Clinical outcome of children with chronic kidney disease in a pre-dialysis interdisciplinary program

The purpose of this retrospective cohort study was to describe the outcome of 107 patients with chronic kidney disease (CKD) admitted to a pre-dialysis interdisciplinary management program from 1990 to 2006. The events of interest were progression to CKD stage 5 (renal survival), patient survival, hypertension, and somatic growth. Survival was studied by the Kaplan–Meier method. Patients were classified into four groups according to their primary renal disease: congenital nephro-uropathies; glomerular diseases; cystic disease, and miscellaneous. Median follow-up time was 94 months [Interquartile (IQ) range 38–145]. The probability of reaching CKD stage 5 was estimated to be 36% by 5 years after admission. As a whole, the mean estimated glomerular filtration rate (GFR) decrease per year was 5.8 ml/min per 1.73 m² body surface area [standard deviation (SD) 12.4]. The glomerular diseases group showed a median rate of GFR deterioration of 10 ml/min per 1.73 m² per year (IQ range −24 to −5.7), whereas the median rate of GFR deterioration for the groups with cystic diseases, congenital nephro-uropathies, and miscellanea were 2.5 ml/min (IQ range −10 to +0.34), 2.2 ml/min (IQ range −5.0 to −0.52), and 0.36 ml/min (IQ range −2.5 to +2.6), respectively (P < 0.001). The results of this study support the view that children and adolescents with glomerular diseases present a faster deterioration of renal function. Therefore, patients with glomerular diseases need to be referred early to a pediatric nephrology center so that suboptimal pre-dialysis care might possibly be avoided.     

Proteinuria and decreased body mass index as a significant risk factor in developing end-stage renal disease

Background  Body mass index (BMI) is a significant predictor of developing end-stage renal disease (ESRD). The relation between a change in BMI (ΔBMI) and the incidence of ESRD has not been examined in any large epidemiologic studies. Methods  We determined the ΔBMI in subjects who participated in the Okinawa General Health Maintenance Association (OGHMA) screenings in 1983 and again in 1993. Screenees were free of ESRD at the 1993 screening and were then monitored until the end of 2000 to determine whether they developed ESRD. Participants were identified using ID numbers, birthdates, and other identifiers. Details of every ESRD patient treated in Okinawa are maintained in an independent community-based dialysis registry. Multivariate logistic analyses were performed to determine the significance of a ΔBMI on the incidence of ESRD using SAS. The ethics committee of the OGHMA approved the study protocol. Only coded data were used for this study. Results  Among the 92,364 subjects aged 30–89 years screened in 1983, 29,011 (31.4%) returned for the 1993 screening. The median ΔBMI was 2.1%, and the subjects were divided into two groups: ΔBMI < 2.1% (G1) and ΔBMI ≥ 2.1% (G2). The cumulative incidence of ESRD was 0.31% in G1 (ESRD in 44) and 0.14% in G2 (ESRD in 21). The odds ratio (95% confidence interval) of developing ESRD based on a ΔBMI was 2.268 (1.284–4.000, P < 0.01) after adjusting for age, sex, systolic blood pressure, BMI in 1983, and proteinuria. Conclusion  The findings of the present study suggest that a ΔBMI is an independent risk factor for the incidence of ESRD, especially for those with proteinuria. The reasons for the BMI change were not recorded in this study. Unintentional weight loss, however, might warrant evaluation for the presence or progression of chronic kidney disease.     

Chronic tubulo-interstitial nephropathy in children with cranioectodermal dysplasia

We report two pairs of siblings with the syndrome cranioectodermal dysplasia who have subsequently developed chronic renal failure secondary to tubulo-interstitial nephropathy. Renal disease has not been described before in this rare syndrome but has now occurred in four of the seven reported cases. Children with cranioectodermal dysplasia appear to be at significant risk of developing chronic renal failure. This is important information for clinicians looking after such children, and their families, when considering the long-term prognosis and management. Received October 23, 1995; received in revised form and accepted July 19, 1996     

Therapeutic strategies to slow chronic kidney disease progression

Childhood chronic kidney disease commonly progresses toward end-stage renal failure, largely independent of the underlying disorder, once a critical impairment of renal function has occurred. Hypertension and proteinuria are the most important independent risk factors for renal disease progression. Therefore, current therapeutic strategies to prevent progression aim at controlling blood pressure and reducing urinary protein excretion. Renin-angiotensin-system (RAS) antagonists preserve kidney function not only by lowering blood pressure but also by their antiproteinuric, antifibrotic, and anti-inflammatory properties. Intensified blood pressure control, probably aiming for a target blood pressure below the 75th percentile, may exert additional renoprotective effects. Other factors contributing in a multifactorial manner to renal disease progression include dyslipidemia, anemia, and disorders of mineral metabolism. Measures to preserve renal function should therefore also comprise the maintenance of hemoglobin, serum lipid, and calcium-phosphorus ion product levels in the normal range.     

