Showing papers in "Pediatric Nephrology in 2000"

Molecular basis of renal fibrosis.

Abstract: All progressive renal diseases are the consequence of a process of destructive fibrosis This review will focus on tubulointerstitial fibrosis, the pathophysiology of which will be divided into four arbitrary phases First is the cellular activation and injury phase The tubules are activated, the peritubular capillary endothelium facilitates migration of mononuclear cells into the interstitium where they mature into macrophages, and myofibroblasts/activated fibroblasts begin to populate the interstitium Each of these cells releases soluble products that contribute to ongoing inflammation and ultimately fibrosis The second phase, the fibrogenic signaling phase, is characterized by the release of soluble factors that have fibrosis-promoting effects Several growth factors and cytokines have been implicated, with primary roles suggested for transforming growth factor-beta, connective tissue growth factor, angiotensin II and endothelin-1 Additional factors may participate including platelet-derived growth factor, basic fibroblast growth factor, tumor necrosis factor-alpha and interleukin-1, while interferon-gamma and hepatocyte growth factor may elicit antifibrotic responses Third is the fibrogenic phase when matrix proteins, both normal and novel to the renal interstitium, begin to accumulate During this time both increased matrix protein synthesis and impaired matrix turnover are evident The latter is due to the renal production of protease inhibitors such as the tissue inhibitors of metalloproteinases and plasminogen activator inhibitors which inactivate the renal proteases that normally regulate matrix turnover Fourth is the phase of renal destruction, the ultimate sequel to excessive matrix accumulation During this time the tubules and peritubular capillaries are obliterated The number of intact nephrons progressively declines resulting in a continuous reduction in glomerular filtration

Non-compliance and transfer from paediatric to adult transplant unit.

Abstract: Adolescents and young adults appear to be a particularly high-risk group for problems of non- compliance and associated graft loss. We reviewed the progress of 20 young adults (9 female) who had been transferred to three different adult centres at a mean age of 17.9 years (range 15.7–20.9 years) having been transplanted at a mean age of 14.3 years (range 9.6–18.1 years) in the paediatric unit. Eight transplants failed within 36 months of transfer, and in 7 of 20 (35%) the transplant failure was unexpected (3 <12 months, 3 12–24 months, 1 31 months post transfer). Although many of the patients had recognised problems in family dynamics, only 1 had had a major rejection episode prior to transfer due to admitted non-compliance. In 3 others low cyclosporin levels had been noted. Two young men had been transplanted pre-emptively in the paediatric unit at 15.3 and 16.7 years, and 3 patients had been transferred to the adult unit via the recently established transition clinic. The results suggest that close attention needs to be paid to this group of patients who require ongoing education and support. Improved dialogue between staff of the paediatric and adult units about transition issues is also essential.

Severe left ventricular hypertrophy in pediatric dialysis: prevalence and predictors.

Abstract: Left ventricular hypertrophy (LVH) has been recognized as an independent risk factor for cardiovascular morbidity and mortality in adults with end-stage renal disease. However, the prevalence and severity of LVH in children on chronic dialysis therapy is not well established. Retrospectively, 64 chronic dialysis patients, aged 20 months to 22 years, on chronic dialysis had echocardiographic evaluation of LV mass (LVM) and geometry. Forty-eight (75%) children had LVH, including 22 of 26 (85%) on hemodialysis (HD) and 26 of 38 (68%) on peritoneal dialysis (PD). The prevalence of LVH in patients on HD was significantly higher than those on PD (P=0.02). Abnormal LV geometry was found in 51 of 64 (80%) patients: 25 patients (39%) had eccentric hypertrophy, 3 (5%) had concentric remodelling, and 23 (36%) had concentric LVH. Twenty-six children (41%) had severe LVH, defined as LVM index greater than 51 g/m2.7, which is associated with a fourfold greater risk for development of cardiovascular disease in adults. Patients with severe LVH had a significantly lower hemoglobin level (P=0.027) and longer duration of renal disease prior to the start of dialysis therapy (P=0.003) than patients without LVH. Multiple logistic regression analysis revealed HD as opposed to PD as a significant independent predictor for severe LVH (P=0.036). Higher systolic blood pressure remained in the final model as an independent predictor with a borderline level of significance (P=0.065). The results indicate that severe LVH and abnormal left ventricular geometry are common in young dialysis patients. Better control of blood pressure, anemia, and hypervolemia may be important in prevention or improving LVH.

Progression of renal function in preterm neonates with gestational age ≤32 weeks

Abstract: Serum creatinine (SeCr), creatinine clearance (CrCl), and fractional excretion of sodium (FeNa) were measured in 83 preterm neonates divided into four groups according to gestational age (GA). At birth, there were no differences in mean SeCr values in the four groups nor any significant correlation between initial values and GA. In all groups there was an initial SeCr increase; an inverse correlation between SeCr and GA was observed from the 3rd day of life to the 5th week (p<0.001). CrCl showed a positive correlation to GA from the first week onwards (p<0.001); in each group CrCl values correlated positively to days of life (p=0.0001). Rate of CrCl increase correlated positively to GA(p=0.0005). FeNa showed an inverse correlation to GA from the first week (p<0.001). In each group, the FeNa value correlated negatively to postnatal age (p<0.001) and the velocity of decrease was directly correlated to GA (p=0.0358). Our findings indicate that glomerular function shows a progression directly correlated to GA and postnatal age, while tubular function correlates inversely to the same parameters. The values reported could be useful for following renal function in very low birth weight infants.

