Use of experimental models to study the development of renal function

By use of animal experiments it has been demonstrated that renal cells are immature at birth. Membrane transport is quantitatively and qualitatively different. The control of fluid and electrolyte balance is therefore different in infancy. The increased filtered load at birth as well as hormones will induce tubule maturation. The use of animal experiments will in the future give an insight into how external factors influence growth and maturation.     

Pharmacologic probing of renal development in the neonatal rat

This study was designed to examine the ontogeny of renal functions in the neonatal rat using various pharmacologic agents as probes. The renal responses of 2-, 6-, and 10-day-old rats to diuretic agents known to act on proximal tubules, loops of Henle and distal tubules were assessed. These included acetazolamide, furosemide, mercaptomerin, chlorothiazide and amiloride. Following administration of a diuretic agent, urine was collected at 90-min intervals for 6 h and urine volume, osmolality, chloride and pH were measured. Acetazolamide, furosemide, chlorothiazide and amiloride induced diuresis at each age indicating that the respective reabsorptive mechanisms were present and functional by 2 days of age. At all ages furosemide evoked a maximal response in eliminating the interstitial fluid gradient as indicated by the formation of an isosmotic urine in treated pups. However, the volume of the diuresis at 2 days of age was half those at 6 and 10 days, reflecting enhanced activity of the countercurrent multiplication apparatus in the maturing pups. Administration of mercaptomerin did not produce pharmacologic diuresis, but rather resulted in acute renal failure; although the nephrotoxicity was to a lesser extent in 2-day-old pups. The ability of the neonatal rat to respond to these pharmacologic probes demonstrates that the integrity of these renal functions is established in this species early in postnatal life.     

Successful renal transplantation accelerates development in young uremic children

To examine the impact of renal transplantation on subsequent development of children with chronic renal failure, 37 children undergoing primary renal transplantation at or before 30 months of age whose allograft functioned for at least 1 year were prospectively studied. Psychometric tests were performed an average of 4 months before transplantation; reevaluation was done an average of 14 months after surgery. Comparison of individual pretransplantation and posttransplantation mental development scores in 33 patients, assessed by either Bayley Mental Development Index or Stanford-Binet Intelligence Quotient, revealed an average increase of 12.6 (P less than .001). After transplantation, there was a significant improvement in mental performance in 12 of 18 patients (P less than .02) from the range of mild delay (Mental Development Index or Stanford-Binet IQ score = 50 to 69) to the range of normal mental development (greater than or equal to 70). The Bayley Psychomotor Development Index scores were frequently lower than Mental Development Index scores and also increased an average of 14.4 (P less than .01) after transplantation in all 12 patients with paired data. Significant individual improvement in occipital-frontal circumference standard deviation score (P less than .001) was noted in 24 children after transplantation. It is concluded that successful renal transplantation in young children with chronic renal failure is often associated with significant improvements in cognitive and psychomotor function, as well as improved cephalic growth.     

Radioisotopic evaluation of the renal parenchymal function in children with ureteropelvic junction obstruction. A retrospective study

Separate glomerular filtration rates were evaluated in 21 children with uni- or bilateral ureteropelvic junction stenosis, using the Tc-99m DTPA complex and the scintillation camera.The grade of alteration seen on urograms has influenced the surgeon in his decision to use a conservative or a surgical treatment, whereas the type of intervention (pyeloplasty or nephrectomy) was mainly based on the scintigraphic quantitation. The morphological data provided by an excretory urogram could not predict the degree of functional impairment.The scintigraphic evaluation of single kidney clearance was useful in the evaluation of the effects of medical and surgical treatment.Abbreviations PUJ Pelvi-ureteric junction obstruction - SGFR separate glomerular filtration rate - GFR glomerular filtration rate Offprint requests to: St Peter's Hospital, Dept. of Radioisotopes, Rue Haute 322, B-1000 Brussels, Belgium     

Hormonal regulation of renal function during development

The present review summarizes current and new knowledge concerning the major hormonal systems that directly or indirectly affect renal function during development. The role of the renin-angiotensin-aldosterone system in regulating renal function during fetal and postnatal life is reviewed. A summary of the role of this system during fetal and postnatal stresses is also provided. The physiological role of the renal kallikrein-kinin system in the control of renal blood flow, renin release and sodium excretion during development is examined. Possible influences of the prostaglandin system on regulation of renal function and renin secretion during fetal and postnatal maturation are explored. The effect of vasopressin on the ability of the fetal and postnatal kidney to concentrate urine and regulate body fluid homeostasis is reviewed in detail. The physiologic action of vasotocin on renal sodium and water homeostasis is described. New information regarding the role of the sympathetic system in the regulation of renal hemodynamics and in the control of renal function during development is presented. Finally, recent studies demonstrating the effect of atrial natriuretic factor and corticosteroids on the developing kidney are discussed.     

