared to the rest of the cohort. Kidney injury (KI) was defined as proteinuria, high blood pressure (BP), or estimated glomerular filtration rate (eGFR) < 90 ml/min/1.73 m prior to army recruitment. Risk factors for KI were examined using logistic regression.

Results: Of 979,630 screened candidates, 353 were diagnosed with SFK. The yearly incidence of SFK gradually increased in the first years of the study, reaching a plateau in 1995 (5.5 ± 1.2/10,000 births/year). The male to female ratio was 2.7:1. Concomitant genital malformations were documented in 5.5% of those with SFK. KI was more prevalent in the SFK than the control group (42.2% vs. 23.5%, p < 0.001). All three components of KI were more common in the SFK than the control group: high BP (31.7% vs. 23.1%, p < 0.001), proteinuria (18.2% vs. 0.4%, p < 0.001), and eGFR <90 ml/min/1.73m (12.0% vs 0.1%, p < 0.001). Multivariate analysis of the SFK group revealed associations of higher mean BMI, male sex, and smaller ultrasonographic kidney length with KI.

Conclusions: This large population-based study documents a significant risk for KI among adolescents with SFK. Obesity represents a major modifiable risk factor for KI, implicating the need for closer follow-up in this group during childhood.
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http://dx.doi.org/10.1007/s00467-021-04980-6DOI Listing
February 2021

Long-term outcomes during 37 years of pediatric kidney transplantation: a cohort study comparing ethnic groups.

Pediatr Nephrol 2021 Jul 18;36(7):1881-1888. Epub 2021 Jan 18.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: This study aimed to evaluate short- and long-term outcomes of kidney transplantation over 37 years in a national referral center and compare outcomes between Israeli Jewish and Arab children.

Methods: Data on 599 pediatric transplantations performed in 545 children during 1981-2017, including demographic parameters, kidney failure disease profile, and pre-transplant dialysis duration, were retrieved from our computerized database and patient files. Patient and graft survival were estimated using the Kaplan-Meier method.

Results: Twenty-year patient survival was 91.4% for live donor (LD) and 80.2% for deceased donor (DD) kidney recipients. Respective 10-year and 20-year graft survival rates for first kidney-only transplants were 75.2% and 47.0% for LD and 60.7% and 38.4% for DD grafts. Long-term graft survival improved significantly (p < 0.001) over the study period for recipients of both LD and DD allografts and reached 7-year graft survival of 92.0% and 71.3%, respectively. The proportion of DD transplantations was higher in the Arab subpopulation: 73.8% vs. 48.4% (p < 0.001). Graft survival was not associated with age at transplantation and did not differ between the Arab (N = 202) and Jewish children (N = 343). Median (IQR) waiting time on dialysis did not differ significantly between the Arab and Jewish children: 18 (10-30) and 15 (9-30) months, respectively (p Mann-Whitney = 0.312).

Conclusions: Good and progressively improving long-term results were obtained in pediatric kidney transplantation at our national referral center, apparently due to expertise gained over time and advances in immunosuppression. Equal access to DD kidney transplant and similar graft survival were found between ethnic groups.
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http://dx.doi.org/10.1007/s00467-020-04908-6DOI Listing
July 2021

Lower prednisone dosing for steroid-sensitive nephrotic syndrome relapse: a prospective randomized pilot study.

Eur J Pediatr 2020 Feb 14;179(2):279-283. Epub 2019 Nov 14.

Institute of Nephrology, Schneider Children's Medical Center of Israel, 4920235, Petach Tikva, Israel.