Progression of chronic renal failure in children with dysplastic kidneys

The aim of this study is to describe progression of chronic renal failure (CRF) in children with renal malformations and to study factors influencing this progression. We reviewed retrospectively 176 children with CRF secondary to renal dysplasia, reflux nephropathy or renal obstruction with at least 5 years of follow-up. Serum creatinine was recorded at least every third month, and an estimated glomerular filtration rate (eGFR) was calculated. Number of febrile urinary tract infections (UTI), blood pressure, albuminuria (UaUc), and number of functioning kidneys was also recorded. We found that the development of renal function could be separated into three time periods: (1) During the first years of life, 82% of the children showed early improvement of their kidney function, which lasted until a median age of 3.2 years (median improvement 6.3 ml/year). (2) From the age of 3.2 years until 11.4 years, 52.5% of the studied children showed a stable kidney function, whereas in 47.5%, kidney function immediately started to deteriorate. (3) Around puberty, 42.9% started deterioration in kidney function, whereas 57.1% even after puberty showed a stable function. Patients with UaUc >200 mg/mmol deteriorated faster (−6.5 ml/min per 1.73 m² per year compared with −1.5 ml/min per 1.73 m² per year) in those with UaUc <50 mg/mmol. Children with more than two febrile UTIs, hypertension or an eGFR at onset of less than 40 ml/min per 1.73 m² deteriorated faster than the others. Most children experienced early improvement of kidney function. The further prognosis, early or late deterioration of kidney function or stable function during the whole follow-up, was related to albuminuria, number of febrile UTIs, eGFR at onset of deterioration, hypertension and puberty.     

Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in children with chronic kidney disease

Very few biomarkers exist for monitoring chronic kidney disease (CKD). We have recently shown that serum neutrophil gelatinase-associated lipocalin (NGAL) represents a novel biomarker for early identification of acute kidney injury. In this study, we hypothesized that serum NGAL may also represent a biomarker for the quantitation of CKD. Forty-five children with CKD stages 2–4 were prospectively recruited for measurement of serum NGAL, serum cystatin C, glomerular filtration rate (GFR) by Ioversol clearance, and estimated GFR (eGFR) by Schwartz formula. Serum NGAL significantly correlated with cystatin C (r=0.74, P<0.000). Both NGAL and cystatin C significantly correlated with measured GFR (r=0.62, P<0.000; and r=0.71, P<0.000, respectively) as well as with eGFR (r=0.66, P<0.000 and r=0.59, P<0.000, respectively). At GFR levels of ≥30 ml/min per 1.73 m², serum NGAL, cystatin C, and eGFR were all significantly correlated with measured GFR. However, in subjects with lower GFRs (<30 ml/min per 1.73 m²), serum NGAL levels correlated best with measured GFR (r=0.62), followed by cystatin C (r=0.41). We conclude that (a) both serum NGAL and cystatin C may prove useful in the quantitation of CKD, and (b) by correlation analysis, NGAL outperforms cystatin C and eGFR at lower levels of measured GFR.     

Urinary excretion of urodilatin in healthy children and children with renal disease

Urodilatin (URO) is a natriuretic peptide isolated from human urine which is thought to be produced by distal tubular cells. We measured urinary URO excretion in 50 healthy children and 23 children with acute (ARF), chronic renal failure (CRF), or hereditary tubular disorders, using a specific radioimmunoassay. The mean URO excreted in these four groups was 56, 45, 94, and 121 fmol/min per 1.73 m², respectively (differences between first three groups not significant). The variation in URO excretion was larger in patients with kidney disease than in controls. There were significant correlations between urinary URO and sodium excretion in controls and CRF, but not in ARF. URO excretion also correlated with urine flow rate in CRF. Although no correlation was found between URO excretion and creatinine clearance, urinary URO was increased in some patients with advanced CRF, which suggests stimulated tubular production to compensate for reduced sodium excretion. In view of the therapeutic potential of URO in renal insufficiency, further study of the renal handling of URO is warranted. Received December 4, 1996; received in revised form and accepted June 13, 1997     