The stressed neonatal kidney: from pathophysiology to clinical management of neonatal vasomotor nephropathy.

Abstract: The healthy term, and particularly the premature infant, is born with a very low glomerular filtration rate (GFR), controlled by a delicate balance of intrarenal vasoconstrictor and vasodilator forces. Vasoactive disturbances can easily further reduce the already low GFR. The newborn infant is thus prone to develop vasomotor nephropathy (VMNP) or acute renal failure (ARF). The main causes for ARF at this young age are prerenal mechanisms, and include hypotension, hypovolemia, hypoxemia perinatal asphyxia, and neonatal septicemia. Other causes include the administration of angiotensin converting enzyme inhibitors, indomethacin and tolazoline. The most-important factors governing the ultimate renal prognosis are the severity of the underlying disorder, the rapidity of an accurate diagnosis, prompt treatment, and avoidance of severe iatrogenic complications. The immediate treatment is of particular importance in VMNP, i.e., prerenal ischemic ARF, and consists of correcting abnormalities in fluid homeostasis and reduction of the complications of the acute azotemic state (uremia, hyperkalemia, acidosis, and hypertension). In severe and prolonged (established) ARF, temporary dialysis therapy may be indicated. Prerenal ARF with oliguria or anuria warrants immediate volume resuscitation. Special attention should be given to infants with congestive heart failure (CHF). The sick neonate with persistent oliguria and CHF should be treated with intravenous dopamine. Furosemide (FM) is the second line of therapy for babies with indomethacin-induced ARF. In most other conditions, the therapeutic effect of FM is limited to a transient increase in urine flow, without improving basic renal function. The special conditions of the maturing kidney have to be appreciated in order to protect babies from undue renal injury. With the increasing knowledge of the mechanisms governing the development of ARF, progress has been made in the development of new treatment modalities. For example theophylline, calcium antagonists, ATP-MgCl2, thyroxine, and a variety of cytokines may in the near future be used to prevent or ameliorate VMNP and/or recently established ARF. With a combination of time-honored and new therapeutic strategies, there may well be a brighter future for neonates with vasomotor, prerenal, ischemic ARF.

Dialysis therapy for children with acute renal failure: survey results

Abstract: We surveyed 123 pediatric nephrologists to investigate the current dialytic management of acute renal failure (ARF) in children. Data collected from 92 responding physicians revealed that hemodialysis (HD), peritoneal dialysis (PD), and continuous renal replacement therapy (CRRT) are currently used as the primary means of acute renal replacement therapy in a nearly equal percentage of centers. The preferential use of CRRT appears to be increasing, while PD usage is decreasing except for the youngest infants and those patients likely to develop end-stage renal disease (ESRD). Additional data correlating patient outcome to dialytic modality should be collected to compare the efficacy of the three techniques.

Neonatal hypertension: diagnosis and management

Abstract: Hypertension in the term or preterm neonate may be seen in up to 2% of all infants cared for in the modern neonatal intensive care unit. Although the definition of hypertension in this age group has not been completely standardized, recent studies have provided new normative data that may be used to facilitate identification of such infants. Common causes of hypertension in neonates include thromboembolic events related to umbilical catheterization, congenital problems such as aortic coarctation, structural renal malformations and renovascular disease, as well as acquired renal disease and certain medications. A careful history and physical examination will usually identify the probable cause in most cases without the need for extensive laboratory or radiologic testing. Therapy of neonatal hypertension should be tailored to the severity of the blood pressure elevation, and to the underlying cause of hypertension as appropriate. A wide range of therapeutic agents are now available for management of neonatal hypertension in both the acute and chronic settings. In most cases hypertension will resolve, but some infants may require prolonged treatment.

Risk factors for urolithiasis in children on the ketogenic diet.

Abstract: Kidney stones have been associated with use of the ketogenic diet in children with refractory seizure disorders. We performed a case-control study examining risk factors for the development of stones on the ketogenic diet, and prospectively followed children initiating the ketogenic diet to evaluate the incidence of urolithiasis. Clinical characteristics of 18 children presenting with stones (8 uric acid stones, 6 mixed calcium/uric acid stones, 1 calcium oxalate/phosphate stone, 3 stones not evaluated) were compared with characteristics of non-stone-forming children initiating the ketogenic diet at Johns Hopkins since July 1996. Since July 1996, 112 children initiating the ketogenic diet have been followed for development of stones. Follow-up times on the diet range from 2 months to 2.5 years. Of 112 children, 6 have developed stones (3 uric acid, 3 mixed calcium/uric acid stones) (0.8 children developing stones/ 100 patient-months at risk). Comparisons of children presenting with stones on the ketogenic diet with characteristics of the entire cohort initiating the ketogenic diet suggest younger age at diet initiation and hypercalciuria are risk factors for the development of stones. Prospective evaluation of children initiating the ketogenic diet revealed that almost 40% of patients had elevated fasting urine calcium: creatinine ratios at baseline; this increased to 75% after 6 months on the diet. Median urine pH was 5.5 at diet initiation, and remained at 6.0 thereafter. In a subset of patients tested, urinary citrate excretion fell from a mean of 252 mg/24 h pre diet initiation to 52 mg/24 h while on the diet. Uric acid excretion remained normal. Patients maintained on the ketogenic diet often have evidence of hypercalciuria, acid urine, and low urinary citrate excretion. In conjunction with low fluid intake, these patients are at high risk for both uric acid and calcium stone formation.