Relapses of steroid-sensitive nephrotic syndrome are traditionally treated with prednisone 2 mg/kg/day or 60 mg/m/day. Retrospective data support the use of lower doses. We designed a prospective randomized pilot study to investigate the efficacy of different doses in achieving remission of steroid sensitive nephrotic syndrome relapse. The cohort included 30 children with relapsed steroid sensitive nephrotic syndrome, mean age 6.3 ± 3 years and mean disease duration 2.2 ± 1.8 years. The children were randomized to receive 2, 1.5, or 1 mg/kg/day prednisone. The corresponding times to response, defined as the first of 3 consecutive days without proteinuria, were 7.2 ± 1.4, 10.2 ± 5.1, and 9 ± 3.3 days; the difference between the 1.5 and 2 mg/kg/day groups was statistically significant. One patient each in the 1 mg/kg/day and the 1.5 mg/kg/day groups failed to respond and were switched to 2 mg/kg/day, leading to a response after 3 and 10 days, respectively. Mean cumulative prednisone doses in the 3 groups were 45.5 ± 3.4, 42.7 ± 25.9, and 24.9 ± 7.4 mg/kg, respectively (P < 0.05).Conclusion: In the present study, treatment of childhood steroid sensitive nephrotic syndrome relapse with prednisone 1-1.5 mg/kg/day led to a significantly lower cumulative dose than the standard dose. Treatment with a lower dose may be equally safe and effective to the standard dose.What is Known:• Relapses of steroid-sensitive nephrotic syndrome are traditionally treated with standard-dose steroids.• Treatment with corticosteroids may have significant adverse effects mainly with long-term use.What is New:• Treatment of steroid sensitive nephrotic syndrome relapse with 1-1.5 mg/kg/day prednisone may lead to a significantly lower cumulative dose.• Treatment with a lower steroid dose may be as effective as the standard dose in achieving remission of steroid sensitive nephrotic syndrome relapse.
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http://dx.doi.org/10.1007/s00431-019-03506-5DOI Listing
February 2020

Long-term Outcome of 1-step Kidney Transplantation and Bladder Augmentation Procedure in Pediatric Patients.

Transplantation 2018 06;102(6):1014-1022

Institute of Nephrology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.

Background: Guidelines for bladder augmentation (BA) in kidney transplantation (KT) recipients are not well-defined. In our center, simultaneous BA with KT (BA-KT) is performed. We assessed transplantation outcomes of this unique extensive procedure.

Methods: A case-control single center retrospective study. Transplantation outcomes were compared with those of KT recipients who did not need BA.

Results: Compared with 22 patients who underwent KT only, for 9 who underwent BA-KT, surgical complications and the need for revision in the early posttransplantation period were similar; early graft function was better: estimated glomerular filtration rate, 96.5 ± 17.1 versus 79.4 ± 16.6 mL/min at 0 to 6 months (P = 0.02); posttransplantation clean intermittent catheterization was more often needed: by 78% (7/9) versus 13% (3/22); and asymptomatic bacteriuria was more common: 100% versus 9% during the first 6 months (P < 0.001), 55% versus 9% (P = 0.02) and 66.6% versus 9% during the first and second years, respectively (P = 0.004). Urinary tract infection (UTI) incidence was also higher: 100% versus 23% during the first 6 months and 44% versus 9% during the second year posttransplantation. Graft function deteriorated significantly in the BA-KT group by the fifth posttransplantation year: estimated glomerular filtration rate was 47.7 ± 39.7 mL/min versus 69 ± 21.3 mL/min, with only 6 (66%) of 9 functioning grafts versus 100% in the KT only group. Causes of graft loss were noncompliance with drug therapy in 2 patients and recurrent UTIs in 2 patients.

Conclusions: Excellent short-term outcome for simultaneous BA-KT is threatened by graft loss due to a high prevalence of UTIs and patient noncompliance with the demanding complex posttransplantation therapy.
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http://dx.doi.org/10.1097/TP.0000000000002050DOI Listing
June 2018

Increasing Prevalence of Nephrolithiasis in Association with Increased Body Mass Index in Children: A Population Based Study.

J Urol 2018 04 20;199(4):1044-1049. Epub 2017 Oct 20.

Institute of Nephrology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Purpose: Epidemiological studies demonstrate an association of increased body mass index and risk of kidney stone formation in adults. We conducted a population based pediatric study to examine the epidemiology of nephrolithiasis in Israeli children during a 30-year period, and to determine body mass index distribution during the same period.

Materials And Methods: We accessed data from the compulsory medical evaluations of 17-year-old military service candidates in Israel before their enlistment during 1980 to 2013. Candidates for the army with a history of stone disease were compared to those without such a history.

