ACE I/D gene polymorphism predicts renal damage in congenital uropathies

We investigated angiotensin converting enzyme gene (ACE I/D) polymorphism as a risk for progressive renal damage in congenital uropathies. The ACE I/D genotype was determined in 196 Caucasian patients with congenital uropathies and 163 individuals with no clinical or sonographic evidence of any urological malformations. The study group included patients with ureteropelvic junction obstruction (n=49), primary obstructive megaureter (n=19), primary vesicoureteral reflux (VUR) (n=67), and posterior urethral valves (n=27). Thirty-four patients were excluded because of additional diseases or insufficient follow-up. There was no difference in the ACE I/D distribution between children with uropathies and normal controls (II 16%, ID 56%, DD 28% vs. II 26%, ID 50%, DD 24%). Renal lesions were found in 99 of 162 children by ultrasonography, intravenous pyelography, and nuclear scans. In these children there was significant over-representation of the DD genotype (II 11%, ID 53%, DD 36%) compared with normals (P<0.005, X²=14.9) or with patients with uropathies but no renal lesions (II 23%, ID 62%, DD 15%, P<0.005, X²=14.9). Because ACE I/D has been linked with progressive deterioration of renal function, we evaluated a subset of patients with initially normal kidneys who developed radiographic renal lesions (n=28). Among these patients there was an even greater over-representation of the DD genotype (II 0%, ID 43%, DD 57%, P<0.001, X²=22.6) compared with patients with uropathies but no radiographic lesions. Multivariate analysis revealed that the DD genotype is a risk factor for parenchymal destruction, which was independent of time of diagnosis, surgical intervention, or urinary tract infection. This finding was particularly relevant in patients with VUR who constituted the majority with initially normal kidneys who developed radiographic damage (22/28). Indeed, the odds ratio of developing parenchymal damage with VUR was significantly increased if the individual had the DD genotype (4.2, 95% confidence interval 1.4–13.0). In conclusion the ACE I/D gene polymorphism is a risk factor for renal parenchymal damage in patients with congenital urological abnormalities and appears particularly relevant in children with VUR, where it is an independent predisposing factor. Received: 3 November 1998 / Revised: 3 March 1999 / Accepted: 3 March 1999     

Polymorphisms of renin-angiotensin system genes in childhood IgA nephropathy

We investigated whether polymorphisms of the renin-angiotensin system genes are involved in IgA nephropathy in Japanese children. We identified the M235T polymorphism of the angiotensinogen (AGT) gene, the I/D polymorphisms of the angiotensin-converting enzyme (ACE) gene, and the A1166C polymorphism of the angiotensin II type 1 receptor gene in 95 Japanese children with IgA nephropathy and 99 healthy Japanese adults. There were no differences in the genotype and allele frequencies of these genes between patients with IgA nephropathy and controls. Urinary protein excretion at the time of biopsy was significantly greater in patients with the TT genotype of the AGT gene than in those with the MM/MT genotypes of the AGT gene (1.32± 1.42 versus 0.75±0.78 g/day; P=0.01) and in patients with the ID/DD genotypes of the ACE gene than in those with the II genotype of the ACE gene (1.45±1.50 versus 0.63±0.56 g/day; P=0.001). Thus, the TT genotype of the AGT gene and the ID/DD genotype of the ACE gene are associated with increased severity of proteinuria, suggesting that AGT and ACE gene polymorphisms may play a significant role in the progression of IgA nephropathy in Japanese children. Received: 21 July 2000 / Revised: 8 December 2000 / Accepted: 11 December 2000     

ACE I/D gene polymorphism in primary FSGS and steroid-sensitive nephrotic syndrome

