Factors influencing the response to growth hormone in children with renal disease

The effects of age, height velocity over the preceding year, glomerular filtration rate (GFR) and prednisolone dose on growth response have been assessed by single and multiple linear regression analysis in 23 prepubertal children [age, mean (SD), 8.2 (2.5) years] with chronic renal failure (CRF) and 16 prepubertal children [12.1 (2.3) years] with renal transplants treated for 1 year with recombinant human growth hormone (rhGH), 30 U/m² per week. Height velocity [mean (SD), cm/year increased from 4.7 (1.3) to 9.7 (2.1) (P<0.0001) in the CRF group and 3.1 (1.6) to 7.3 (2.8) (P<0.0001) in the transplant group. In the CRF group, there was a correlation between age and height velocity, both in the pretreatment year (r=–0.755,P<0.0001) and during treatment (r=–0.421,P=0.045). There was no correlation between pretreatment height velocity or GFR and response to rhGH. In the transplanted children height velocity during the treatment year correlated with age (r=–0.647,P=0.007), prednisolone dose (r=–0.689,P=0.003), GFR (r=0.542,P=0.030) and pretreatment height velocity (r=0.655,P=0.006). Multiple regression analysis showed prednisolone dose and age to be the most important predictors of response.     

Growth over 10 years following a 1-year trial of growth hormone therapy

The growth of short children with chronic renal failure (CRF) and renal transplants was assessed over 10 years following entry into a 1-year trial of recombinant human growth hormone (rhGH) therapy. Patients were divided into three groups: 6 prepubertal patients with CRF (group 1), mean (range) age at start of trial 7.7 (5.0–10.4) years; 6 prepubertal patients with renal transplants (group 2), age 11.9 (9.5–14.6) years; and 6 pubertal patients with renal transplants (group 3), age 15.6 (14.1–18.3) years. In group 1, the mean (range) height standard deviation score (Ht SDS) increased from –2.9 (–3.7 to –2.2) to –1.9 (–2.9 to –0.5) over 4.0 (0.3–9.1) years of rhGH (P=0.04), and was –1.6 (–2.9 to –0.4) after 10 years of follow-up (NS). In group 2 Ht SDS increased from –3.3 (–4.5 to –1.9) to –2.9 (–5.4 to –0.5) over 2.7 (1.0–6.0) years and was –3.0 (–6.3 to –0.1) at final height (NS). In group 3 Ht SDS increased from –3.4 (–4.3 to –2.6) to –3.0 (–3.4 to –2.2) over 1.4 (0.2–2.3) years (NS) and was –2.5 (–3.0 to –1.9) at final height (P=0.03 from stopping rhGH to final height). Final height was attained in 13 patients, in whom Ht SDS increased from –3.2 (–4.3 to –1.9) to –2.6 (–3.9 to –0.5) on rhGH (P=0.004) and to –2.2 (–4.4 to –0.1) after stopping treatment (P=0.04). Four patients died, 2 have chronic hepatitis C, and 1 has had surgery for parathyroid adenomata. In conclusion, the majority of patients had an improvement in Ht SDS while on rhGH, which was maintained after stopping treatment. Received: 18 November 1998 / Revised: 10 August 1999 / Accepted: 13 August 1999     

Accelerated growth in short children with chronic renal failure treated with both strict dietary therapy and recombinant growth hormone