Head circumference and development in young children after renal transplantation

Background:  Growth impairment, microcephaly and developmental delay in young children with chronic renal failure improve after successful renal transplantation. There have been few reports on head circumference (HC) and development after transplantation.
Method:  Standard deviation scores (SDS) of height and HC and developmental quotient (DQ) after successful renal transplantation were evaluated in 12 recipients under 5 years of age. At the time of transplantation their mean age was 2.5 years and mean bodyweight was 9.0 kg.
Results:  Mean height SDS was −3.0 at transplantation and increased to −2.3 at 1 year after transplant (P = 0.002). Mean HC-SDS increased from −1.4 to −0.9 at 1 year after transplant (P = 0.02). As for each category of DQ examined 1 year after transplant, mean scores of gross motor function, basic practice, personal relations, speech and recognition increased from 69 to 90 (P = 0.007), from 77 to 102 (P = 0.02), from 87 to 103 (P = 0.04), from 71 to 90 (P = 0.0006), and from 88 to 101 (P = 0.03), respectively.
Conclusion:  In young children, physical growth, HC growth and DQ scores increased 1 year after transplantation. Dialysis and transplantation program should be planned in young children with end-stage renal failure in anticipation of growth and development of each patient.     

Hypothyroidism impairs colonic motility and function. An experimental study in the rat.

Hypothyroidism (HT) may be associated with either megacolon or severe constipation that mimics Hirschsprung's disease. The exact nature of this relationship is unclear. This report evaluates colonic motility in experimental HT. HT was produced by a total thyroidectomy in 20 male Sprague-Dawley rats (200-300 g). Ten of the HT rats were given thyroxin (30 micrograms/kg/day i.p. for 4 weeks) for a replacement study (RS). Ten sham operated rats (SH) and 50 unoperated rats (UN) were studied as controls. HT was documented at 4 weeks following total thyroidectomy by measuring serum T3, T4 uptake, and TSH. At four to 6 weeks the animals were evaluated for several studies concerning colonic motility. Normal weight gain was significantly impaired under HT. In addition, daily stool volume as well as the number of fecal pellets were significantly reduced in HT. A barium enema showed a dilated colon in HT with an increase of recto-colonic ratio. Anal canal pressure was relatively low in HT. HT rats had a decreased frequency of rhythmic colonic activity (cycle/min) (HT: 10.22 +/- 2.16 vs. UN: 18.09 +/- 4.79, SH: 15.88 +/- 3.92, p less than 0.001). RS rats showed a recovery of rhythmic frequency (15.56 +/- 4.46, p less than 0.001). A positive recto-anal reflex was seen in all UN and SH rats, but only 40% in HT and 80% in RS. The effect of isoproterenol on anal canal pressure was significantly less in HT. Colonic transit at 4 hours was considerably slower in HT (HT: 29.0 +/- 21.0% vs. US: 60.4 +/- 18.3%, SH: 58.7 +/- 14.8%, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Postnatal development of renal function in very low birthweight infants

The postnatal development of renal function was compared in infants with a gestational age of 25-30 weeks, mean 27.8 weeks (GA 28), and in infants with a gestational age of 31-34 weeks, mean 32.5 weeks (GA 32). The infants were comparable with regard to postnatal course, fluid, caloric and salt intake. Observations were made during the 1st, 2nd and 4th-7th (mean 5th) postnatal weeks. From the 1st to the 5th postnatal week the creatinine clearance (CCr ml/min/1.73 m2), increased from 11 to 20 in GA 28 and from 15 to 30 in GA 32. At 2 weeks of age CCr was significantly lower in GA 28 than in GA 32. During the first week of life diuresis was lower in GA 28 than in GA 32 but thereafter was the same in both groups. We interpret this as a sign of dehydration in GA 28. Serum arginine vasopressin (S-AVP) concentrations were high in both groups at all ages. Mean urine osmolality was low (less than 300) regardless of postnatal age and S-AVP. Urinary sodium excretion was high at 1 week of age in both groups and decreased with increasing postnatal age. Na excretion was slightly higher in GA 28 than in GA 32 at 1 but not at 2 and 5 weeks. UK/UNa was below 1 in both groups during the first week of life and increased with postnatal age. Urinary aldosterone excretion was high in both GA 28 and GA 32 at all ages. Serum sodium levels were lower in GA 28 than in GA 32 at all ages.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neurologic development of the newborn and young child in relation to maternal thyroid function