Results: Of 1,908,893 candidates 1,691 reported a history of nephrolithiasis, yielding an average prevalence rate of 88.6 per 100,000. During 1980 to 1995 the average reported prevalence of nephrolithiasis was 69 cases per 100,000. From 1995 onward the reported prevalence increased by an average of 6% yearly, reaching 120 per 100,000 during 2010 to 2012. This increased prevalence was observed for males and females but was more prominent among males. Mean ± SD body mass index of stone formers was higher than that of controls (22.7 ± 3.5 vs 22.1 ± 3.9 kg/m, p <0.001). The trend of increasing body mass index among male candidates during 1995 to 2012 parallels the trend of increasing nephrolithiasis during these years. The odds ratio for nephrolithiasis in candidates with body mass index 30 or greater kg/m was 1.7 (range 1.4 to 2.1) compared to candidates with a body mass index of 18.5 to 24.9 kg/m.

Conclusions: This large, population based study documents an increasing prevalence of nephrolithiasis in children. The possible association of this finding with the increase in body mass index during the same period warrants further investigation.
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http://dx.doi.org/10.1016/j.juro.2017.10.023DOI Listing
April 2018

Improvement in Creatinine Clearance after Open Heart Surgery in Infants as an Early Indicator of Surgical Success.

Isr Med Assoc J 2016 Dec;18(12):735-738

Institute of Cardiac Intensive Care Unit, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.

Background: Early surgical correction of congenital heart malformations in neonates and small infants may be complicated by acute kidney injury (AKI), which is associated with higher morbidity and mortality rates, especially in patients who require dialysis. Glomerular filtration rate (GFR) is considered the best measurement of renal function which, in neonates and infants, is highly dependent on heart function.

Objectives: To determine whether measurements of creatinine clearance after open heart surgery in neonates and young infants can serve as an early indicator of surgical success or AKI.

Methods: We conducted a prospective observational study in 19 neonates and small infants (body weight < 5 kg) scheduled for open heart surgery with cardiopulmonary bypass. Urine collection measurement of creatinine clearance and albumin excretion was performed before and during surgery and four times during 48 hours after surgery.

Results: Mean creatinine clearance was lowest during surgery (25.2 ± 4. ml/min/1.73 m2) and increased significantly in the first 16 hours post-surgery (45.7 ± 6.3 ml/min/1.73 m2). A similar pattern was noted for urine albumin which was highest during surgery (203 ± 31 µg/min) and lowest (93 ± 20 µg/min) 48 hours post-surgery. AKI occurred in four patients, and two patients even required dialysis. All six showed a decline in creatinine clearance and an increase in urine albumin between 8 and 16 hours post-surgery.

Conclusions: In neonates and small infants undergoing open heart surgery, a significant improvement in creatinine clearance in the first 16 hours postoperatively is indicative of a good surgical outcome. This finding has important implications for the early evaluation and treatment of patients in the intensive care unit on the first day post-surgery.
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December 2016

Anemia and markers of erythropoiesis in pediatric kidney transplant recipients compared to children with chronic renal failure.

Pediatr Transplant 2016 Nov 12;20(7):958-962. Epub 2016 Sep 12.

Institute of Nephrology, Schneider Children's Medical Center of Israel, Petach Tikvah, Israel.

PTA and anemia of CKD share a similar pathogenesis. However, PTA may be disproportionate to the reduction in the GFR. Data relating to the mechanism of PTA are scarce. We evaluated the erythropoiesis parameters in pediatric kidney recipients compared to children with CKD. A total of 100 patients (54 post-kidney TX, 46 with CKD) were enrolled in the single-center cohort study. GFR was found to be significantly lower in the CKD group (49.7±22.4 vs 72.9±28.5 mL/min/1.73 m², P<.001); anemia was significantly more common in the TX patients (52% vs 41.3%, P<.001). Iron transferrin saturation and serum ferritin levels were lower in the CKD patients. In both groups, hemoglobin Z scores significantly correlated with GFR (R=.31, P=.07). This correlation was more prominent in the CKD group (R=.43, P=.008) compared to the TX group (R=.31, P=.04). Anemia was significantly more common in the TX patients than in the CKD patients despite a better GFR. The higher prevalence of anemia in the TX group could not be explained by an iron deficiency or reduced EPO production. We speculate that immunosuppressive therapy together with resistance to EPO may play a role in the pathogenesis of post-transplantation anemia.
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http://dx.doi.org/10.1111/petr.12792DOI Listing
November 2016

Impact of Pediatric Chronic Dialysis on Long-Term Patient Outcome: Single Center Study.

Int J Nephrol 2016 15;2016:2132387. Epub 2016 Aug 15.

