The prevalence of hypertension and abnormal kidney function in children with sickle cell disease -a cross sectional review.

BACKGROUND: Renal disease is a known contributor to mortality in adults with sickle cell disease (SCD) and renal abnormalities are evident in childhood. Hyperfiltration (evidenced by elevated glomerular filtration rate, GFR) occurs in children with SCD early in disease. However, the incidence of low GFR (<90 ml/min/1.73 m(2)) suggestive of chronic kidney disease (CKD), is not well established. The prevalence of hypertension is also not well known. The goal of this study was to determine the prevalence of hypertension and CKD in a cohort of children with SCD. METHODS: We performed a retrospective chart review of patients followed at the Rainbow Babies and Children's Sickle Cell Disease Clinic who were seen during routine follow up visits. Inclusion criteria were all patients ages 3-18. Exclusion criteria included recent (within 2 weeks) hospitalization and/or episode of acute chest, pain crises, febrile illness or red blood cell transfusion. Data collected included serum creatinine, blood pressure and history of sickle cell complications (acute chest syndrome, stroke or stroke risk). Estimated GFR (eGFR) was calculated using the updated Schwartz creatinine-based estimating formula. Analysis examined the associations among eGFR, blood pressure and sickle cell complications. The Institutional Review Board at University Hospitals Case Medical Center approved this study. RESULTS: A total of 48 children had complete data available. Mean eGFR was 140 mL/min/1.73 m(2) +/- 34.9 (range 71.9-404.2 mL/min/1.73 m(2)). Four patients (8.3%) had eGFRs < 90 mL/min/1.73 m(2), 35 patients (72.9%) had eGFRs > 120 mL/min/1.73 m(2) and 9 patients (18.8%) had eGFRs in the normal range. Eight patients (16.7%) had evidence of elevated blood pressures (pre-hypertension or hypertension). There was no correlation between eGFR and age, and no association of eGFR with acute chest or stroke risk. CONCLUSION: In this SCD cohort, we identified abnormally low eGFR (suggestive of early CKD) in 8.3% of patients and elevated blood pressure in 16.7%. These findings are in contrast to other published studies that show primarily normal or elevated GFR and the absence of or minimal hypertension. These findings indicate that elevated blood pressure and decreased eGFR are not uncommon in children with SCD, and should be more rigorously studied.

The spectrum of polycystic kidney disease in children.

Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are important inherited kidney diseases with distinct clinical features and genetics. Although these diseases have classically been considered "adult" (ADPKD) or "infantile/pediatric" (ARPKD), it is now clear that both diseases can present in children and adults. ADPKD and ARPKD also share important pathophysiologic features, including cilia dysfunction. ADPKD is a systemic disease involving cysts in the kidneys and abdominal organs as well as abnormalities in the heart and vasculature. Although it typically presents in adults, ADPKD has been diagnosed in fetuses, infants, children, and adolescents. The majority of children diagnosed with ADPKD are asymptomatic. Those with symptoms typically present with hypertension or gross hematuria. Routine screening for renal cysts in asymptomatic children who have a parent with ADPKD is generally not recommended. ARPKD is a disorder confined to the kidneys (polycystic kidneys) and liver (a developmental biliary lesion called congenital hepatic fibrosis). Although most children with ARPKD present in infancy with large, echogenic kidneys, a subset present later in childhood and even adulthood, primarily with complications related to the liver disease. As more patients with ARPKD survive to adulthood, these liver complications are likely to become more prevalent.

The renin-angiotensin system and hypertension in autosomal recessive polycystic kidney disease.

Hypertension is a well-recognized complication of autosomal recessive polycystic kidney disease (ARPKD). The renin-angiotensin system (RAS) is a key regulator of blood pressure; however, data on the RAS in ARPKD are limited and conflicting, showing both up- and down-regulation. In the current study, we characterized intrarenal and systemic RAS activation in relationship to hypertension and progressive cystic kidney disease in the ARPKD orthologous polycystic kidney (PCK) rat. Clinical and histological measures of kidney disease, kidney RAS gene expression by quantitative real-time PCR, angiotensin II (Ang II) immunohistochemistry, and systemic Ang I and II levels were assessed in 2-, 4-, and 6-month-old cystic PCK and age-matched normal rats. PCK rats developed hypertension and progressive cystic kidney disease without significant worsening of renal function or relative kidney size. Intrarenal renin, ACE and Ang II expression was increased significantly in cystic kidneys; angiotensinogen and Ang II Type I receptor were unchanged. Systemic Ang I and II levels did not differ. This study demonstrates that intrarenal, but not systemic, RAS activation is a prominent feature of ARPKD. These findings help reconcile previous conflicting reports and suggest that intrarenal renin and ACE gene upregulation may represent a novel mechanism for hypertension development or exacerbation in ARPKD.