In a 12-month study, nine boys, aged 4.8–15.6 years, with bone ages 4.6–13 years, with moderate to severe chronic renal failure and resultant growth failure were treated with daily recombinant human growth hormone (rhGH), in conjunction with a strict low-protein/low-phosphate diet supplemented with keto and amino forms of the essential amino acids, histidine and additional energy. Improved growth had previously been observed with this dietary management over that obtained with conventional treatment for chronic renal failure. Each child had been on this diet for at least 2 years before rhGH was commenced. Mean height velocity increased from 4.6±1.3 to 9.0±1.3 cm/year (P<0.001) in the pre-pubertal group, and in the pubertal group from 5.4±1.4 to 10.4±1.8 cm/year (P<0.01). The mean height velocity standard deviation scores (SDSs) increased from –1.2±0.6 to +2.3±0.9 (P<0.001) in the pre-pubertal group and from –0.4±0.6 to +1.9±1.1 (P<0.01) in the pubertal group. Mean height SDS for chronological age increased from –2.2±0.7 to –1.5±0.5 (P<0.01) in the pre-pubertal group and from –1.9±0.7 to –1.3±0.9 in the pubertal group (P<0.02). There was no significant deterioration in renal function or renal bone disease, and bone age did not advance more than chronological age over the 12-month period.     

Serum insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 in children with chronic renal failure: relationship to growth and glomerular filtration rate

Growth retardation in children with chronic renal failure (CRF) is partly due to an inhibition of insulin-like growth factor (IGF) activity by an excess of high-affinity IGF-binding proteins (IGFBPs). The aim of this study was to analyze the serum levels and forms of IGFBP-4 and IGFBP-5 in CRF patients using specific, recently developed radioimmunoassays (RIAs) and immunoblot analysis. We examined 89 children [age 11.5 (2.8–19.0) years] with CRF [glomerular filtration rate 26.6 (7.0–67.4) ml/min per 1.73 m²], nine of them with end-stage renal disease undergoing peritoneal dialysis. Serum-immunoreactive IGFBP-4 levels were fourfold increased in CRF (prepubertal 1080±268 ng/ml; pubertal 989±299 ng/ml) compared to healthy prepubertal controls (265±73 ng/ml). In contrast, serum IGFBP-5 levels were not significantly increased neither in prepubertal (361±120 ng/ml vs 282±75 ng/ml in controls) nor pubertal CRF children (478±165 ng/ml vs 491±80 ng/ml in controls). Immunoblot analysis showed the presence of intact as well as fragmented IGFBP-4 and IGFBP-5. Serum IGFBP-4, but not IGFBP-5, levels were inversely correlated with GFR (r=–0.39, P<0.001). In prepuber- tal children, IGFBP-4 levels were inversely correlated with standardized height (r=–0.40; P<0.005). In contrast, IGFBP-5 levels were positively correlated both with standardized height (r=0.32, P<0.02) and baseline height velocity (r=0.45, P<0.005). A 3-month therapy with rhGH stimulated serum IGFBP-5 levels by 43% (P<0.01); there was no consistent effect on IGFBP-4 levels. There was a positive correlation between IGFBP-4 and IGFBP-2 (r=0.46, P<0.001); IGFBP-5 was positively correlated with IGF-I (r=0.59, P<0.001), IGF-II (r=0.42, P<0.001) and IGFBP-3 (r=0.47, P<0.001) and inversely correlated with IGFBP-1 (r=–0.41, P<0.001). In summary, serum IGFBP-4 is fourfold elevated in children with CRF in relation to the degree of renal dysfunction and contributes to the marked increase in IGF-binding capacity in CRF serum. The inverse correlation of serum IGFBP-4 with standardized height is consistent with its role as another inhibitor of the biological action of the IGFs on growth plate cartilage. In contrast, serum IGFBP-5 is not elevated in CRF serum and circulates mainly as proteolysed fragments. The positive correlation of serum IGFBP-5 with growth and its increase during GH therapy indicate that IGFBP-5 is a stimulatory IGFBP in patients with CRF, either by enhancing IGF activity through better presentation of IGF to its receptor or by an IGF-independent effect through activation of a specific, recently described putative IGFBP-5-receptor. Received: 24 September 1999 / Revised: 6 January 2000 / Accepted: 13 January 2000 / Accepted: 13 January 2000     

Growth hormone treatment started in the first year of life in infants with chronic renal failure