The role of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism in various renal disorders has been investigated. We evaluated the association between the clinical characteristics and ACE genotypes of Turkish children with primary focal segmental glomerulosclerosis (FSGS) and steroid-sensitive nephrotic syndrome (SSNS). Patients with FSGS (n=30) were classified into two groups: one with remission together with stable renal function (n=22) and the other without remission and with impaired renal function (n=8). We classified children with SSNS (n=43) that were followed for at least 4 years into two subgroups as having more frequent (n=19) and less frequent relapses (n=11). The DD genotype was more frequent in the SSNS group than that in controls (37% vs. 17%, ²=4.98, P=0.025). However, among SSNS subgroups, the frequency of the DD genotype was not different. The distribution of ACE genotype was similar among patients with FSGS and SSNS. There was no difference in the ACE I/D distribution between children with FSGS and normal controls (II 10%, ID 60%, DD 30% vs. II 13%, ID 70%, DD 17%). The frequency of the DD genotype was higher in FSGS patients with declining renal function (63%) than in those with stable renal function (18%) (P=0.031). Progressive renal impairment was significantly more frequent in patients with FSGS with the homozygous D allele compared with FSGS patients with ID and II genotypes. Our results indicate that the DD genotype may be a risk factor for the development of progressive renal impairment in children with FSGS; however, larger studies are required to confirm this.The abstract of this study was accepted as a poster for the 36th meeting of the European Society of Paediatric Nephrology, Bilbao, September 2002. This study was supported in part by a grant from the Istanbul University Research Fund (no T-849/17072000)     

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     

Advanced glycation end products in children with chronic renal failure and type 1 diabetes

Serum levels of advanced glycation end products (AGEs) are markedly elevated in adults with chronic renal failure (CRF) and diabetes mellitus. Accumulation of AGEs in tissues contributes to the development of long-term complications. Up to now little has been known about the formation of AGEs in childhood. We determined serum levels of the well known AGEs pentosidine and Nɛ-carboxymethyllysine (CML) in children with CRF (n=12), end-stage renal disease (ESRD) (n=9), renal transplantation (n=12), and type 1 diabetes mellitus (n=42) and in healthy children (n=20). Pentosidine was measured by high-performance liquid chromatography (HPLC), CML by a competitive enzyme-linked immunosorbent assay (ELISA) system. Serum levels of pentosidine and CML were significantly higher in the children with CRF and ESRD than in controls (P<0.001), but nearly within the normal range after transplantation. Both AGEs showed a significant negative correlation with creatinine clearance (P<0.001). During a single session of low-flux hemodialysis, total pentosidine and CML levels did not change. Free pentosidine, however, was reduced by 78% (P=0.04). Diabe-tic children showed significantly elevated pentosidine levels (P<0.001) despite normal renal function. We conclude that, similar to adults, increased formation and accumulation of AGEs also exist in children with CRF and type 1 diabetes mellitus. At present the best prevention of AGE-related complications is an early renal transplantation in children with ESRD, as well as a careful metabolic monitoring of diabetics. Received: 25 July 2001 / Revised: 14 November 2001 / Accepted: 18 November 2001     

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     

Early prognostic factors of infants with chronic renal failure caused by renal dysplasia

Renal dysplasia (RD) is a common cause of chronic renal failure (CRF) in children. The evolution towards end-stage renal failure is unpredictable due to the paucity of early prognostic factors. In order to identify early prognostic clinical criteria, we have retrospectively analyzed renal function and growth in 11 infants with RD and CRF from birth up to 4 years of age. Children with obstructive RD were not included. Glomerular filtration rate (GFR) was estimated from Schwartz formula. In infants with a GFR below 15 ml/min per 1.73 m² at 6 months of age (group A, n=5), kidney function did not further improve; 4 reached end-stage renal failure between 8 months and 6 years of age. In contrast, infants with a GFR above 15 ml/min per 1.73 m² at 6 months of age (group B, n=6) experienced a significant improvement in renal function during follow-up, and none required renal replacement therapy. During the first 3 months of life all infants with RD and CRF developed severe growth retardation. Between 6 months and 4 years of age, children from group B grew significantly better than those from group A. In conclusion, our experience suggests that GFR, estimated from Schwartz formula at 6 months of age, is a useful prognostic factor in infants with RD and CRF. Infants with a GFR below 15 ml/min per 1.73 m² are at risk of severe growth delay and the need for early renal replacement therapy, whereas those with a GFR above 15 ml/min per 1.73 m² have a relatively favorable long-term prognosis. Received: 4 October 1999 / Revised: 26 October 2000 / Accepted: 26 October 2000     