Institute of Nephrology, Schneider Children's Medical Center of Israel, 49202 Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, 6997801 Tel Aviv, Israel.

Objective. Owing to a shortage of kidney donors in Israel, children with end-stage renal disease (ESRD) may stay on maintenance dialysis for a considerable time, placing them at a significant risk. The aim of this study was to understand the causes of mortality. Study Design. Clinical data were collected retrospectively from the files of children on chronic dialysis (>3 months) during the years 1995-2013 at a single pediatric medical center. Results. 110 patients were enrolled in the study. Mean age was 10.7 ± 5.27 yrs. (range: 1 month-24 yrs). Forty-five children (42%) had dysplastic kidneys and 19 (17.5%) had focal segmental glomerulosclerosis. Twenty-five (22.7%) received peritoneal dialysis, 59 (53.6%) hemodialysis, and 6 (23.6%) both modalities sequentially. Median dialysis duration was 1.46 years (range: 0.25-17.54 years). Mean follow-up was 13.5 ± 5.84 yrs. Seventy-nine patients (71.8%) underwent successful transplantation, 10 (11.2%) had graft failure, and 8 (7.3%) continued dialysis without transplantation. Twelve patients (10.9%) died: 8 of dialysis-associated complications and 4 of their primary illness. The 5-year survival rate was 84%: 90% for patients older than 5 years and 61% for younger patients. Conclusions. Chronic dialysis is a suitable temporary option for children awaiting renal transplantation. Although overall long-term survival rate is high, very young children are at high risk for life-threatening dialysis-associated complications.
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http://dx.doi.org/10.1155/2016/2132387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002458PMC
September 2016

Focal segmental glomerulosclerosis in pediatric kidney transplantation: 30 years' experience.

Clin Transplant 2016 10;30(10):1324-1331

Institute of Nephrology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.

From 1982 to 2011, 53 kidney transplantations (KT) for pediatric focal segmental glomerulosclerosis (FSGS) were recorded in the National Israeli Kidney Transplant Registry (NIKTR): 22-primary (1◦) FSGS, 25-proved/suspected genetic-secondary (2◦) FSGS, six lost/incomplete files/other. Half (56%) of 23 patients with 2◦ FSGS were Israeli-Arabs vs 29% of 1◦ FSGS KT recipients. 1◦ FSGS recurrence occurred in 64% (14/22) of 22 KT in 17 patients aged (median) 14 years vs 1/25 of 2◦ FSGS (P<.001). Early graft days/nonfunction occurred in 9/14 (64%), 2/8 (25%) and 2/25 (4%) of recurrent 1◦ FSGS (rFSGS), nonr1◦ FSGS and 2◦ FSGS, respectively. Twelve biopsies performed in nine of these grafts at (median) 8 days (range 5-60 days) post-KT showed: ATN-5, suspected rejection-4, rFSGS-2, normal kidney-1; rFSGS was diagnosed eventually in 8/9. Dialysis need during the first month post-KT was significantly associated with FSGS recurrence: 6/14 (43%) for rFSGS vs 2/8 (25%) for non-rFSGS. Plasmapheresis (PP) achieved complete and partial rFSGS remission in 5/9 and 2/9 grafts, respectively. Three grafts were excised during the first 60 days post-KT for: nonfunction (1) and bleeding (2). Remaining grafts' GFR was: 78, 42, and 91 mL/min (median) at 5.3, 4.75, and 8 years follow-up for non-rFSGS, rFSGS, and 2◦ FSGS grafts, respectively.

Conclusions: Early PP implementation should be considered after KT for 1◦ FSGS patients with early graft dysfunction despite delayed proteinuria and nonspecific biopsy.
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http://dx.doi.org/10.1111/ctr.12825DOI Listing
October 2016

Is serum CRP level a reliable inflammatory marker in pediatric nephrotic syndrome?

Pediatr Nephrol 2016 08 8;31(8):1287-93. Epub 2016 Mar 8.

Institute of Pediatric Nephrology, Schneider Children's Medical Center of Israel, Petach Tikva, 49202, Israel.

Background: This study tested the hypothesis that during massive proteinuria, C-reactive protein (CRP) may be lost into the urine along with other proteins, making serum CRP (sCRP) level an unreliable marker of infection severity in nephrotic syndrome (NS).