The 'breakpoint' test, a new statistical method for studying progression of chronic renal failure

The application of a new statistical method ('breakpoint' test) to the study of the progression of chronic renal failure is described. This test establishes whether the best fit of a series of GFR measurements is linear or broken. Such an approach avoids the analytical constraint of the time of intervention assumed by other methods. Re-analysis by this test of previous studies of low-protein diet suggests that in some cases the effect of the dietary regimen has been overemphasized.     

Somatic and renal effects of growth hormone in rats with chronic renal failure

Recombinant human growth hormone (rhGH) has been widely used to improve growth in children with chronic renal failure (CRF). However, there has been great concern that GH may aggravate renal disease and hasten the progression to end-stage renal failure. We therefore investigated the effect of prolonged administration of rhGH at various doses on somatic growth and renal function and structure in rats with CRF, divided into four groups based on rhGH dose (vehicle, 0.4, 2.0, and 10.0 IU/day). rhGH was administered subcutaneously daily for 8 weeks. The mean growth was significantly greater in rats treated with high-dose rhGH (10.0 IU) than those treated with low-dose rhGH (P = 0.0089) or vehicle (P = 0.0011). Body weight gain increased in parallel with body length (Creatinine clearance at the end of the experiment was significantly lower in rats on high or medium-dose rhGH than those on low-dose rhGH and controls (P <0.05). The glomerular sclerosing index was greater in rats treated with higher doses of rhGH. There were significant differences between rats treated with high-dose rhGH and controls (P = 0.0144) and also between rats on medium-dose rhGH and controls (P = 0.0065). Although there was no significant difference, rats treated with higher doses of rhGH tended to excrete more protein. Renal insulin-like growth factor-I (IGF-I) content and circulating IGF-I and IGF-II levels did not significantly differ among groups. We conclude that: (1) GH improves somatic growth failure in rats with CRF, but prolonged administration of GH dose-dependently induces deterioration in renal function and structure and (2) this effect was induced neither via circulating IGF-I and IGF-II nor by local production of IGF-I, but seems to be direct. Received June 7, 1996; received in revised form and accepted November 19, 1996     

Neuropathic bladder as a cause of chronic renal failure in children in developing countries

Neuropathic bladder is considered a threat to the kidneys if not managed appropriately. In this study, we report our experience with neuropathic bladder at King Abdulaziz University Hospital (KAUH) as a cause of chronic renal failure (CRF) in the pediatric age group. This retrospective study included all children diagnosed with neuropathic bladder who presented with moderate or severe CRF over a 4-year period from December 2000 to December 2004 [glomerular filtration rate (GFR) at presentation <50 ml/min per 1.73 m²]. Fifteen patients were diagnosed with neuropathic bladder; group A consisted of ten patients with spina bifida and one with sacral agenesis and group B consisted of four patients with nonneurogenic neurogenic bladders (NNNB). The mean age±SD at presentation was 6.2±3.8 years, GFR was 24.2±12.4 ml/min per 1.73 m², and creatinine was 289.9±253.2 μmol/l. There were no differences in the age at presentation to a pediatric nephrologist or the degree of renal failure at presentation between the two groups. Clean intermittent catheterization (CIC) was not started in all patients before presentation to KAUH, except in two children. Five children required dialysis as they were in end-stage renal failure (ESRF). All except one received peritoneal dialysis (PD). Their mean age at the start of dialysis was 10.8±1.7 years. Neuropathic bladder due to spina bifida or NNNB is an important cause of CRF in developing countries. There was a considerable delay in the diagnosis of NNNB and a significant delay in starting CIC in all neuropathic patients.     