Optimising nutrition in chronic renal insufficiency—progression of disease

There is a lack of evidence to support the belief that dietary measures are beneficial in slowing the progression of chronic renal insufficiency (CRI). We prospectively monitored nutrient intakes and progression of CRI over a 2-year period in children aged 2–16 years with differing levels of severity of CRI, as part of their ongoing joint medical/dietetic care. Children were grouped following [⁵¹Cr]-labelled EDTA glomerular filtration rate (GFR, ml/min per 1.73 m²) estimations, into normal kidney function [GFR >75, mean 106 (SD 19.5), n =58], providing baseline data only, mild (GFR 51–75, n =25), moderate (GFR 25–50, n =21), and severe (GFR <25, n =19) CRI. Children with CRI were followed for 2 years, with 51 completing the study (19 mild, 19 moderate, 13 severe CRI) and were excluded if they subsequently required dialysis. Regular medical and dietary advice was provided and yearly 3-day semi-quantitative dietary diaries and baseline and 6-monthly measurements of blood pressure and urinary protein/creatinine ratio were obtained. Mean reductions in estimated GFR over 2 years were –9.4, –5.8, and –6.0 ml/min per 1.73 m² for mild, moderate, and severe CRI, respectively. Mean systolic blood pressure standard deviation score (SDS) fell significantly in all groups by 0.7 SDS, whereas there was little change in proteinuria. From reported dietary intakes, median sodium intakes increased (+10 mmol/day) and protein intakes decreased (–0.4 g/kg per day). Median phosphate intakes did not change significantly, whereas calcium intakes fell in all groups, with an overall median of –20% reference nutrient intake (RNI) (F =33.3, P <0.001). Of children with moderate CRI, 65% finished with calcium intakes below 80% RNI, and parathyroid hormone (PTH) concentrations significantly increased in this group (F =6.0, P =0.021). Higher phosphate and sodium intakes were associated with greater deterioration in estimated GFR in children with mild CRI (r ²=0.30, P =0.02; r ²=0.31, P =0.02, respectively). There was no such correlation for protein intake or PTH. This study emphasises the need for a joint medical and dietetic approach and indicates a number of interventions other than protein restriction, which could be commenced early in children with CRI in an attempt to delay progression.     

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.     

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.     

The D-allele of the ACE gene polymorphism predicts a stronger antiproteinuric response to ACE inhibitors

SUMMARY: Angiotensin converting enzyme (ACE) inhibitors have additional renoprotective effects over other antihypertensive drugs in retarding the development and progression of diabetic and non-diabetic nephropathies. This additional beneficial effect has been attributed to their antiproteinuric action. However, individual antiproteinuric responses to ACE inhibitors vary considerably. the mechanism underlying the variable response is unresolved. the role of the insertion/deletion (I/D) polymorphism of the ACE gene in this response was examined. the case series consisted of 96 patients (69 males, median age 46.5 years) on ACE inhibitors with an initial proteinuria in excess of 1.0 g/24h. A control series consisted of 103 patients (43 males, median age 40 years) with autosomal polycystic kidney disease. A second control series consisted of 82 patients (52 males, median age 39 years) with a diagnosis of insulin-dependent diabetes mellitus (IDDM) without microalbuminuria after more than 15 years of IDDM. Angiotensin converting enzyme genotyping was performed by polymerase chain reaction (PCR) analysis of chromosomal DNA. the ACE genotype distribution (DD 44%, ID 28%, II 28%) in the case series was not in accordance with the Hardy-Weinberg equilibrium (χ²= 17.2, P<0.001), whereas it was in both control series. the difference in ACE genotype distribution between the case series and both control series combined was significant as a result of an overrepresentation of patients with the DD genotype (χ²=9.2, P=0.01). the allele frequencies were compared in patients with a reduction of proteinuria above and below the median value of 45%. the antiproteinuric effectiveness of ACEI therapy in the whole group was greater in the presence of the D-allele (OR 1.6, 95% CI 0.9-2.9). the effect of the D-allele was more pronounced in the subgroup of patients with an initial proteinuria in the non-nephrotic range (relative risk 2.8, 95%CI 1.0-8.0) and in patients not receiving diuretics (relative risk 2.3, 95% CI 1.1–4.5). In conclusion, the DD genotype seems to predispose the development of proteinuria in the presence of a kidney disorder. the presence of the D-allele predicts a stronger antiproteinuric efficacy of ACE inhibitor therapy in patients with an initial proteinuria in the non-nephrotic range and in the patients not requiring comedication with diuretics.     