A prospective observational study was performed in pregnant women with known thyroid disease. We studied the effect of maternal thyroid function in the first half of pregnancy on the neurologic development of the infant in the first 2 y of life. Clinical and thyroid function data were collected from 20 pregnant women with known thyroid disease and their newborn children. Infants were divided into three groups according to their maternal thyroid function within the first half of pregnancy: Group A (n = 7): maternal subclinical hypothyroidism, Group B (n = 6): maternal euthyroidism, and Group C (n = 7): maternal hyperthyroidism or subclinical hyperthyroidism. Neurophysiologic, i.e. motor nerve conduction velocity and somatosensory evoked potentials and neurologic and developmental (Bayley scales) assessments were done. One infant, born to a mother with Graves' disease, developed transient hyperthyroidism. At the age of 6 and 12 mo, the mean mental developmental index (MDI) score was 16 points lower for infants in Group A than for those in Group B (p = 0.03 and 0.02, respectively). At the age of 24 mo, the mean MDI score was 6 points lower, which was not statistically significant. Neurophysiologic and neurologic assessments and the mean Psychomotor Developmental scores did not differ among the three groups. In conclusion, maternal subclinical hypothyroidism in the first half of pregnancy was associated with a lower mean MDI score in their infants during the first year of life.     

A study of the renal handling of water in lipoid nephrosis.

Children with lipoid nephrosis were studies during clinical relapse and after complete remission. As expected, the calculated serum oncotic pressure was reduced severely from the remission value of 28.6 +/- 0.9 mm Hg to 15.4 +/- 1.1 (P less than 0.005) during relapse. Although no apparent change in plasma volume was noted using the volume of distribution of labeled human albumin, calculated plasma volume was reduced 13 +/- 8% during relapse when estimated from changes in hematocrit. After a water load, the ability to excrete water was markedly blunted during relapse. The clearance of solute-free water (CH2O) was 0.9 +/- 0.8 ml/min during relapse, compared with 3.6 +/- 0.6 ml/min during remission (P less than 0.005). In addition, there was a reduced maximal urinary concentrating ability during relapse in four of the six patients examined. Mean urine osmolality for the group during relapse was 778 +/- 82 mOsm/kgH2O and 991 +/- 71 during remission (P less than 0.05). The demonstrated alteration in nephron function during relapse of nephrotic syndrome could result from either (1) a decrease in the amount of sodium delivered to the ascending limb of the loop of Henle because of increased proximal reabsorption or (2) a change in the intrinsic characteristics for sodium reabsorption in that segment. Although this observation does not prove that proximal reabsorption is increased, it suggests a common underlying mechanism for altered nephron function in all of the major edema-forming conditions.     

Intestinal macromolecular transmission in the young rat: influence of protease inhibitors during development

Intestinal macromolecular transmission in young rats of 10, 14, 18, 22 and 30 days of age was measured as the blood serum levels of markers 6 h after oral feeding of a solution containing bovine IgG (BIgG), bovine serum albumin (BSA) and fluorescein-isothiocyanate-labeled dextran 70,000 (FITC-D), either alone (controls) or with soybean trypsin inhibitor (SBTI) or swine colostrum trypsin inhibitor (SCTI). In the 10- and 14-day-old rats, transmission of all three macromolecular markers was high, with a preference for IgG. Transmission was greatly reduced by the age of 18 days and totally arrested for the protein markers at 22 days, with a low transmission of FITC-D remaining at 30 days of age. Addition of either of the two protease inhibitors significantly elevated the transmission of the protein markers in the rats aged 10, 14 and 18 days, while the transmission of the protease-independent marker FITC-D was unaffected. From 14 days of age, the rats have a functioning intestinal proteolysis, since only small amounts of marker proteins were left in the gut lumen 6 h after feeding, and since the addition of protease inhibitors resulted in increased amounts of undegraded proteins intraluminally. The results indicate that the increase of intraluminal proteolytic activity during development and the presence of protease inhibitors in the food are of importance for the intestinal transmission of undegraded proteins in the young rat. The Fc receptor for IgG in the enterocyte is not sufficient to maintain an optimal transmission of IgG, since the intraluminal proteolytic activity also appears to be of importance.     

Continuous doxorubicin infusions. A pilot study in young patients

Eleven young patients with relapsed childhood malignancies received continuous infusions of 5-10 mg/m2/day doxorubicin. 30 infusions were given via a central venous access until signs of mucositis showed up (7-52 days). Other toxicity was low, both bone marrow depression and fever and neutropenia occurred in 7/30 and 5/30 courses of therapy, respectively. No signs of liver or cardiac toxicity were seen in these heavily pretreated patients. In 8/11 patients tumor regression was documented, though only two partial remission were noted. Continuous infusions of doxorubicin are an effective and relatively non-toxic treatment for relapsed childhood malignancies. Since this form of therapy enables good quality of life and medical care on ambulatory basis, a phase II-study of low-dose doxorubicin for relapsed tumors is justified.     