Infants with chronic renal failure (CRF) are at high risk of experiencing severe growth retardation. We report a study of 12 infants with CRF who have been treated with recombinant human growth hormone (rhGH) since the age of 0.5 ± 0.3 years. A control group comprised 15 infants with less severe CRF who were being treated during the same period, but who did not receive rhGH. Despite the infants in the rhGH group had more severe renal failure, they grew at least as well as those in the control group and experienced catch-up growth that started earlier and was more sustained; they also gained more weight. Between the age of 0.5 and 2.5 years, the height standard deviation score (HtSDS) improved from −2.0 ± 1.2 to −0.9 ± 0.9 in the rhGH group (p < 0.005) and from −1.6 ± 1.6 to −1.0 ± 1.9 in the control group (p=non significant, n.s.). The average gain in HtSDS was +1.1 ± 0.8 in the treated group and +0.6 ± 1.4 in the control group (p = n.s.). During the same period, the weight SDS improved from −2.2 ± 0.9 to −0.6 ± 1.2 (p < 0.005) and from −1.9 ± 1.2 to −1.3 ± 1.2 (p=n.s.) in the treatment and control groups, respectively. Nutritional intake was similar in both groups, while parathyroid hormone levels tended to increase, although not significantly, after rhGH treatment (p=n.s.). The results of this pilot study suggest that very early treatment with rhGH in patients with early-onset CRF may improve growth.     

Nutritional status, protein intake and progression of renal failure in children

Nutritional status and progression of renal failure in 35 children (22 males and 13 females; mean age: 8.85±4.13 years) with moderate renal failure were followed for 2 years. All children were on an “ad libidum” diet. Protein intake was determined by a minimum of two dietary diaries kept by the parents and the appearance of urea nitrogen. The children were divided into two groups according to their protein intake: Group 1 – sub-optimal intake (46% of the children, all with significantly lower protein intake); Group 2 – adequate protein intake. The mean protein intake (expressed as a percentage of the WHO recommendations) based on the diets of the patients was 94.79% in Group 1 children and 175.45% in Group 2 children (p<0.05). All patients had a calorie intake of at least 80% of the WHO recommendations. Nutritional status was determined by anthropometric measurements expressed as a standard deviation score. There was no significant anthropometric or biochemical evidence of malnutrition in children with moderate chronic renal failure (CRF). The glomerular filtration rate (GFR) in patients with a sub-optimal intake of protein was −5.41±2.87 ml/2 year versus−9.53±8.61 ml/2 year in the normal protein intake group. There was no correlation between protein intake, nutritional status and progression of renal failure in children with moderate CRF within the 2-year study period.     

Body growth of children with steroid-resistant nephrotic syndrome

Whilst it is assumed that body growth is retarded in children with steroid-resistant nephrotic syndrome (NS), the degree of growth failure and the pathomechanisms involved are poorly understood. We collected serial growth data in 45 children (24 males) with steroid-resistant NS usually from onset to end-stage renal disease (ESRD) during childhood (n=10) or until final height was attained (n=27). Mean follow-up time was 9 (2–19) years. Mean initial standardized height was –0.3±1.2 standard deviation scores (SDS). Mean final height was +0.4 SDS in males and –1.0 SDS in females (sex difference not significant). In 16 patients with serum creatinine levels consistently <1.2 mg/dl, mean final height SDS was 0.3 SDS higher than that obtained within 6 months of onset. In contrast, 9 children who entered ESRD lost an average of 1.3 SDS from the initial record to ESRD (P=0.017). In prepubertal patients without renal insufficiency, mean height SDS decreased during corticosteroid treatment by 0.3 SDS, followed by a partial catch-up after discontinuation of treatment; the change from initial to final height SDS was inversely correlated with the total prednisone dose given (r=–0.50, P=0.03). In 16 prepubertal children with serial height and serum protein measurements who were off steroids and maintained normal creatinine levels, mean individual albumin concentrations correlated with the change in height SDS per year (r=0.65, P=0.0006) and in boys with final height (r=0.73, P=0.03). In conclusion, growth in steroid-resistant NS depends on the preservation of renal function, the cumulative dose of steroids applied, and the severity of hypoproteinemia. Received: 15 July 1998 / Revised: 30 November 1998 / Accepted: 11 December 1998     