Angiotensin-converting enzyme gene polymorphism and the progression rate of focal segmental glomerulosclerosis in Iranian children

Aim: Focal segmental glomerulosclerosis (FSGS) is one of the most common forms of glomerulonephritis leading to end-stage renal disease (ESRD). A few clinical and paraclinical factors are considered as contributing factors in progression rate. However, there are controversial reports on the relationship between ACE gene polymorphism and rapidity of progression of FSGS to ESRD in different populations. To elucidate this issue, we investigated the relationship between the insertion (I) and deletion (D) ACE gene polymorphism and rapidity of progression of FSGS to ESRD in Iranian children. Methods: Forty-one children aged 1–18 years admitted to St AlZahra Hospital, Isfahan, and St Ali Asghar Hospital, Tehran, Iran, with idiopathic FSGS were enrolled. Renal death was defined as a glomerular filtration rate (GFR) of less than 50 mL/min per 1.73 m² or a decreased GFR to less than 50% compare to baseline. Reaching renal death in less or more than 2 years were labelled as rapid progressors (RP) or slow progressors (SP), respectively. Intron 16 of the ACE gene was amplified by the polymerase chain reaction technique. Results: Twenty-eight patients were male and 13 were female. In 15 RP patients, the genotype distribution was 26.6% DD, 6.7% II and 66.7% ID. In 26 SP patients, the genotype was similar (38.6% DD, 7.6% II and 53.8% ID, P > 0.05). There were no statistically significant differences for ACE I/D gene polymorphism between the two groups of patients (P > 0.05). Conclusion: Our study revealed no correlation between ACE I/D gene polymorphism and rapidity of progression of FSGS to ESRD in Iranian children.     

Effects of mTOR inhibitor–related proteinuria on progression of cardiac allograft vasculopathy and outcomes among heart transplant recipients

We have previously described the use of sirolimus (SRL) as primary immunosuppression following heart transplantation (HT). The advantages of this approach include attenuation of cardiac allograft vasculopathy (CAV), improvement in glomerular filtration rate (GFR), and reduced malignancy. However, in some patients SRL may cause significant proteinuria. We sought to investigate the prognostic value of proteinuria after conversion to SRL. CAV progression and adverse clinical events were studied. CAV progression was assessed by measuring the Δ change in plaque volume (PV) and plaque index (PI) per year using coronary intravascular ultrasound. Proteinuria was defined as Δ urine protein ≥300 mg/24 h at 1 year after conversion to SRL. Overall, 137 patients were analyzed (26% with proteinuria). Patients with proteinuria had significantly lower GFR (P = .005) but similar GFR during follow-up. Delta PV (P < .001) and Δ PI (P = .001) were significantly higher among patients with proteinuria after adjustment for baseline characteristics. Multivariate Cox regression analysis showed higher all-cause mortality (hazard ratio 3.8; P = .01) with proteinuria but similar risk of CAV-related events (P = .61). Our results indicate that proteinuria is a marker of baseline renal dysfunction, and that HT recipients who develop proteinuria after conversion to SRL have less attenuation of CAV progression and higher mortality risk.     