Pharmacokinetics of mycophenolate mofetil are influenced by concomitant immunosuppression.

Abstract: The recommended dosage for mycophenolate mofetil (MMF) in combination with cyclosporin (CyA) for pediatric kidney transplant recipients is 600 mg/m2 twice daily (b.i.d.). We recently published pharmacokinetic (PK) profiles of MMF in combination with tacrolimus (FK506): in order to keep the mycophenolic acid (MPA) pre-dose trough concentration between 2 and 5 µg/ml and to avoid side effects, mean MMF doses were reduced to 300 mg/m2 b.i.d.. In order to investigate whether this striking difference was due to alterations of MPA clearance by CyA or FK506, we analyzed PK profiles from 13 patients who received MMF without CyA or FK506, and compared these data with 14 patients who received a combination of MMF and FK506 and 15 patients who received MMF and CyA. Mean area under the curve (AUC) in all PK profiles was 61.9±23.8 µg×h/ml. Although the AUCs did not differ between the groups, the dose per square meter was significantly lower in patients receiving concomitant FK506 compared with CyA, and the dose-normalized AUC was significantly higher. The MMF doses were 1,158±301 mg/m2 per day in the CyA group, 555±289 mg/m2 per day in the tacrolimus group, and 866±401 mg/m2 per day in the group without concomitant calcineurin inhibitor treatment. The apparent clearance of MPA is reduced in combination with tacrolimus. The reason for this remains unknown. There was a trend towards lower dose-normalized AUCs in the CyA group compared with the group without calcineurin inhibitor treatment. We conclude that concomitant medication alters the clearance of MPA. It is noteworthy that there was substantial interindividual variation, despite the rather marked differences between the groups, and therefore we recommend starting MMF in combination with CyA at a dose of 600 mg/m2 b.i.d., in combination with tacrolimus at a dose of 300 mg/m2 b.i.d., and without a calcineurin inhibitor at a dose of 500 mg/m2 b.i.d., and adjusting doses using therapeutic drug monitoring of MPA.

Management of acute renal failure in newborns.

Abstract: Acute renal failure (ARF) is a frequent clinical condition in neonatal intensive care units. Plasma creatinine concentrations should be used with some caution for ARF diagnosis in the first days of life. An intravenous fluid challenge allows differentiation of prerenal failure and intrinsic renal failure. All clinical conditions associated with hypovolemia, hypoxemia, and hypotension in the newborn infant may lead to renal insufficiency, the leading causes being perinatal anoxia-ischemia and sepsis. The initial treatment mainly relies on correction of hypotension, acidosis, and hypoxemia, in order to reduce renal vasoconstriction and improve renal perfusion. If necessary, the main renal replacement therapy is usually peritoneal dialysis even if skilled medical and nursing personnel are available in some neonatal intensive care units to perform hemofiltration and hemodiafiltration safely.

Increased blood pressure but normal renal function in adult women born preterm.

Abstract: It has been suggested that children born small for gestational age may develop hypertension and renal dysfunction in adulthood due to impaired fetal kidney development Very little information on this issue is available on children born preterm The objective of this study was to investigate the relationship between birth weight, blood pressure, and kidney function in adult subjects who were born preterm or born small for gestational age (SGA) Study design: Subjects (n=50), all women born between 1966 and 1974, were evaluated at a mean age of 26±19 years They were allocated to three groups: (1) born before gestational week 32 (n=15), (2) born full term with birth weight 130 mmHg/subject during ABPM was calculated, the preterms had significantly more recordings above this value (P 130 mmHg and >140 mmHg systolic (P<005) compared to the controls SGA subjects were not significantly different from controls There were no significant differences in GFR, ERPF or urinary albumin excretion between the three groups Conclusion: Women born preterm seem to have a disturbance in blood pressure regulation in adulthood, a finding that is not observed for those born small for gestational age Kidney function in early adulthood seems to be normal in subjects born preterm or small for gestational age

Hemostatic problems and thromboembolic complications in nephrotic children.