Methods: Children with active NS (n = 23) were compared with two matched control groups: patients with febrile non-renal infectious disease (n = 30) and healthy subjects (n = 16). Laboratory measurements included sCRP, urine protein, creatinine, IgG, and protein electrophoresis. Urinary CRP (uCRP) was measured by ELISA.

Results: Sixty-nine patients were enrolled: 23 patients with NS, 30 patients with non-renal febrile infectious diseases, and 16 healthy children. Median uCRP concentrations were 0 mcg/gCr (0-189.7) in NS, 11 mcg/gCr (0-286) in the febrile group, and 0 mcg/gCr (0-1.8) in the healthy group. The uCRP/creatinine ratio was similar in the NS and healthy groups (p > 0.1) and significantly higher in the febrile group than the other two groups (p < 0.0001). There was no association of uCRP concentration with severity of proteinuria or IgG excretion.

Conclusions: NS in children is not characterized by significant loss of CRP into the urine. Therefore, sCRP may serve as a reliable marker of inflammation in this setting. The significant urinary excretion of CRP in children with transient non-renal infectious disease might be attributable to CRP synthesis in renal epithelial cells.
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http://dx.doi.org/10.1007/s00467-016-3328-2DOI Listing
August 2016

Cryptosporidiosis in children following solid organ transplantation.

Pediatr Infect Dis J 2012 Nov;31(11):1135-8

Institute of Pediatric Nephrology, Schneider Children's Medical Center of Israel, Petah-Tiqva, Israel.

Background: Cryptosporidium parvum is a common cause of diarrhea. In immunocompetent individuals, spontaneous recovery is the rule. In immunocompromised patients, it may cause a serious disease. Data on cryptosporidiosis in children after solid organ transplantation are few. We report on 6 pediatric solid organ recipients with gastroenteritis caused by Cryptosporidium.

Patients And Methods: All episodes of gastroenteritis in solid organ transplant recipients hospitalized in Schneider Children's Medical Center from January 2008 to August 2011 were identified. Data on the episodes with positive staining for Cryptosporidium antigen in stool were reviewed.

Results: Fifty-seven episodes of gastroenteritis were recorded. In 6 (11%) patients (4 kidney recipient, 1 liver and kidney recipient and 1 heart transplant recipient) Cryptosporidium antigen was detected in stool. Mean age at transplantation was 3.7 ± 2 years, mean time between transplantation and cryptosporidial disease was 39 ± 53.9 months. Symptoms included prolonged diarrhea, fever, abdominal pain and weight loss. Mean duration of symptoms before diagnosis was 10.5 ± 8.7 days. In 5 children, kidney function deteriorated, blood concentrations of tacrolimus increased in 5 patients and abnormal values of liver enzymes were detected in 4 patients. All patients were hospitalized and received intravenous fluid replacement and were treated with nitazoxanide for 5-21 days. Two patients had recurrence of symptoms after short course (5 days) therapy. All patients recovered eventually from the disease.

Conclusion: Cryptosporidium should be routinely tested in solid organ transplant recipients with diarrhea. Delay in initiation of treatment can result in serious complications including acute renal failure. Long-term therapy with nitazoxanide (at least 14 days) may facilitate recovery.
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http://dx.doi.org/10.1097/INF.0b013e31826780f7DOI Listing
November 2012

Hypothyroidism in children with steroid-resistant nephrotic syndrome.

Nephrol Dial Transplant 2012 Jun 13;27(6):2171-5. Epub 2011 Dec 13.

Institute of Nephrology, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel.

Background: Non-autoimmune hypothyroidism has been reported in children with congenital nephrotic syndrome. The hypothyroid state was attributed to massive prolonged thyroid hormone loss. However, this endocrine abnormality has not been reported in steroid-resistant nephrotic syndrome (SRNS) despite similar long-standing proteinuria.

Method: We describe all the patients with SRNS in our clinic's follow-up who developed non-autoimmune hypothyroidism.

Results: Five children aged 3-11 years at diagnosis of SRNS and followed for 5-42 months developed hypothyroidism (depressed free thyroxin and elevated thyrotropin levels) without evidence of autoimmune thyroiditis. The diagnosis of hypothyroidism was not temporarily related to disease duration or renal function. The disease was resistant to all therapies, renal function deteriorated in all the patients within 1.5-14.5 years from diagnosis. Despite thyroxine treatment and a decline in renal function, thyroid hormone level normalized only after reaching end stage renal disease (ESRD) and hemodialysis start. Nephrotic syndrome recurrence after kidney transplantation (in three patients with focal segmental glomerulosclerosis) was not accompanied by recurrent hypothyroidism.