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

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. Received: 13 March 2000 / Revised: 11 July 2000 / Accepted: 14 July 2000     

Predictive factors of chronic kidney disease in severe vesicoureteral reflux

The aim of this retrospective cohort study was to evaluate independent predictive factors of chronic kidney disease (CKD) in children with severe bilateral primary vesicoureteral reflux (VUR). Between 1970 and 2004, 184 patients were diagnosed with VUR (grades III–V) and were systematically followed up at a single tertiary renal unit. CKD was defined as estimated glomerular filtration rate <75 ml/min per 1.73 m² body surface area in two consecutive examinations. Risk of CKD was analyzed by the Kaplan–Meier method and Cox’s regression model. The probability of CKD for patients with bilateral severe reflux was estimated at 15% by 10 years after VUR diagnosis. After adjustment, four variables remained independently associated with CKD during follow-up: age at diagnosis >24 months [relative risk (RR)=4.8, 95% confidence interval (95%CI), 1.8–12.7, P<0.001], VUR grade V (RR=3.5, 95%CI, 1.5–7.9, P=0.002), bilateral renal damage (RR=2.86, 95%CI, 1.3–6.1, P=0.007), and decade of admission after 1990 as a protective factor (RR=0.16, 95%CI 0.06–0.43, P<0.001). A delay in the diagnosis of VUR more than 12 months after urinary tract infection (UTI) was also a predictive factor in an alternative model (RR=2.2, 95%CI, 1.1–6.6, P=0.03). Prognosis regarding renal function was relatively poor after a long-term follow-up of patients with bilateral severe reflux.     

Post graft development of short children treated with growth hormone before kidney graft

Sixteen prepubertal patients with chronic renal failure (CRF) were given daily recombinant human growth hormone (rhGH) treatment (1.2 IU/kg per week) for 2.6±1.6 years until kidney transplant. Therapy was then discontinued and the patients followed for a further 3.5±1.4 years. During treatment, mean height increased from –3.0±0.9 standard deviation score (SDS) to –1.9±1.4 SDS (P<0.001) at the time of transplantation, corresponding to a mean height gain of +1.2±0.9 SDS. After discontinuation of rhGH therapy, prepubertal children continued a partial catch-up growth with a height gain of +0.5±0.8 SDS for the follow-up period. Conversely, negative changes of height were observed in pubertal transplanted children: –0.5±0.4 SDS in patients grafted at early stages of puberty (P2–P3) and –0.15±0.9 SDS in patients grafted at late stages of puberty (P4–P5). These data confirmed the benefit of rhGH therapy in CRF patients. Nevertheless, only early initiation of rhGH treatment led some of these patients to their target height at transplantation, thus preserving their potential growth. Reinitiation of rhGH therapy after transplantation should be considered in order to complete catch-up growth to target height in prepubertal children. Received: 23 July 1998 / Revised: 8 December 1998 / Accepted: 13 December 1998     

Kidney transplantation decreases the tissue level of advanced glycosylation end-products

We have studied the effect of chronic renal failure (CRF) andkidney transplantation on advanced glycosylation end-products(AGE) measured as collagen-linked fluorescence (CLF) in theskin and peritoneum of non-diabetic patients. Of 34 patientswith CRF, 18 were studied before the commencement of peritonealdialysis (CRF group), and 16 were studied 5–31 weeks afterkidney transplantation (transplant group). The control groupconsisted of 24 patients with normal renal function. Skin CLFin the CRF group (20.9 ± 2.02 U/mg) was higher than inthe control (8.52±1.08 U/mg, P = 0.0001) and transplantgroups (10.7 ± 2.43 U/mg, P=0.003). Peritoneal CLF inthe CRF group (30.5 ± 5.64 U/mg) was higher than in thecontrol group (16.1 ±2.25 U/mg, P=0.031) but was notdifferent from the transplant group (19.4 ± 3.66 U/mg,P=0.11). Peritoneal CLF of control and transplant groups werenot different (P= 0.45). The results of this study suggest thatrestoration of renal function affects tissue AGE levels.     