Abstract: A hypercoagulable state and the risk of thromboembolism in both arterial and venous circulation is a relatively frequent and serious feature of nephrotic syndrome (NS) in children and adults. The aim of this study was to evaluate the coagulation states of children with NS before and after corticosteroid (CS) therapy and to compare the results with a healthy control group. The first group consisted of 49 nephrotic children (30 boys and 19 girls) with a mean age of 6. 5+/-4.9 years (range 1-16 years). The control group included 17 healthy children (9 boys and 8 girls). At the time of admission, all patients were evaluated for the presence of clinical thromboembolism, hematological and biochemical indicators of a hypercoagulative state, and renal disease. This was repeated after CS treatment. Deep vein thrombosis was observed in 2 nephrotic patients who had very low plasma antithrombin III (AT III) levels and fibrinogen levels above 750 mg/dl. Thus, the prevalence of thromboembolism was 4% in our pediatric nephrotic population. The mean AT III level of the study group was 68.2+/-23.4% at the onset of the disease, which was significantly lower than the level of the control group (84.0+/-7. 6%). Plasma AT III levels increased to 74.4+/-15.3% after CS treatment, which correlated with the serum albumin levels. However, there was no correlation with urinary protein excretion. Protein C levels were higher than controls during all stages of the disease in both steroid-responsive and -unresponsive patients. The mean protein S level was similar in both groups. Plasma fibrinogen and cholesterol levels were significantly higher in the study group but decreased to within normal limits with remission. Our study suggests that thromboembolic complications are not infrequent in children with NS, and may be related to low plasma AT III and albumin and high fibrinogen and cholesterol levels.

Experimental intrauterine growth retardation alters renal development.

Abstract: Vascular placental insufficiency is considered a common pathogenic factor in human intrauterine growth retardation (IUGR), resulting in small-for-gestational-age, asymmetric newborns. IUGR neonates experience higher morbidity and mortality rates, as well as a possible contribution towards late sequelae, such as hypertension, and cardiovascular disease in adulthood. To simulate vascular placental insufficiency, an experimental rabbit IUGR model was used. Intrauterine growth retardation was achieved by ligation of 25–30% uteroplacental vessels of half of the fetuses during the last third of gestation. Ischemic fetuses were significantly small, asymmetric, and had a disproportionately small body with a relatively large head. The kidneys from all groups were analyzed for relative estimated glomeruli number (REGN) using an unbiased blind design. The glomeruli number was significantly reduced in the asymmetric IUGR rabbit fetuses, probably due to decreased renal vascular supply. Our results support the concept that the reduced number of glomeruli may contribute to impaired renal function, thus predisposing to neonatal renal dysfunction and late sequelae, such as adult hypertension. This study emphasizes the clinical importance of early IUGR diagnosis and prevention.

Reference intervals for cystatin C in pre- and full-term infants and children.

Abstract: Cystatin C is a non-glycated, 13-kDa basic protein produced by all nucleated cells. Recent studies have indicated that the plasma concentration of cystatin C is a better marker for glomerular filtration rate (GFR) than plasma creatinine, which is most commonly used for this purpose. We established reference values for plasma cystatin C in pre- or full-term infants and children. For comparison we also measured the creatinine concentration in the same samples. Cystatin C was measured by a commercially available immunoturbidimetric method with a Hitachi 704 analyzer in sera obtained from 58 pre-term infants, 50 full-term infants and 299 older children (132 girls, 167 boys, median age 4.17 years, range 8 days to 16 years). No sex differences were found. The pre-term infants had higher cystatin C concentrations (mean 1.88 mg/l, SD 0.36 mg/l) than the full-term (mean 1.70 mg/l, SD 0.26 mg/l, P=0.0145). The reference interval for pre-term infants calculated non-parametrically was 1.34–2.57 mg/l and for full-term infants 1.36–2.23 mg/l. The cystatin C concentration decreased rapidly after birth, and above 3 years of age did not depend on age. The reference interval for children 3–16 years of age calculated non-parametrically was 0.51–1.31 mg/l. Younger children (<1 year: 0.75–1.87 mg/l; 1–3 years: 0.68 –1.60 mg/l) had slightly, but significantly, higher plasma cystatin C levels.

Nephrotic syndrome associated with Kimura disease.

Abstract: Kimura disease presents as benign subcutaneous swelling predominantly around the head and neck region. It has a high incidence of renal involvement. However, the pathogenesis of this association remains elusive. Only 2 pediatric cases and 11 adult cases of Kimura disease with renal involvement have been reported in the literature. In recent years many immunopathogenetic features suggesting an underlying T-cell and related cytokine defect have been noted in Kimura disease. We describe a unique case of an Asian boy who presented with nephrotic syndrome resistant to steroid and cytotoxic therapy, and 5 years later developed cervical lymphadenopathy consistent with Kimura disease. We also review the literature, summarizing the presentation, differential diagnosis, incidence of renal disease, prognosis, immunopathogenetic features, and therapy.

Thromboembolic complications in children with nephrotic syndrome in Bulgaria (1974-1996).