苯那普利降尿蛋白时对肾病幼鼠肾功能的影响

目的观察血管紧张素转换酶抑制剂苯那普利时幼龄肾病大鼠起降尿蛋白作用的同时对其肾功能的影响.方法将SD幼龄大鼠(1个月龄,体重100 g左右)行单侧肾切除后加阿霉素(5 mg/kg)注射建立动物模型,术后即给予苯那普利6 mg/(kg@d)治疗12周,观察大鼠尿蛋白及血肌酐、尿素氮的变化.结果治疗第7、9、12周,苯那普利组尿蛋白与同期模型组相比分别为(7.4±4.4)、(2.0±1.2)、(5.2±3.5)mg/24 h比(14.4±1.8)、(17.5±10.0)、(15.2±4.7)mg/24 h(P均<0.01).苯那普利组与模型组肾功能相比实验中期,血尿素氮为(11.1±2.5)mmo/L比(8.5±1.9)mmol/L;实验结束,血肌酐为(63.8±6.3)μmol/L比(54.5±6.3)μmol/L(P均<0.05).结论在单侧肾切除后1周注射阿霉素的幼龄肾病大鼠模型上,苯那普利在实验过程中显示降尿蛋白作用的同时,尚致血肌酐或尿素氮升高,此点值得重视.     

Neonatal renal function assessment.

Urine samples from neonates admitted to a special care baby unit were analysed to establish ranges for urinary retinol binding protein, albumin, and total protein concentrations in healthy term and preterm infants and to investigate changes seen in disease states. Urinary excretion of retinol binding protein was greater in preterm infants and was increased in sick infants. This was greater than would be predicted from changes in creatinine excretion with gestational or postconceptional age. Urinary retinol binding protein appeared more sensitive to illness than did urinary albumin or total protein.     

小于胎龄儿生后早期肾脏功能初探

目的对小于胎龄儿(SGA)生后早期肾脏功能进行回顾性对照研究,以探寻SGA儿早期肾功能损害的诊断方法。方法选择早产SGA儿40例、足月SGA儿33例作为研究组,并以早产适于胎龄儿(AGA)80例、足月儿AGA 33例作为对照组。比较各组入院48 h内血清尿素氮(BUN)、血清肌酐(SCr)、估算肾小球滤过率(eGFR)、血压、单位体重尿量以及蛋白尿的发生情况。结果早产儿SGA组的BUN低于AGA组(P0.05),两组间SCr、eGFR、血压的差异无统计学意义(P0.05)。与足月儿AGA组比较,SGA组的SCr较高、eGFR较低,差异均有统计学意义(P0.05);两组间BUN、血压的差异无统计学意义(P0.05)。早产儿或足月儿AGA与SGA之间单位体重尿量的差异无统计学意义(P0.05)。早产儿AGA与SGA之间蛋白尿发生率的差异无统计学意义(P0.05),足月儿AGA与SGA组均无蛋白尿发生。结论 SCr、eGFR对评估SGA早期肾脏损害较为敏感。足月儿SGA较AGA肾脏功能减低。     

A cohort study of 20,822 young drivers: the DRIVE study methods and population.

BACKGROUND AND OBJECTIVE: Research on young drivers directly linking risk factors to serious injury and death outcomes is required. The DRIVE Study was established to facilitate this aim. This paper outlines the study methods and describes the population that has been recruited, in order to demonstrate that the necessary heterogeneity in risk factors has been attained. Design, SETTING AND PARTICIPANTS: Drivers aged 17-24 years holding their first-stage provisional driver's licence from New South Wales, Australia, were recruited into a prospective cohort study. The participants were contacted by mail and asked to complete the study questionnaire at an online site or via a mailed questionnaire. Baseline data collection involved a questionnaire with questions to drivers about their training, risk perception, driver behavior, sensation-seeking behavior and mental health. Participants gave consent for prospective data linkage to their data on licensing, crashes and injuries, held in routinely collected databases. RESULTS: 20 822 drivers completed the baseline questionnaire, of whom 45.4% were men, 74.3% resided in capital cities and 25.7% in regional or remote areas. The recruited study population showed a wide variation in the risk factors under examination. For example, almost 40% of drivers reported drinking alcohol at hazardous levels and about 32% of participants seemed to be at a high or very high risk of psychological distress. Participants reported a mean of 67.3 h (median 60 h) of supervised driver training while holding their learner's permit. CONCLUSIONS: The DRIVE Study has a robust study design aimed at minimizing bias in the collection of outcome data. Analyses of baseline data showed substantial heterogeneity of risk factors in the study population. Subsequent prospective linkages comparing relative differences in exposures at baseline with the outcomes of interest have the potential to provide important new information needed to develop targeted interventions aimed at young drivers.