Urinary gamma-glutamyl transferase-to-creatinine ratio as an indicator of tubular function in Bence Jones Proteinuria

Increased urinary gamma-glutamyl transferase (GGT) activity suggests early renal tubular damage. The aim of this study was to evaluate the urinary GGT activity as a marker of renal injury in different types of Bence Jones Proteinuria (BJP). One hundred and three individuals with BJP were included in the study. Urinary GGT activity, urinary GGT-to-creatinine ratio and urinary protein-to-creatinine ratio were studied. Urine samples were tested by immunofixation agarose gel electrophoresis. Total urinary excretion of kappa and lambda light chains were measured by nephelometric method. There were no significant differences in demographic characteristics of the patients in Lambda BJP, Kappa BJP and Control groups. GGT-to-creatinine ratio of the Lambda BJP group was significantly higher than Kappa BJP group and controls (p?=?0.018 and 0.002, respectively). There was no correlation between the quantitative kappa and lambda BJP and urinary GGT-to-creatinine ratio. Our data have demonstrated that urinary GGT-to-creatinine ratio could be a tubular damage marker of lambda light chain proteinuria.     

CD44 standard form expression as a predictor of progression in high risk superficial bladder tumors

Objective: The purpose of this study was to assess the significance of the standard CD44 adhesion molecule expression in predicting progression of high risk superficial bladder carcinoma in the short term.Methods: Sixty-six patients (51 males and 15 females, aged 27 to 89 years (mean 64.75 years) with primary superficial transitional cell bladder cancer initially treated with transurethral resection (TURBT) were enrolled in the study. Only pTa/pT1 grade 2 multiple tumors as well as all grade 3 tumors were included in this study. All tumor samples obtained after the resection were immunohistochemically evaluated for the expression of the CD44 standard molecule. Fifty eight patients remained during the follow up period which ranged from 3 to 36 months (mean 11.8 months). Tumor progression in the short term was considered as the critical end point of interest in this study. The prognostic significance of tumor stage, grade, presence of carcinoma-in-situ (CIS) and expression of CD44 in determining the risk for progression, was studied with both univariate (log rank test) and multivariate (Cox proportional hazards) methods of analysis.Results: Kaplan-Meier survival curves indicated that a shorter median progression-free survival is expected for those patients with G3 bladder tumors (p = 0.0055), concomitant CIS (p = 0.0051), and loss of expression of CD44 (p = 0.0015), whereas a similar association with stage was not detected (p = 0.5793). The cox regression multivariate analysis did not yield a significant result for any of the studied parameters therefore no one of the factors taken into account can serve as an independent predictor of progression in superficial bladder cancer in the short term.Conclusion: The immunohistochemically detectable loss of the expression of CD44 standard form from superficial bladder tumor samples may be, complementary to the established prognostic factors, a useful predictor of tumor progression in the short term.     

Reduction of Blood Pressure Retards the Progression of Chronic Renal Failure in Man

The effect of blood pressure reduction on the progression rateof chronic renal failure (CRF) was studied in 28 patients withCRF of diverse aetiology entering a prospective study (observationtime 7–24 months, mean 16 months). Endogenous creatinineclearance was 12–66 ml/mm (mean 30±3 ml/mm). Weaimed to keep the blood pressure below 160/90 mmlHg. Dietaryprotein was not restricted. The progression rate of CRF wasassessed from the regression coefficients of the regressionsof creatinine clearance and the inverse of s-creatinine, respectively,on time. Progression rate and the means of all recordings ofmean arterial blood pressure (MAP) and urinary protein excretion,respectively, in each patient during the prospective phase werecompared with retro spective data from the proceeding period(observation time 4–25 months, mean 19 months). The patientsreceived various combinations of antihypertensive drugs includingdiuretics, beta-blockers and vasodilatory drugs. In 19 patientsMAP decreased from 109±2 to 102±2 mmHg (groupI), whereas MAP increased from 105±2 to l08±2mmHgin nine patients (group II). In group I proteinuria was significantlylower (P<0.05) and the progression of CRF was approximately50% slower (P.<0.01) in the prospective phase than in theretrospective phase; no changes were observed in group II. Calculatedfor all patients, significant correlations were observed betweenthe change in MAP and the change in progression rate and proteinexcretion, respectively. These results indicate that loweringof blood pressure results in decreased proteinuria and retardationof the progression of CRF irrespective of the aetiology.     