Abstract: Over a period of 22 years, 447 children with nephrotic syndrome (NS) have been retrospectively studied for clinically apparent thromboembolic complications (TEC). The incidence of TEC is 2% (9/447); 16 clinically apparent TEC were registered in 9 children. The incidence of TEC was 1.5% among patients with steroid-sensitive NS and 3.8% among those with steroid-resistant NS. TEC were predominantly venous (81% venous vs. 19% arterial). The most commonly affected vessels were deep leg veins, followed by inferior vena cava (IVC). Rare locations of TEC were also observed – superior vena cava (SVC), mesenteric artery, IVC, and hepatic veins with the development of Budd-Chiari syndrome Depending on the location of the TEC, imaging techniques used were: X-ray, computed tomography, and Doppler sonography. The major iatrogenic risk factor was furosemide, administered to 7 of the 9 children with TEC. In some patients additional predisposing factors were infections, dehydration, trauma, venepuncture, and immobilization. Treatment with heparin was followed by oral anticoagulation. Fibrinolytic therapy was effective in 3 of 4 patients. No new TEC occurred under oral anticoagulant prophylaxis. The outcome was a full recovery in 6 patients and a partial recovery in 1 patient. Two children died – 1 with SVC thrombosis and the other with recurrent TEC affecting cerebral vessels. Although rare, TEC are among the most serious life-threatening complications in children with NS and require intensive care.

Regulatory molecules in kidney development.

Abstract: The molecular regulation of the complex inductive events associated with formation of the vertebrate excretory system has been progressively elucidated as a result of both genetic and tissue culture approaches. Kidney organogenesis is initiated and maintained by a series of reciprocal inductive interactions between different tissues derived from the intermediolateral mesoderm to form the nephrons and collecting system of the metanephric kidney. Recent progress in this area has resulted in the identification of regulatory systems controlling branching morphogenesis of the ureteric bud, formation of the early renal vesicle and the glomerulus. These events are controlled by genes that regulate pattern formation, cellular proliferation, and differentiation in other tissues. Although it is not yet possible to completely identify a complete genetic pathway required for any one of the many steps in nephrogenesis, it is now evident that pathways previously identified in studies of mesenchymal-epithelial inductive mechanisms in limb bud, neural tissues, lung, and gut have direct relevance to the study of these processes in kidney development. For instance, a primary system for pattern formation involving retinoic acid, homeobox genes, sonic hedgehog, fibroblast growth factor (FGF), and an FGF receptor all appear to function in limb, lung, and kidney organogenesis. A major challenge is determining how this common cast of signalling molecules plays a specific role in kidney development essential to nephrogenesis, which results in the unique structural organization of the adult kidney. From this more-sophisticated understanding will come important insights relevant to understanding the molecular basis of developmental malformations of the kidney necessary for the prevention and treatment of these disorders.

Renovascular disease and hypertension in children with neurofibromatosis

Abstract: Neurofibromatosis type 1 (NF1) is associated with vascular lesions, such as renal artery stenosis, and secondary hypertension. The real prevalence is largely unknown, particularly in children. We observed 27 patients with NF1, mean age 12.8 years (range 4.2-24 years), for 2-10 years to assess the association of NF1 with vascular abnormalities and secondary hypertension. Patients were studied with angiography, 24-h blood pressure monitoring, a captopril test, and Doppler ultrasonography of aorta and renal arteries. The prevalence of hypertension was 18.5%; 61.5% of patients studied with angiography had vascular lesions, half of whom were apparently normotensive. However, they had abnormal 24-h blood pressure monitoring, which was a first sign of poor blood pressure control. Those patients with severe hypertension (11.1%) were successfully treated with percutaneous transluminal angioplasty (PTA); stenosis recurred in 2 of 3 patients after a 2-year follow-up period, and was responsive to drugs. We conclude that hypertension is a frequent complication of NF1 in pediatric patients, it is usually secondary to typical vascular lesions, and requires careful follow-up. Ambulatory blood pressure monitoring (24-h) is a sensitive method for detecting initial alterations of the blood pressure pattern. PTA may be an effective treatment in this condition.

New insights into the pathogenesis of renal tubular acidosis--from functional to molecular studies.

Abstract: The diagnosis and classification of renal tubular acidosis (RTA) have traditionally been made on the basis of functional studies. On these grounds, RTA has been separated into three main categories: (1) proximal RTA, or type 2; (2) distal RTA, or type 1; and (3) hyperkalemic RTA, or type 4. In recent years significant advances have been made in our understanding of the subcellular mechanisms involved in renal bicarbonate (HCO3-) and H+ transport. Application of molecular biology techniques has also opened a completely new perspective to the understanding of the pathophysiology of inherited cases of RTA. Mutations in the gene SLC4A4, encoding Na+-HCO3- cotransporter (NBC-1), have been found in proximal RTA with ocular abnormalities; in the gene SLC4A1, encoding Cl(-)-HCO3- exchanger (AE1), in autosomal dominant distal RTA; in the gene ATP6B1, encoding B1 subunit of H+-ATPase, in autosomal recessive distal RTA with sensorineural deafness; and in the gene CA2, encoding carbonic anhydrase II, in autosomal recessive osteopetrosis. Syndromes of aldosterone resistance have been also characterized molecularly and mutations in the gene MLR, encoding mineralocorticoid receptor, and in the genes SNCC1A, SNCC1B, and SCNN1G, encoding subunits of the epithelial Na+ channel, have been found in dominant and recessive forms of pseudohypoaldosteronism type 1, respectively. It can be concluded that, although functional studies are still necessary, a new molecular era in the understanding of disorders of renal acidification has arrived.