Compliance and effects of nutritional treatment on progression and metabolic disorders of chronic renal failure

Low-protein, low-phosphorus diets (LPD) are prescribed to patientswith chronic renal failure (CRF) to slow down the rate of progressionof CRF and to control uraemic symptoms. A satisfactory adherenceof patients to the prescribed diet is needed to meet these twogoals. We studied the compliance of CRF patients to a LPD providingdaily (per kg body weight) 0.3 g protein, 3–5 mg phosphorus,35 kcal, and supplemented with essential amino-acids and ketoanalogues.Forty CRF patients were studied for 23.3±10.8 months(range 12–45). Compliance to LPD was evaluated by dietaryinquiry and protein intake estimated from urinary urea excretion.According to compliance to LPD, patients were retrospectivelyassigned to the compliant (n=27) or the non-compliant (n=13)group. GFR measured by the urinary clearance of [⁵¹Cr]-EDTAwas identical in the two groups at the start of the study: compliantpatients 15.7±5.3 ml/mn, non-compliant patients 15.4±5.9ml/mn. The decrease of GFR was – 0.08±0.22 ml/minper month in compliant patients versus –0.31±0.37ml/min per month in non-compliant patients (P<0.02). Theseresults were not demonstrated if the progression of CRF wasassessed by the linear regressions over time of creatinine clearanceor the reciprocal of creatinine. Serum bicarbonate, serum phosphorusand PTH levels were corrected by LPD in compliant patients (P<0.005 for all parameters) but not in non-compliant patients.These results suggest that evaluation of compliance is necessaryto assess the response of CRF patients to LPD, whether the aimis to slow the progression of CRF or to control its metabolicconsequences. A beneficial effect of compliance to LPD was demonstratedupon these two goals.     

Bone mineral density and bone turnover markers in children with chronic renal failure

Bone mineral density (BMD) at lumbar spine (L₂-L₄) was measured by dual-energy X-ray absorptiometry (DEXA) in 21 children with predialysis chronic renal failure (CRF) and 44 children with end-stage renal failure (ESRF) on regular hemodialysis. BMD results were expressed as Z-scores. Osteopenia was documented in 13 predialysis patients (61.9%) and 26 patients (59.1%) with ESRF. No significant correlation was observed between Z-scores and the duration of CRF or estimated creatinine clearance. In osteopenic children there was a negative correlation between Z-scores and serum phosphorus (r=–0.61, P=0.004), intact parathyroid hormone (iPTH) (r=–0.47, P=0.03), and bone-specific alkaline phosphatase (r=–0.52, P=0.02) and a positive correlation with total calcium (r=0.41, P=0.07) and 25-hydroxycholecalciferol (r=0.53, P=0.02). Osteopenic children who had iPTH values 200 pg/ml were more osteopenic than those who had lower iPTH levels (P=0.006). In conclusion, osteopenia, assessed by DEXA, is frequent in children with CRF. It occurs early irrespective of the duration or the severity of CRF. In children with ESRF the degree of osteopenia is correlated with laboratory markers of renal osteodystrophy and patients with biochemical findings of secondary hyperparathyroidism are more osteopenic than the others.     