Renin-angiotensin system activation in congenital hepatic fibrosis in the PCK rat model of autosomal recessive polycystic kidney disease.

OBJECTIVES: Congenital hepatic fibrosis (CHF) is an important cause of morbidity and mortality in patients with autosomal recessive polycystic kidney disease (ARPKD). The pathogenesis of CHF remains undefined. Several recent studies suggest that the renin-angiotensin system (RAS) is an important mediator of progressive hepatic fibrosis through activation of profibrotic mediators, such as transforming growth factor-beta (TGF-beta). RAS activation has not previously been studied in patients with CHF or in animal models. The aim of the present study was to characterize RAS expression during the course of CHF in the PCK rat. MATERIALS AND METHODS: Studies were conducted in the PCK rat, an orthologous ARPKD/CHF model, and age-matched normal control Sprague-Dawley rats. Expression of the RAS components, renin, angiotensinogen, angiotensin-converting enzyme (ACE), and angiotensin II type 1 receptor (AT1R), as well as the profibrotic mediator TGF-beta, was examined in cystic PCK and control rat livers at 2, 4, and 6 months of age by quantitative real-time polymerase chain reaction (qRT-PCR). Angiotensin II (ANG II) was examined by immunohistochemistry (IHC). Fibrosis was assessed by IHC using reticulin staining and Masson trichrome. Collagen content was determined by hydroxyproline analysis. RESULTS: Progressive fibrosis and increased hepatic collagen content occurred in PCK rats with age. In 4- and 6-month-old PCK rat livers, ACE gene expression was markedly increased, 8- and 17-fold, respectively, compared with age-matched control livers. Expression of the other RAS components, renin, angiotensinogen, and AT1R were not significantly different. IHC demonstrated prominent ANG II protein expression in periportal regions in PCK rats. In contrast, no expression was noted in control livers. TGF-beta expression was also increased in PCK rat livers with progressive disease. CONCLUSIONS: The present study demonstrates, for the first time, RAS upregulation in an orthologous rat ARPKD/CHF model. Increases in ACE and ANG II, as well as the downstream target, the profibrotic mediator TGF-beta, suggest that RAS activation may be an important mediator of CHF disease progression. The findings also suggest that treatment with RAS inhibitors, specifically ACE inhibitors or AT1R blockers, could be therapeutic in slowing disease progression in CHF.

Diagnosis of pediatric urolithiasis: role of ultrasound and computerized tomography.

PURPOSE: Pediatric urolithiasis is believed to be uncommon, and may present without the classic symptoms of renal colic. The objectives of this study were to describe the presenting features and radiographic evaluation of pediatric urolithiasis, and to determine the accuracy of ultrasound and unenhanced computerized tomography (CT) in detecting urolithiasis. MATERIALS AND METHODS: We retrospectively reviewed the charts of children 0 to 18 years old with urolithiasis. Data collected included age, sex, race, presenting symptoms, radiographic studies performed during initial evaluation, calculus location and family history of urolithiasis. RESULTS: A total of 75 patients had complete data for analysis. Of these patients 54 (72%) had urolithiasis symptoms (flank pain, gross hematuria or both). Patients with urolithiasis symptoms were older at diagnosis (median age 11.9 years vs 1.0 years, p <0.001) and were more likely to have a family history of urolithiasis (54% vs 14%, p = 0.002). The 39 CTs performed were accurate in detecting calculi in children with urolithiasis symptoms (96% to 100%) and in those without symptoms (100%). The 36 ultrasounds performed had more variable accuracy in children with urolithiasis symptoms (33% to 100%) vs those without symptoms (89%). Ultrasound failed to detect urolithiasis in 41% of the patients with urolithiasis symptoms, compared to 5% with CT. CT was also highly accurate regardless of calculus location (89% to 100%), whereas ultrasound was again more variable (kidney 90%, kidney and ureter 75%, ureter alone 38%). CONCLUSIONS: Ultrasound failed to detect calculi in 41% of the children with urolithiasis symptoms, whereas CT was highly accurate in all situations. Unenhanced CT should be performed in all children with persistent urolithiasis symptoms and nondiagnostic ultrasound.

Transforming growth factor alpha (TGF-alpha) and other targets of tumor necrosis factor-alpha converting enzyme (TACE) in murine polycystic kidney disease.