Conclusion: It is our impression that non-autoimmune hypothyroidism is a potential significant complication of SRNS, and should be actively sought for especially in cases with renal function deterioration. Hypothyroidism usually resolved when these patients reach ESRD. The incidence and pathogenesis of this condition require further study.
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http://dx.doi.org/10.1093/ndt/gfr665DOI Listing
June 2012

Effect of prenatal dexamethasone on postnatal serum and urinary angiotensin II levels.

Am J Hypertens 2010 Apr 14;23(4):420-4. Epub 2010 Jan 14.

Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, TX, USA.

Background: Prenatal programming of hypertension has been described in humans and in animal models that receive a prenatal insult, but the mechanism for the increase in blood pressure remains elusive.

Methods: In male rats whose mothers received dexamethasone between days 15 and 18 of gestation systemic and urinary levels of angiotensin II were measured to determine whether angiotensin II was a potential factor for the generation (4 weeks of age) or maintenance (8 weeks of age) of hypertension.

Results: A group 4- and 8-week-old male rats that were the product of a pregnancy where the mother received prenatal dexamethasone between days 15 and 18 of gestation had comparable plasma renin and angiotensin II levels to the offspring of vehicle-treated controls. Renal angiotensin II levels were not different at 4 and 8 weeks of age between the controls and the prenatal dexamethasone group. Urine angiotensin II/Creatinine levels, a reflection of filtered and renally generated and secreted angiotensin II, were higher at both 4 and 8 weeks of age in male rats that received prenatal dexamethasone compared to controls.

Conclusions: The high-urine angiotensin II levels in prehypertensive and hypertensive rats that were the product of mothers that received dexamethasone compared to vehicle suggest that luminal angiotensin II may play a role in the generation and maintenance of hypertension in this model of prenatal programming.
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http://dx.doi.org/10.1038/ajh.2009.274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130337PMC
April 2010

Prenatal programming of rat thick ascending limb chloride transport by low-protein diet and dexamethasone.

Am J Physiol Regul Integr Comp Physiol 2009 Jul 29;297(1):R93-9. Epub 2009 Apr 29.

Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9063, USA.

Prenatal administration of dexamethasone and a low-protein diet has been shown to result in hypertension in the offspring when they are adults. The cause for the hypertension is unknown. The purpose of this study was to examine whether there was prenatal programming of thick ascending limb transport. Rats were administered either dexamethasone for 4 days (0.2 mg/kg body wt) by intraperitoneal injection daily between the 15th and 18th day of gestation, or they were fed a low-protein diet (6% protein) or an isocaloric normal protein diet (20% protein) from day 12 gestation until birth. The offspring were studied as adults. Prenatal dexamethasone and dietary protein deprivation resulted in an increase in blood pressure. Offspring of mothers fed a low-protein diet had an increase in medullary but not cortical bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) protein abundance (P < 0.01). There was not a statistically significant increase in medullary NKCC2 by prenatal dexamethasone (P = 0.07). Both prenatal administration of dexamethasone and a low-protein diet resulted in an increase in medullary thick ascending limb chloride transport compared with control (298 +/- 33 pmoles x mm(-1) x min(-1), 280 +/- 26 pmoles x mm(-1) x min(-1), and 191 +/- 21 pmoles x mm(-1) x min(-1), respectively P < 0.05). There was a higher lumen-positive transepithelial potential difference in the prenatal dexamethasone and low-protein group compared with control as well. Administration of furosemide for 24 h resulted in a decrease in blood pressure in the low-protein group but not the control group. This study demonstrates that insults administered to the fetus can program altered sodium transport. Increased tubular sodium transport is a likely cause for the hypertension by prenatal programming.
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http://dx.doi.org/10.1152/ajpregu.91006.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711704PMC
July 2009

Effect of renal denervation on prenatal programming of hypertension and renal tubular transporter abundance.

Am J Physiol Renal Physiol 2008 Jul 9;295(1):F29-34. Epub 2008 Apr 9.

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9063, USA.