Serum zinc and copper levels in children with chronic renal failure

We evaluated changes in serum zinc (Zn) and copper (Cu) levels in two groups of children with chronic renal failure (CRF) – children with CRF who were on regular hemodialysis (Group 1, n=40) and children with CRF who were on conservative management (Group 2, n=31) – and in one group of healthy children (Group 3, n=30). All of the participants in the study were between 5–18 years old, and the composition of the three groups was almost identical with respect to age and sex. The length of time the children in Group 1 had been on hemodialysis varied between 3 and 52 months (mean: 20.97±14.8 months). To evaluate the impact of the duration of dialysis on serum levels of Zn, we further sub-divided Group 1 patients into two subgroups: Subgroup A patients (n=20) had been on hemodialysis therapy for less than 18 months (mean: 8.85±4.83 months); Subgroup B patients (n=20) had been on hemodialysis therapy for longer than 18 months (mean: 33.1±10.86 months). The PIXE (proton-induced X-ray emission) was used for measuring the trace elements. Results: The mean serum level of Zn was lower in the Group 1 (hemodialysis group) children than in the children of Group 2 (on conservative management) and group 3 (healthy children) (p<0.001), but the difference was not significant between Groups 2 and 3. No significant differences in serum levels of Cu were found among the three groups. The serum level of Zn was lower in Subgroup B than in Subgroup A (p<0.001). The correlation test showed that there was an inverse linear relation between the length of time the child was on the hemodialysis regimen and serum Zn levels. Conclusion: Chronic hemodialysis may lead to abnormalities in the serum levels of some trace elements in children with CRF that increase in severity with increasing duration of hemodialysis. Deficiencies of these trace elements – zinc in particular – may contribute to various conditions and symptoms in children undergoing chronic hemodialysis.     

Growth hormone for children with chronic renal failure and on dialysis

We studied all children with CRF who received recombinant human growth hormone (rhGH) for more than a year (mean±SD duration of therapy 3.7±2.5 years) over an 11-year period. There were 32 children. Twenty-one children were conservatively managed, with a mean glomerular filtration rate (GFR) of 24±12 mL min^–1/1.73 m² at the start of rhGH. Their height standard deviation score improved from –2.5±1.4 to –2.1±0.7 at 1 year (P=0.3), –2.0±0.7 at 2 years (P=0.01), and –1.6±0.6 at 3 years (P=0.001). After that there was no improvement. Eleven children were on dialysis, six on haemodialysis (HD) and five on peritoneal (PD). Ht SDS improved from –2.7±0.5 to –2.3±0.5 at 1 year (P=0.02). Thereafter there was no further improvement. RhGH was stopped because of transplantation in 29 patients at a mean±SD age of 12.1±4.0 years. Mean Ht SDS was –1.8±0.8 at transplant and there was no change over the following 5 years. In conclusion, treatment with rhGH resulted in improvement in Ht SDS in conservatively managed CRF for up to 3.0 years and for 1 year in children on dialysis. Discontinuation of rhGH after transplantation resulted in little change in Ht SDS.     

Annual change in bone mineral density in predialysis patients with chronic renal failure: significance of a decrease in serum 1,25-dihydroxy-vitamin D

Bone disease occurs in the predialysis phase of chronic renal failure (CRF). The aim of this study was to examine how a decrease in renal function affects annual bone mineral density (BMD) changes in predialysis CRF patients and to examine the factors that affect BMD. The BMD of the distal radius in 53 predialysis CRF patients (age, 61.3 ± 10.8 years; serum creatinine 2.7 ± 1.2 mg/dl) was measured by peripheral quantitative computed tomography (pQCT) twice with a 1-year interval. The total BMD of the radius significantly decreased over a year (P < 0.001), and both trabecular and cortical BMD showed a significant decrease. Significant positive correlations with BMD changes were found for estimated creatinine clearance (r = 0.375, P < 0.01) and baseline serum 1,25(OH)₂D (r = 0.434, P < 0.005), indicating that BMD decreased to a greater extent with larger reductions in creatinine clearance and serum 1,25(OH)₂D. Of several bone metabolic markers examined, baseline serum osteocalcin was significantly positively correlated with annual BMD changes (r = −0.276, P < 0.05). Multiple regression analysis showed that baseline serum 1,25(OH)₂D (β = 0.434) was a significant predictor of decreases in total and trabecular BMD (R ² = 0.188, P < 0.01; and R ² = 0.207, P < 0.01), independent of other confounding factors. These results indicate that BMD decreases as renal function deteriorates in predialysis CRF patients, and that osteocalcin is a clinically useful marker associated with the decrease in BMD. The serum 1,25(OH)₂D level is the principal factor affecting BMD of the radius, suggesting that supplementation with an active form of vitamin D is of importance for predialysis CRF patients.     