Endothelin-1 in children with chronic renal failure

Endothelin-1 (ET-1) was meansured after extraction from plasma of normal adults (5.9±1.9 pg/ml,n=22), normal children (7.1±1.86 pg/ml,n=29), nonhaemodialysed children with chronic renal failure (CRF) (11.1±1.8 pg/ml),n=10), renal graft recipients (9.5±3.4 pg/ml,n=37), haemodialysed children 24 h after a haemodialysis session (20.02±10.9 pg/ml,n=26) and haemodialysed children before and after a haemodialysis session (15.31±10.6 and 13.8±8.5 respectively,n=14). A sensitive and specific radioimmunoassay was used. ET-1 was significantly higher in non-haemodialysed CRF children and in renal graft recipients than in normal children (P<0.001 andP<0.01, respectively) and significantly higher in haemodialysed children when compared with normal children, non-haemodialysed CRF children and renal graft recipients (P<0.001). ET-1 concentrations were similar in normal children and normal adults. ET-1 was inversely correlated with glomerular filtration rate in non-haemodialysed CRF children (r=–0.39,P<0.01) and positively correlated with extracellular volume in haemodialysed children (r=0.435,P<0.03). After haemodialysis, ET-1 increased in 6 and decreased in 8 of the 14 children studied before and after a haemodialysis session.     

Effect of chronic renal failure and prednisolone on the growth hormone-insulin-like growth factor axis

Abnormalities of the growth hormone (GH)/ insulin-like growth factor (IGF) axis have been reported in children with chronic renal failure (CRF) and post-transplant, and are thought to contribute to poor growth. This study examined the effect of CRF and steroid therapy (given post-transplant and to children with normal renal function) on the GH-IGF axis in children with normal and abnormal growth. Thirty-one children with CRF, ten on dialysis, 26 with renal transplants and ten taking steroid therapy but with normal renal function, were studied. IGF-I, measured by radioimmunoassay, was normal but IGF bioactivity was low in groups with a decreased glomerular filtration rate (P<0.05). Transplanted children growing at a subnormal growth rate had lower IGF bioactivity than those growing at a normal rate (P=0.03), but there was no such difference in bioactivity in children with CRF. There was no correlation between IGF bioactivity and prednisolone treatment. There was no correlation between IGF binding proteins 1, 2 or 3 and growth. Received: 1 August 2000 / Revised: 11 July 2001 / Accepted: 12 July 2001     

Validation of an Experimental Model to Study Less Severe Chronic Renal Failure

Purpose: The 5/6 nephrectomy, mimics the stages of human chronic renal failure (CRF), but the procedure causes severe renal functional and morphological damage that could interfere with the evaluation of therapies for slowing the progression of the disease. This study summarizes the results of renal function, histology, and immunohistochemical findings in rats undergoing a 2/3 nephrectomy. Methods: The rats were distributed in groups according to the type of nephrectomy: CRF5/6: induced by a 5/6 renal mass reduction and CRF2/3: less severe CRF. The body weight and blood pressure were monitored, and the serum creatinine (SCr), creatinine clearance (CCr), urine osmolality, and 24-h proteinuria (PT24h) were measured. CRF progression was evaluated by the rate of decline of CCr (RCCr). Histology and immunohistochemistry were performed in the remnant kidneys. Statistical analysis was done by unpaired t-test, and a P-value < 0.05 was taken as a statistical significance. Results: Compared to the CRF5/6 group, the CRF2/3 model had a lower SCr, PT24h, CCr, and variations of the SCr from baseline. The disease progression was also significantly slower. The renal histopathological findings revealed fewer chronic lesions in rats with CRF2/3. Similarly, we observed less macrophage accumulation as well as lower proliferative activity and expression of fibronectin and a-smooth muscle-actin in the CRF2/3 model. Conclusions: The CRF2/3 model presented with a pattern of less severe CRF, functionally and morphologically, compared to the classical CRF5/6 model, and the CRF2/3 model may be useful for evaluating therapeutic interventions that target the early stages of CRF.     