Prenatal glucocorticoids are often administered to pregnant women to accelerate pulmonary maturation. We have demonstrated that administration of dexamethasone during specific periods of pregnancy in the rat causes hypertension in the offspring when they are studied as adults. The purpose of the present study was to determine whether the hypertension due to prenatal dexamethasone was mediated by renal nerves. We administered dexamethasone to rats daily for 4 days between days 15 and 18 of gestation. Rats underwent bilateral renal denervation or sham operation at 6 wk of age, and blood pressure was measured at 8 wk of age. Prenatal dexamethasone in the sham operation group resulted in an increase in blood pressure compared with vehicle-treated sham controls (134 +/- 3 vs. 145 +/- 3 mmHg, P < 0.05). Renal denervation did not affect blood pressure significantly in the prenatal vehicle-treated control group but resulted in normalization in blood pressure in the prenatal dexamethasone group and (130 +/- 3 and 128 +/- 5 mmHg, respectively). Prenatal dexamethasone increased type 3 Na+/H+ exchanger (NHE3), Na+K+-2Cl(-) cotransporter (NKCC2), and Na+-Cl(-) cotransporter (NCC), but not alpha-, beta-, and gamma-epithelial Na+ channel (ENaC) protein abundance compared with controls. The increase in NHE3, NKCC2, and NCC protein abundance by prenatal dexamethasone was not seen in 8-wk-old rats 2 wk after renal denervation. Renal denervation did not affect NHE3, NKCC2, and NCC protein abundance in prenatal vehicle-treated animals. This study is consistent with renal nerves playing a role in mediating the hypertension by prenatal programming by dexamethasone.
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http://dx.doi.org/10.1152/ajprenal.00123.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063419PMC
July 2008

Effect of thyroid hormone on the postnatal renal expression of NHE8.

Am J Physiol Renal Physiol 2008 Jan 31;294(1):F198-204. Epub 2007 Oct 31.

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75235-9063, USA.

We previously demonstrated that there are developmental changes in proximal tubule Na(+)/H(+) exchanger (NHE) activity. There is a maturational increase in postnatal brush-border membrane (BBM) vesicle NHE3 protein abundance and decrease in NHE8 protein abundance. The purpose of this study was to determine whether thyroid hormone plays a role in the rat renal maturational isoform switch from NHE8 to NHE3 and whether thyroid hormone regulates NHE8. Administration of thyroid hormone to neonatal rats, before the normal postnatal increase in serum thyroid hormone levels at 3 wk of age, resulted in a premature increase in NHE3/beta-actin BBM protein abundance and mRNA abundance. Thyroid hormone also caused a premature decrease in BBM NHE8/beta-actin protein abundance, whereas there was no change in mRNA expression (standardized to 28s). Rats made hypothyroid from birth were studied at 28 days, after the normal maturational increase in thyroid hormone. In these hypothyroid adult rats, the maturational increase in BBM NHE3 protein abundance and NHE3 mRNA expression was prevented. In contrast, the developmental decrease in BBM NHE8 protein abundance was prevented in hypothyroid adults, but mRNA expression was unchanged in hypothyroid rats. To determine whether the effect of thyroid hormone was due to a direct epithelial effect, we studied normal rat kidney cells in culture. We recently showed that this cell line expresses NHE8, but does not express NHE3. Thyroid hormone caused a decrease in surface expression of NHE8, determined by biotinylation, but total cellular abundance remained unchanged. NHE8 activity, measured as the sodium-dependent rate of intracellular pH recovery from an acid load, was less with thyroid treatment than control. In conclusion, thyroid hormone plays a potential role in the developmental isoform change from NHE8 to NHE3 and decreases NHE8 activity.
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http://dx.doi.org/10.1152/ajprenal.00332.2007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132654PMC
January 2008

Prenatal programming of rat proximal tubule Na+/H+ exchanger by dexamethasone.

Am J Physiol Regul Integr Comp Physiol 2007 Mar 9;292(3):R1230-5. Epub 2006 Nov 9.

Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9063, USA.