Calcium channel blockers: pharmacology and place in therapy of pediatric hypertension

Abstract: The calcium channel blockers (CCBs) are a diverse group of antihypertensive medications with variable pharmacokinetics and clinical effects. Although CCBs have been widely applied to the treatment of hypertensive children, data regarding the pharmacokinetics, efficacy and safety of these agents in children are extremely limited. In this review we briefly summarize the mechanism of action of CCBs and then summarize pertinent pharmacokinetic information on each of the CCBs commonly used in children, including amlodipine, diltiazem, felodipine, isradipine, intravenous nicardipine, nifedipine and verapamil. Clinically important drug interactions and adverse effects are discussed, as well as the potential role of CCBs in renal protection. Available pediatric efficacy and safety data are summarized, and recommendations made regarding the rational use of CCBs in the management of pediatric hypertension.

Peritoneal dialysis catheter infections and peritonitis in children: a report of the North American Pediatric Renal Transplant Cooperative Study.

Abstract: Peritonitis and catheter-related infections remain the two most-common causes of peritoneal dialysis (PD) treatment failure. To define the frequency and risks associated with exit site/tunnel infections (ESI/TI), as well as peritonitis, in pediatric patients on PD, we undertook a retrospective cohort study of patients initiated on PD in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). We examined demographic data and PD catheter characteristics of 1,258 patients, aged < or = 21 years, initiated on PD from 1992 to 1997. We examined the frequency and complications of ESI/TI occurring within 30 days, 6 months, and 1 year of follow-up. For peritonitis episodes, we examined patient risk factors for peritonitis. Almost 11% of patients had an ESI/TI at 30 days, 26% between 30 days and 6 months, and 30% between 6 months and 1 year of follow-up. There was no increased risk of ESI/TI associated with patient age, race, or catheter characteristics. Peritonitis occurred in dialysis patients at a rate of 1 episode per 13.2 patient months. Proportional hazards regression analysis demonstrated that black race, single-cuffed catheters, and upward pointing exit sites were independent risk factors for peritonitis in the pediatric PD population. Patients with ESI/TI had twice the risk of those without these infections of developing peritonitis or needing access revision, and an almost threefold increased risk of hospitalization for access complications/malfunction. ESI/TI occurs commonly in pediatric PD patients. These infections cause significant morbidity, through risk of peritonitis, access revision, and hospitalization for catheter complications. Further study of potentially modifiable risk factors for ESI/TI in pediatric end-stage renal disease patients is warranted.

Renal function in pediatric patients with beta-thalassemia major.

Abstract: In patients with β-thalassemia major, the most important cause of mortality and morbidity is organ failure due to deposits of iron.. In this study, the nature of the kidney injury and possible pathogenetic factors were investigated. Seventy children with β-thalassemia major and 14 age and sex-matched healthy children were involved in the study. Blood and timed urine samples were obtained for hematological and biochemical tests. The mean values of blood urea nitrogen (BUN), serum creatinine, creatinine clearance, serum sodium, urine osmolality, fractional excretion of sodium, potassium, and uric acid were not statistically different between the groups. Serum levels of potassium, phosphorus, and uric acid and the urine volume, high urinary protein to creatinine (UP/Cr), urinary N-acetyl-β-d-glucosaminidase to creatinine (UNAG/Cr), and urinary malondialdehyde to creatinine, (UMDA/Cr) and the tubular phosphate reabsorption (TRP) values were statistically different between two groups (P<0.05). Increased serum levels of potassium, phosphorus, and uric acid in the patient group were attributed to the rapid erythrocyte turnover. The presence of high UP/Cr, UNAG/Cr and UMDA/Cr ratios shows that in these patients with proximal renal tubular damage may be secondary to oxidative lipid peroxidation mediated by the iron overload.

Growth hormone axis overview--somatomedin hypothesis.

Abstract: The possibility that the action of growth hormone (GH) on cartilage is mediated by a separate hormonal agent found in serum was suggested by incubation with hypophysectomized rat costal cartilage. The stability of this tissue permitted long incubations and the measurement of the uptake of 35S-sulfate provided a convenient index of growth stimulation. Under the conditions arbitrarily selected, normal rat serum, but not serum from hypophysectomized rats, induced a great stimulation of 35S uptake. In contrast, GH added directly to cartilage in these incubations was virtually inactive. It was suggested that a serum sulfation factor, now known as insulin-like growth factor-I (IGF-I), was a mediator of GH action. Recently it has been observed that addition of 35S-sulfate after 24 h of preincubation with GH permitted the direct effect of GH to be recognized. Other observations in intact hypophysectomized rats have established that GH can induce the expression of IGF-I in cartilage that acts in an autocrine-paracrine manner. The relative importance of the endocrine and autocrine-paracrine routes of IGF-I action on the growth of cartilage is in dispute. It is clearly established that serum IGF-I exerts a negative feedback on GH secretion by action on the hypothalamus and pituitary. Serum IGF-I concentrations reflect GH action in postnatal life. Measurement of serum IGF-I is the most-valuable index of GH hypersecretion in acromegaly and in conditions of growth impairment. GH receptor deficiency leads to a marked decrease in circulating IGF-I. Hypernutrition and hyperinsulinism of obesity directly promote hepatic IGF-I release and inhibit GH secretion by the pituitary. Differences in hepatic IGF-I synthesis in response to GH may contribute to physiological differences in stature.