Sequential analysis of variation in glomerular filtration rate to calculate the haemodynamic response to a meat meal

BACKGROUND: The renal haemodynamic response to a meat meal is usually measuredas either filtration capacity (maximal achieved GFR), or renalreserve (maximal GFR increase over baseline), or percent renalreserve (maximal GFR increase as a percentage of baseline).The time-course of GFR response to a meat meal varies in differentindividuals as the peak GFR tends to occur late in renal disease.This study proposes a new method to measure the GFR responseindependently of differences in peaking time. METHODS: The study is based on measurement of GFR (inulin clearance,ml/minx1.73 m² BSA) in three 30-min pre-meal clearance periods(baseline) followed by analysis of the GFR changes for up to180 min (four 30-min and one 60-min clearance periods) aftera meat meal (2 g of protein/kg of BW as red cooked meat). Datawere analysed from 85 healthy people (GFR100) and 273 individualswith renal disease (RD) who were divided into three groups basedon their baseline GFR (RD1, n=115, GFR 99–66; RD2, n=85,GFR 65–33; RD3, n=73, GFR<33). RESULTS: In healthy people after the meat meal GFR peaked between 30and 60 min and returned to baseline by 120 min. In the threeRD groups GFR peaked later than in healthy people (P<0.001)and remained higher than baseline for up to 180 min (P<0.001).Cumulative post-meal GFR changes, calculated as cumulative GFRincrease over baseline up to 120 min after meal (ml/120minx1.73m²BSA), were significantly different (P<0.01) in the four groups(healthy people, 937±141; RD1, 1222±141; RD2,587±104; RD3, 361±89). Interindividual variabilityin cumulative GFR increase was only partially explained by thevalue of nitration capacity (r²=0.285), renal reserve (r²=0.640),and percent renal reserve (r₂=0.175). CONCLUSIONS: The data indicate that commonly used parameters are poor indicesof the actual total time-course of the renal response to a proteinload.     

Risk factors for renal failure in children with non-glomerular nephropathies

The aim of the present study was to analyze the progression of chronic renal failure (CRF), the effects of modification of risk factors for disease progression, and to formulate a theoretical model of CRF progression in an unselected group of children with CRF. The study was a cross-sectional, retrospective analysis of 92 patients aged 9.2+/-5.8 years with CRF and low-level proteinuria [glomerular filtration rate (GFR) 43+/-18 ml/min per 1.73 m(2), proteinuria 0.57 g/day, range 0-3.9 g/day]. Inclusion criteria were an established diagnosis of CRF and completion of any surgical treatment. The etiology of CRF in the majority of patients was congenital uropathy. Sixty-nine patients observed for longer than 3 years were divided into two groups according to progression of CRF or improvement of GFR. Forty-three patients were on renoprotective therapy. Over a 3-year period GFR decreased in 39 children and improved in 30 children. There were no differences between the groups in the etiology of CRF. Patients with progression of CRF were older ( P<0.08), grew faster ( P<0.004), had higher blood pressure ( P<0.01), and were more often proteinuric ( P<0.03). Arterial hypertension in patients with progression of CRF was resistant to therapy and these patients needed more intensive treatment. Renoprotective therapy led to improvement of kidney function in 50% of patients, and resistance to renoprotective therapy was correlated with increased body mass and height. Patients who received renoprotective drugs showed stabilized kidney function ( P<0.007) and decreased proteinuria ( P<0.05) and blood pressure ( P<0.02), despite higher basal values. In patients on renoprotective therapy in whom CRF progressed despite treatment, proteinuria was persistent in contrast to patients with improvement ( P<0.02). The best model of CRF progression in the path diagram included systolic blood pressure and anthropometric parameters. In conclusion, in unselected patients with CRF of non-glomerular origin and nil-to-moderate proteinuria the main risk factors for CRF progression are rapid somatic growth, age, and blood pressure. Arterial hypertension and proteinuria, even of mild intensity, differ significantly between patients with progression of CRF and those with stable or improved renal function. Renoprotective therapy is related to significant slowing of CRF progression, but the risk factors for resistance to therapy include persistent proteinuria and somatic growth.     