Prenatal administration of dexamethasone causes hypertension in rats when they are studied as adults. Although an increase in tubular sodium reabsorption has been postulated to be a factor programming hypertension, this has never been directly demonstrated. The purpose of this study was to examine whether prenatal programming by dexamethasone affected postnatal proximal tubular transport. Pregnant Sprague-Dawley rats were injected with intraperitoneal dexamethasone (0.2 mg/kg) daily for 4 days between the 15th and 18th days of gestation. Prenatal dexamethasone resulted in an elevation in systolic blood pressure when the rats were studied at 7-8 wk of age compared with vehicle-treated controls: 131 +/- 3 vs. 115 +/- 3 mmHg (P < 0.001). The rate of proximal convoluted tubule volume absorption, measured using in vitro microperfusion, was 0.61 + 0.07 nl.mm(-1).min(-1) in control rats and 0.93+ 0.07 nl.mm(-1).min(-1) in rats that received prenatal dexamethasone (P < 0.05). Na(+)/H(+) exchanger activity measured in perfused tubules in vitro using the pH-sensitive dye BCECF showed a similar 50% increase in activity in proximal convoluted tubules from rats treated with prenatal dexamethasone. Although there was no change in abundance of NHE3 mRNA, the predominant luminal proximal tubule Na(+)/H(+) exchanger, there was an increase in NHE3 protein abundance on brush-border membrane vesicles in 7- to 8-wk-old rats receiving prenatal dexamethasone. In conclusion, prenatal administration of dexamethasone in rats increases proximal tubule transport when rats are studied at 7-8 wk old, in part by stimulating Na(+)/H(+) exchanger activity. The increase in proximal tubule transport may be a factor mediating the hypertension by prenatal programming with dexamethasone.
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http://dx.doi.org/10.1152/ajpregu.00669.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096979PMC
March 2007

Tubular and glomerular function in children after renal transplantation.

Pediatr Transplant 2005 Aug;9(4):440-4

Pediatric Nephrology Unit, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.

Glomerular and tubular function of transplanted kidneys were assessed in 46 children aged 15.7 +/- 4.6 yr, 4.2 +/- 2.8 yr after renal transplantation. There were 34 cadaveric, and 12 living-related donors. Twelve patients (26%) had acute episodes (acute tubular necrosis, rejection, or urinary tract infection) during follow-up. All patients were on triple immunosuppression. The mean serum creatinine was 1.5 +/- 0.6 mg/dL. Creatinine clearance (Ccreat) calculated from a 24-h urine collection was 48.0 +/- 19.7 mL/min/1.73 m(2), and that estimated from the Schwartz formula, 61.0 +/- 22.5 mL/min/1.73 m(2). A positive correlation was found between the calculated and estimated clearances. Mean urine concentrating ability was 487 +/- 184 mOsmol/kg, with a value lower than 400 mOsmol/kg in 35% of patients. There was a positive correlation between urine osmolality and estimated Ccreat. Metabolic acidosis (bicarbonate <22 mmol/L) was found in 41% of patients, with relatively alkaline urine and high chloride level. Fractional excretion (FE) of sodium was above 1% in 68% of patients (mean 1.66 +/- 1.06%), and FE(Mg) was above 3% (mean 10.9 +/- 5.2%) in 93% of patients. Tubular reabsorption of phosphate (TP)/glomerular filtration rate (GFR) was 3.2 +/- 0.8 mg/dL glomerular filtrate (GF). FE(K), FE(UA), and Ca/creatinine in urine were normal. There were no functional group differences between the cadaveric and living-related kidneys. Significant group differences were found in those with acute episodes and those with a normal course. Estimated Ccreat was 54 +/- 20 vs. 67 +/- 20 mL/min/1.73 m(2) in the acute episodes and the normal course groups, respectively. Also, the FE(NA), FE(UA), and FE(Mg) were higher in the acute episodes group -2.3 +/- 1.6, 10.6 +/- 4.4, and 14.8 +/- 6.5%, respectively, compared with the normal course group -1.4 +/- 0.6, 8.2 +/- 2.8, and 9.6 +/- 4.0%, respectively. There were no between-group differences in plasma bicarbonate, FE(K), TP/GFR, and urine osmolality. We believe that most, if not all tubular dysfunctions in the transplanted kidney are secondary to renal failure and interstitial damage from acute episodes and nephrotoxic drugs. These dysfunctions are similar to those in chronic renal failure, where interstitial fibrosis plays a role in kidney function deterioration.
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http://dx.doi.org/10.1111/j.1399-3046.2005.00302.xDOI Listing
August 2005