Nutrition and growth in relation to severity of renal disease in children

Abstract: Practical joint medical/dietetic guidelines are required for children with chronic renal insufficiency (CRI). Nutritional status and growth were compared in 95 children (59 male) >2 years age with CRI, grouped following [51Cr]-labelled EDTA glomerular filtration rate (GFR, ml/min/1.73 m2) estimations into ’normal’ kidney function [GFR>75 (mean 104 (SD 18.9), n=35], mild (GFR 51–75, n=23), moderate (GFR 25–50, n=19) and severe CRI (GFR<25, n=18). Anthropometry [weight (wt.), height (ht.), and body mass index (BMI)], laboratory investigations and a 3-day dietary record were obtained. All anthropometric indices deteriorated with worsening renal function, from mean SD scores for wt., ht. and BMI in ’normal’ children of 0.32 (SD 1.2), 0.4 (SD 1.0) and 0.1 (SD 1.3), respectively, to values of –1.28 (SD 1.1; P<0.001), –1.52 (SD 1.1; P<0.001) and –0.42 (SD 1.1;NS) in severe CRI. Mean total energy intake decreased from 103% (SD 17) estimated average requirement (EAR) in ’normal’ children to 85% EAR (SD 27; P=0.004) in severe CRI. Mean serum PTH concentrations (normal laboratory range 12–72 ng/l) were higher in moderate [67 ng/l (SD 58), P<0.001] and severe CRI [164 ng/l (SD 164), P<0.001] and mean serum phosphate concentrations were higher in severe CRI (1.54 mmol/l (SD 0.17), P=0.009) compared to ’normal’. Disturbances in nutritional intakes, bone biochemistry and growth occur early in CRI and suggest the need for joint medical/dietetic intervention in children with mild and moderate CRI, in addition to those with more severe CRI.

Factor H and the pathogenesis of renal diseases.

Abstract: Complement factor H is a potent inhibitor of alternative pathway complement activation. The factor H gene, a member of the regulators of complement activation (RCA) gene cluster, encodes two plasma proteins, one 150 kilodaltons (kDa) and one 43 kDa. Homozygous deficiency of factor H results in low plasma levels of complement factor B and C3 and depletion of the terminal complement proteins C5-C9; heterozygotes may have reduced or normal levels of factor B, C3, and C5-C9. Although factor H deficiency is infrequently reported, it has been associated with a number of types of renal disease, the most common being atypical membranoproliferative glomerulonephritis and idiopathic (non-diarrhea-associated) hemolytic uremic syndrome (HUS). The molecular defects responsible for factor H deficiency have been described in only two cases; clearly more research is needed in this area. The possible role of factor H deficiency or dysfunction in the pathogenesis of HUS is discussed.

Treatment of lupus nephritis in children.

Abstract: In children, systemic lupus erythematosus (SLE) is often more severe than in adults. Renal disease is very common in SLE, with clinical symptoms of renal involvement occurring in 30%–70% of patients. In the absence of appropriate treatment the child may die from the disease or progress rapidly to renal failure. However, aggressive treatment regimens, in particular corticosteroids, carry the risk of growth retardation, accelerated atherosclerosis, and severe infectious complications. Lupus nephritis is classified into six groups depending on the severity of the histological lesions. The most-appropriate treatment for optimal efficacy with minimal side-effects depends on the disease severity. Mild lesions (class I or II) require only careful follow-up to identify any disease progression. Patients with class III nephropathy (focal and segmental glomerulonephritis) may have mild clinical symptoms, in which case no specific therapy is indicated, or more-severe symptoms of the nephrotic syndrome, hypertension, and sometimes moderate renal insufficiency. These patients require the same aggressive therapy as those with class IV disease (diffuse proliferative glomerulonephritis). Our current protocol starts with three methylprednisolone pulses followed by 1.5 mg/kg per day oral prednisone and six monthly pulses of cyclophosphamide. After a second renal biopsy the patient may be maintained on azathioprine while the prednisone dosage is slowly tapered. In children with milder disease we use lower doses of oral prednisone (1–1.5 mg/kg per day). Patients with membranous glomerulonephritis (class V) require no specific therapy if they have pure membranous nephropathy, but require aggressive therapy if they have the nephrotic syndrome. In those patients who progress to end-stage renal disease, clinical and serological remission is common and renal transplantation can be performed, as recurrence in the transplant is very rare.