Long term follow-up of bone mineral status in children with renal disease

Bone mineral content (BMC) was measured by photon absorptiometry in the non-dominant forearm of children with chronic renal failure followed for a total of 2472 months. From 48 children, 302 measurements were made, and changes which occurred in BMC over time were correlated with several factors. Patients were divided into those who had received glucocorticoids (group 1) and those who had not (group 2). Group 1 patients had a lower mean serum creatinine (Cr) (p<0.05), a lower growth velocity (p>0.02) and were more demineralized than group 2 patients. There was no correlation between BMC and height velocity or estimated creatinine clearance. BMC and height Z-score (SDS) were highly correlated. Over the period of study, group 1 patients remained shorter, had a lower height velocity, a lower BMC Z-score and a lower BMC for each serum creatinine level. Long-term therapeutic intervention with oral 1,25(OH)₂D improved bone mineral status in three children in the nonsteroid group, but none of those in the steroid group. This study demonstrates that steroid administration is probably the most important factor causing bone demineralization, possibly even more important than renal failure.Supported in part by funds from NIH grants: AM 31682, 37223 and Research Career Development Award K04 AM00421, by grants from Hoffman LaRoche Inc., and from Miles Laboratories.     

Cognitive functioning and school performance in children with renal failure

Although previous studies have documented neuropsychological deficits in children with end-stage renal disease, few have evaluated and compared the cognitive functioning and the school performance of children with renal failure. The current study evaluated the influence of chronic renal failure on cognitive functioning and school performance in children and adolescents with end-stage renal disease undergoing dialysis and after renal transplantation. Participants were given standardized IQ and achievement tests to assess cognitive functioning and ability. Academic performance was determined by evaluating grades for the semester in which the testing was performed; a grade point average (GPA) was calculated based on a 4.0-point scale. The 11 dialysis patients and 13 transplant patients were comparable in age, race, sex, and socioeconomic status. Overall IQ and subtest scores demonstrated no differences between the two groups. Performance on the Woodcock-Johnson achievement tests showed that the transplant patients did better on achievement tests of written language (P=0.04) and in school performance in English compared with dialysis patients (P<0.05). Furthermore the dialysis patients tended to be below age and grade level in all areas, whereas the transplant patients were achieving at or above these levels. There were significant differences in the age equivalent scores between the dialysis and transplant patients in the areas of mathematics and written language (P<0.05). However, when grades were evaluated there were no differences in overall GPA or in the mathematics GPA. Days absent were not different between the two groups. These data demonstrate that both groups of patients were of similar intellectual ability; the achievement of the dialysis patients was behind that of the transplant patients and this lag was not necessarily reflected in school grades. Patients with chronic renal failure should have cognitive and achievement testing on a regular basis, and areas of deficit should be addressed by the schools.     

Etiology of chronic renal failure in Turkish children

The etiology of chronic renal failure (CRF) was studied in 459 Turkish children (205 girls, 254 boys) for the period January 1979-December 1993. Their mean age at onset of CRF was 9.5±4.2 years (range 1–16 years); CRF was defined as a glomerular filtration rate (GFR) below 50 ml/min per 1.73 m² for at least 6 months. When a GFR determination was not available, the serum creatinine concentration was used: greater than 1 mg/dl for children aged 1–3 years, greater than 1.5 mg/dl for those 3–10 years and greater than 2 mg/dl for those 10–16 years. Primary renal disorders were as follows: reflux nephropathy 32.4% glomerular diseases 22.2%, hereditary renal disorders 11.4%, amyloidosis 10.6%, urinary stones 8% and other renal disorders 15.4%. Twenty-three cases of reflux nephropathy (15.4%) were associated with neural tube defects (NTD) and 20 (13.4%) were caused by infravesical obstruction. CRF caused vesicoureteral reflux associated with NTD and amyloidosis are more frequent in our series compared with west European and Nordic countries.     

Focal segmental glomerulosclerosis and nephrotic syndrome in a child with embryonal rhabdomyosarcoma

A case of nephrotic syndrome (NS) and acute renal failure (ARF) associated with embryonal rhabdomyosarcoma (RMS) in a 10-year-old boy is reported. Ultrasound revealed irregular, echogenic, circumferential urinary bladder base mass, bilateral hydroureter and hydronephrosis. Histopathology of percutaneous renal and urethrocystoscopic biopsy specimens, respectively, revealed focal segmental glomerulosclerosis (FSGS) and embryonal RMS. Tumour remission was induced with pulse doses of intravenous vincristine, cyclophosphamide, methotrexate and actinomycin D over a 15-month period. He has been followed-up for 28 months and has maintained a drug-free tumour and proteinuria remission for 1 year. While some malignancies have been reported in association with NS, its occurrence in association with RMS is quite exceptional. We conclude that RMS may be associated with FSGS and NS. Effective treatment of the RMS was associated with sustained remission of the nephrotic proteinuria.