Is Administration of Preoperative Angiotensin-Converting Enzyme Inhibitors Important for Renal Protection after Cardiac Surgery?

Objective: There are various reasons for renal dysfunction after cardiac surgery; however, activation of the renin–angiotensin system has an important role following cardiac surgery. We investigated the effect of preoperative angiotensin-converting enzyme (ACE) inhibitors on renal functions after cardiovascular surgery. Material–methods: Three hundred sixty-six patients awaiting elective cardiac surgery were allocated to two groups, namely the treatment group, comprising the ACE inhibitor group (n = 186), and the control group, which was without ACE inhibitor (n = 180). The renal parameters [blood urea nitrogen, creatinine, creatinine clearance, and glomerular filtration rate (GFR)] and the need for dialysis were evaluated associated with renal functions between the two groups in the postoperative period. Results: After cardiac surgery, renal dysfunction requiring dialysis developed in 11 (3.8%) patients in the control group patients. There was no required dialysis in the treatment group (p < 0.05). As an indicator of renal dysfunction, the increase in creatinine and blood urea nitrogen levels and the decrease in GFR and creatinine clearance were higher in the control group (p < 0.05). The multivariate analysis indicated that therapy with ACE inhibitors was found to decrease the incidence of postoperative renal dysfunction (odds ratio, 1.07; 95% confidence interval, 0.45–2.50; p < 0.05). The other independent predictors were age, preoperative intra-aortic blood pump, hypertension, diabetes mellitus, and a left ventricular ejection fraction below 0.40. Conclusion: Preoperative therapy with ACE inhibitors has an influence on renal functions. This study demonstrates that administration of ACE inhibitors provides better renal protection after cardiac surgery.     

Changes in body composition of children with chronic renal failure on growth hormone

Body composition is altered in children with chronic renal failure (CRF) and contributes to the significant growth failure seen in these children. Recombinant human growth hormone (rhGH) has been used in the past several years to improve the somatic growth of children with CRF. To determine if the growth achieved in these children occurs concomitantly with body compositional changes, seven prepubertal (n=6) and pubertal (n=1) children with chronic renal insufficiency (n=4) and end-stage renal disease (n=3) underwent measurements of total body fat (FM), fat free mass (FFM), bone mineral density (BMD), total bone mineral mass (TBBM), total body water (TBW), and total body potassium (TBK) before and 6 months after initiation of subcutaneous recombinant human growth hormone (rhGH) at 0.35 mg/kg per week. The techniques used included dual- energy X-ray absorptiometry (for measurement of FM, BMD, and TBBM), total body potassium counting (for measurement of TBK), and deuterated water for assessment of TBW. Significant increases in both height and weight were seen following 6 months of rhGH therapy. These increases were accompanied by significant re- ductions in FM (4.4±1.4 kg vs. 3.6±1.2 kg, P=0.002) and percentage fat (18.6±3.9% vs. 14.5±3.4%, P=0.04), while FFM (17.9±3.0 kg vs. 20.7±3.6 kg, P=0.04) increased significantly as did TBBM (776±171 g vs. 844±177 g, P=0.001). Increases in TBK, a measure of body cell mass, were also seen. No difference in total BMD was observed. Thus, growth in CRF is occurring with repletion of the FFM and TBBM compartments. Despite these improvements, no change was observed in the body mass index (BMI). Measurement of BMI alone does not define the compartmental catabolic losses in FFM. Received: 20 September 1999 / Revised: 31 January 2000 / Accepted: 8 February 2000