Impact of ACE I/D gene polymorphism on congenital renal malformations

To investigate the role of the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism on prevalence and progression of disease in children with chronic renal failure (CRF), we determined the ACE I/D genotype in 95 children with CRF due to renal malformations (hypo- /dysplasia, obstructive uropathy, reflux nephropathy; n=59), other congenital or hereditary diseases (n=23), or acquired glomerular disorders (n=13), who had been followed prospectively over a 2-year period. CRF progression rate was followed in each individual by linear regression analysis of estimates of glomerular filtration rate (GFR) obtained every 2 months. Actuarial renal ’survival’ analysis was performed, using a GFR loss of 10 ml/min per 1.73 m² as a cutoff point. The distribution of the ACE genotype did not differ among the disease groups. There was also no difference in ACE genotype distribution between the patients and a control group of healthy Caucasian children (n=163). Among the children with renal malformations, the 2-year renal survival was significantly lower in those with the DD genotype (61%) than in patients with ID or II genotype (89%, P<0.01). In the other disease groups, the ACE I/D genotype was not predictive of CRF progression. In a multivariate analysis of risk factors, the adverse effect of the DD genotype (risk ratio 10.2, P<0.05) was independent of and additive to those of arterial hypertension (RR 13.2, P<0.001) and gross proteinuria (RR 4.7, P<0.05). We conclude that the ACE DD genotype is a significant risk factor for children with congenital renal malformations to develop progressive CRF. The effect of the ACE polymorphism in this patient group is independent of hypertension and proteinuria. Received: 25 August 2000 / Revised: 10 December 2000 / Accepted: 15 December 2000     

Intestinal bacteria-derived putrefactants in chronic renal failure

Background. Phenols and indoles are fermentation products and putrefactants of intestinal bacterial origin. They present a problem in chronic renal failure and hemodialysis patients because they accumulate in the body as uremic toxins. Methods. A comparative study was performed in groups of patients with chronic renal failure (CRF) before the initiation of dialysis, hemodialysis patients (HD), and healthy adults to investigate changes in intestinal flora and to measure the blood levels of uremic toxins. Results. The level of Escherichia coli was significantly increased in the CRF and HD groups compared with the healthy controls (P= 0.02, controls vs CRF before dialysis; P= 0.0014, controls vs HD). Fecal concentrations of phenol and scatole were most highly elevated in the HD group, and the difference between the CRF and HD groups was significant (P= 0.02 for phenol; P= 0.01 for scatole). Serum concentrations of phenol, p-cresol, and indican were significantly elevated in the CRF group (P= 0.01; P= 0.008; and P < 0.0001 vs controls, respectively). For indican, a correlation was found between fecal and serum concentrations only in the HD group (correlation coefficient of 0.821; P= 0.04). In the CRF group, a correlation was obtained between the urine and serum concentrations of phenol and p-cresol (0.852, P= 0.01; 0.758, P= 0.02, respectively). A correlation was also found between the serum concentrations of indican and serum creatinine (SCr) (0.610; P= 0.004) and β2-microglobulin (β2-MG) (0.739; P= 0.005). Conclusions. An abnormal balance of intestinal bacterial flora and increased intestinal bacteria-derived putrefactants were observed in the CRF group. The increased concentration of toxins with renal sclerosing effects, such as indican, may contribute to further deterioration of renal function. Received: September 14, 2001 / Accepted: February 13, 2002     