Transforming growth factor-alpha (TGF-alpha) is abnormally expressed in autosomal recessive polycystic kidney disease (ARPKD). Tumor necrosis factor-alpha converting enzyme (TACE), a metalloproteinase, mediates TGF-alpha processing. In this study, we sought to determine whether TGF-alpha was an absolute requirement for renal cystogenesis and whether its absence would modulate disease severity or related growth factors/receptors expression. Bpk heterozygotes were bred with TGF-alpha null mice to produce cystic and noncystic offspring with or without TGF-alpha. Assessments included kidney weight (KW), body weight (BW), blood urea nitrogen (BUN), and kidney and liver immunohistology. Western analysis assessed kidney expression of amphiregulin (AR), epidermal growth factor (EGF), heparin-binding EGF (HB-EGF), and their receptors, EGFR and ErbB4. A PCR-based methodology for genotyping bpk mice was also developed. No significant differences in KW, BW, KW/BW%, or BUN were seen in cystic mice with versus without TGF-alpha. Cystic kidney disease and liver disease histology were similar. AR, EGF, HB-EGF, EGFR, and ErbB4 were abnormally expressed to an equal degree in kidneys of mice with versus without TGF-alpha. Although previous data suggest a critical role of TGF-alpha in murine PKD, these data show that TGF-alpha is not required for renal cyst formation or kidney or liver disease progression. We speculate that the therapeutic effect of WTACE2 could have been due to effects on several TACE targets, including TGF-alpha, AR, and ErbB4, as well as metalloproteinases other than TACE.

Accelerated intravenous rehydration.

To determine whether accelerated intravenous (i.v.) rehydration using a new Isotonic Dehydration Worksheet results in: (1) complications in serum sodium or volume status, and (2) decreased duration of i.v. fluid therapy or length of hospital stay, we conducted a retrospective cohort study utilizing chart review. An intervention group of 98 children, ages 1 month to 12 years, treated with the Isotonic Dehydration Worksheet from December 2000 through March 2001 was compared to a control group of 61 children treated from December 1999 through March 2000 before introduction of the Worksheet. Complication rates were low and did not differ between the 2 groups. Mean unadjusted lengths of i.v. therapy (35.3 vs. 33.7 hours) and of hospital stay (47.0 vs. 49.3 hours) were not significantly different between the 2 groups. Introduction of an accelerated rehydration protocol was well-tolerated by patients but did not result in a significant decrease in the outcome variables examined. Other factors may have a greater impact on the outcome variables, and a prospective study to address these questions is planned.

Accelerated intravenous rehydration.

This study was undertaken to determine whether accelerated intravenous (i.v.) rehydration using a new Isotonic Dehydration Worksheet results in: (1) complications in serum sodium or volume status; and (2) decreased duration of i.v. fluid therapy or length of hospital stay. A retrospective cohort study utilizing chart review method was used. An intervention group of 98 children ages 1 month to 12 years treated with the Isotonic Dehydration Worksheet from December 2000 to March 2001 was compared to a control group of 61 children treated from December 1999 to March 2000 before introduction of the worksheet. Complication rates were low and did not differ between the 2 groups. Mean unadjusted lengths of i.v. therapy (35.3 vs. 33.7 hours) and of hospital stay (47.0 vs. 49.3 hours) were not significantly different between the 2 groups. Introduction of an accelerated rehydration protocol was well tolerated by patients, but did not result in a significant decrease in the outcome variables examined. Other factors may have a greater impact on the outcome variables, and a prospective study to address these questions is planned.

Complications of peritoneal dialysis in children with Eagle-Barrett syndrome.

Eagle Barrett syndrome (EBS) is characterized by the triad of abdominal muscle deficiency, urinary tract abnormalities, and cryptorchidism. Approximately 25% of patients with EBS progress to end-stage renal disease. It is speculated that the abdominal muscular defects in EBS pose technical problems in achieving successful peritoneal dialysis (PD). In this retrospective analysis, we reviewed the medical records of EBS and non-EBS PD patients cared for at Rainbow Babies and Children's Hospital from 1985 to 2002; 5 EBS and 9 non-EBS patients were analyzed. PD duration, total complication rates, and catheter usage rates in the two groups were not significantly different. The two most frequent complications were peritonitis and catheter mechanical malfunction during 103 patient-months in EBS patients and 296 patient-months in non-EBS patients. Peritonitis occurred 1 episode every 20.6 patient-months and 14.8 patient-months in EBS and non-EBS patients, respectively. The time from PD initiation to onset of any complication, including first peritonitis, was not significantly different in the two groups. Although the age at PD initiation was significantly different between the groups, there was no correlation between age at onset of PD and complication rates or time to first complication. Despite their abdominal muscle defects, EBS patients do not have more-frequent PD complications.