Long-term effects of growth hormone treatment on growth and puberty in patients with chronic renal insufficiency

Abstract: Several prospective trials have shown that recombinant human growth hormone (GH) accelerates growth significantly during the first years of therapy, but the effects of long-term GH therapy with regard to long-term growth response and safety have not yet been established. Forty-five Dutch prepubertal children [28 boys, 17 girls, mean (SD) age 7.8 (3.4) years] with chronic renal insufficiency (CRI) and severe growth retardation started GH therapy between 1988 and 1991 within one of the randomized Dutch trials. Long-term GH therapy, in this study a maximum of 8 years, resulted in a sustained and significant improvement of height standard deviation score (SDS) compared with baseline values (P<0.001). The mean height SDS reached the lower end (-2 SDS) of the normal growth chart after 3 years of GH therapy. During the following years the mean height SDS gradually increased, thereby approaching the mean target height SDS after 6 years of GH therapy. Three factors were significantly associated with the height SDS after 4 years of GH therapy: height SDS at the start (+) of therapy, age at the start of therapy (-), and the duration of dialysis treatment (-). Bone maturation did not accelerate during long-term GH therapy. Children on a conservative regimen at the start of GH therapy had no accelerated deterioration of renal function during 6 years of GH therapy. The average daily GH dose administered over the years had no significant influence on the glomerular filtration rate after 4 years. GH therapy had no adverse effects or significant effect on parathyroid hormone concentration, nor were there any radiological signs of renal osteodystrophy. Puberty started at a median age, within the normal range, of 12.4 years in boys and 12.0 years in girls, respectively. Long-term GH therapy leads to a sustained improvement in height SDS in children with growth retardation secondary to CRI, resulting in a normalization of height in accordance with their target height SDS, without evidence of deleterious effects on renal function or bone maturation. A GH dosage of 4 IU/m2 per day appears efficient and safe. Our long-term data show that final height will be within the normal target height range when GH therapy is continued for many years.

Ureteropelvic junction obstruction: morphological and clinical studies.

Abstract: This study included 27 patients with ureteropelvic (UPJ) obstruction. Both renal parenchyma and the junctional abnormality were examined and correlated with clinical findings. Renal biopsies were categorized into grades 1-4. Those with normal or minimal findings (grade 1 and 2, respectively) had excellent renal function as assessed by radionuclide studies. Those with grade 4 had severe histological abnormalities associated with poor renal function. Grade 3 renal changes were seen in patients whose renal function varied greatly and did not correlate with the extent of the limited histological abnormalities. Although there was great variation in the renal biopsies, glomerulosclerosis was a consistent finding, associated with extracapillary proliferation and periodic acid-Schiff-positive material (? Tamm-Horsfall protein) in the urinary space of glomeruli in 91% (10/11) of grade 3 or 4 renal biopsies. No extracapillary proliferation was seen in grade 1 renal biopsies. The UPJ obstruction area was consistently inflamed and markedly thickened due to varying degrees of perifascicular fibrosis and muscular hypertrophy. Extensive fibrosis with associated muscular atrophy was the most-severe change in this spectrum.

Role of insulin receptors and IGF receptors in growth and development.

Abstract: Observations in targeted mouse mutants and patients with genetic abnormalities grant insight into the various and distinct roles of insulin-like growth factor receptors (IGF-Rs) and insulin receptors (IRs) during early development. While IGF-1Rs (mediating both IGF-1 and IGF-2 actions) are important for embryonic and fetal growth, IRs (mediating IGF-2 rather than insulin action) play a minor role. However, it is an oversimplification to conclude that IGF-1Rs mediate growth and IRs mediate metabolic responses. Mice lacking both IRs and IGF-1Rs are more severely growth retarded than mice lacking either receptor alone. The phenotype of combined deficiency of IRs and IGF-1Rs is similar to the phenotype caused by the absence of IGF-1 and IGF-2. This provides genetic proof that these two receptors account for the entirety of the growth promoting effects of IGF-1 and IGF-2. There is little evidence that hybrid insulin/IGF-1 receptors promote embryonic growth to a significant degree. The clinical presentation regarding severity of growth retardation and metabolic disturbances observed in animal models versus in humans may differ greatly and the reasons will be reviewed in detail.

Echo-enhanced ultrasound voiding cystography in children: a new approach.

Abstract: The development of echo-enhancing agents has significantly improved the detection of the movement of fluid within the urinary tract by ultrasonography (US). The purpose of our study was to compare ultrasound voiding cystography (USVC) for the detection of vesicoureteric reflux (VUR) in children with direct radionuclide voiding cystography (DRVC). Ninety-nine children, aged 1.1-12.3 years, with 198 potentially refluxing units, were investigated simultaneously by DRVC and USVC. The indications for cystography were urinary tract infection, follow-up of a previously detected VUR, and screening of siblings of children with VUR. During the investigation an echo-enhancing agent (Levovist) was administered intravesically through a catheter already in place for the DRVC. The movement of both agents, radiotracer and Levovist, was registered simultaneously by a computerized gamma camera and US, respectively. The results were analyzed with DRVC representing the reference diagnostic test. The overall sensitivity and specificity of USVC for the detection of VUR were 79% and 92%, respectively. USVC may represent a reliable diagnostic tool for the detection and follow-up of VUR in children.