Increased prevalence of dialysis-dependent renal failure in ethnic minorities in the West Midlands

A total of 1038 adult patients with dialysis-dependent renalfailure were treated at this centre between 1981 and 1991. Dataon racial origin and primary renal diagnosis have been analysedin order to determine the prevalence of end-stage renal failure(ESRF) and its causes. Compared with Caucasians there was a greater proportion of Asians(P < 0.001) and Blacks (P < 0.001) with ESRF. The relativerisk of ESRF in Asians compared with Caucasians was 1.76 (95%CI 1.46–2.10) and for Blacks 1.76 (95% CI 1.39–2.2).Hypertension/renal vascular disease and systemic lupus erythematosuswere more frequent causes of ESRF in Blacks than in Caucasians(P < 0.005). Hypertension/vascular disease and tuberculosiswere more frequent causes of ESRF in Asians than Caucasians(P < 0.005) respectively. Diabetes mellitus appeared to bemore common as a cause of ESRF in Blacks than Asians or Caucasians(0.1 >P>0.05). Adult polycystic disease was significantlyless common in Asians compared to Caucasians and Blacks (P<0.05). The prevalence of ESRF in Asians and Blacks in the West Midlandsappears to be greater than that of Caucasians, mostly as a consequenceof hypertension/vascular disease and to a lesser extent of systemiclupus erythematosus in Blacks and of tuberculosis in Asians.If these data are confirmed by prospective study then they haveimplications for service provision.     

Delayed acute renal failure in post-transplant period in young children from unexplained etiology

This report describes six young children (5 male) who developed delayed acute renal failure (DARF) in the early post-kidney-transplant (Tx) period in the absence of acute rejection (AR) or other diagnosable conditions. These young children, aged 16.5 ± 3.1 (12–21) months [mean ± SD, (range)] and weighing 8.5 ± 1.7 (7.1 – 11.4) kg received a primary renal Tx (5 living-related donor, 1 cadaver) between 1984 and 1992. Immunosuppression included prednisone, azathioprine, and Minnesota antilymphocyte globulin (MALG, n = 5); one patient received cyclosporine and no MALG. Initially, all patients had good urine output (UO). They became systemically ill and abruptly developed diminished UO on post-operative day (POD) 6.5 ± 1 (4 – 8). DARF was accompanied by fever (39.1 – 40.4°C, n = 6), thrombocytopenia (platelets <100,000/mm³, n = 6), leukocytosis, or leukopenia (white cell count >20,000/mm³, n = 4 or <1,000/mm³, n = 1). Four patients had diarrhea. Three had ascites and one was surgically explored for suspected urinary leak. None showed significant urinary obstruction by renal ultrasound. Renograms showed intact blood flow. Renal biopsy showed tubular ectasia (n = 6), vascular congestion (n = 5), focal glomerular endothelial swelling (n = 4), and capillary thrombi (n = 3). None showed AR. Five patients required dialysis for 11 ± 4 (7 – 15) days. All patients survived. One patient, treated for suspected AR with the monoclonal antibody OKT3, developed shock and lost her graft on POD 12 due to vascular thrombosis. Renal functional recovery in the remaining five patients took 14 ± 5 (6 – 20) days and their serum creatinine at discharge was 0.7 ± 0.5 (0.3 – 1.6) mg/dl. We report DARF from undetermined etiology occurring in the first 2 weeks of renal Tx in young children. Treatment is supportive care including dialysis. Recognition of this complication will help avoid risky investigations or unnecessary treatment for rejection. Received August 21, 1996; received in revised form February 14, 1997; accepted March 4, 1997