Limitations to body length/serum creatinine ratio as an estimate of glomerular filtration in children

The ability of the Schwartz formula (C _SCH) to estimate glomerular filtration rate (GFR) accurately was investigated in children with renal disease. ¹²⁵Iodine-iothalamate clearance (C _IO) was used as the reference standard for measuring GFR. Data from 176 C _IO studies performed on 133 children (aged between 1 and 18 years) were compared with the simultaneous estimation of GFR by C _SCH. The overestimation of GFR by C _SCH was inversely proportional to the level of renal function. When C _IO was >90 ml/min per 1.73 m², C _SCH overestimated GFR by only 0.1%±3%, but when C _IO was ≤15 ml/min per 1.73 m², C _SCH overestimated GFR by 164%±42%. When renal function is normal or mildly reduced (GFR >50 ml/min per 1.73 m²), C _SCH overestimated C _IO by only 10.3±3.0%, compared with 90.3±14.5% when renal function was moderately to severely curtailed (GFR ≤50 ml/min per 1.73 m²). We conclude that C _SCH is valid in predicting GFR only in children with normal renal function and mild insufficiency. Received January 30, 1996; received in revised form and accepted May 14, 1996     

Creatinine for estimation of glomerular filtration rate

The aim of this study was to evaluate the plasma creatinine concentration (P_Cr) and creatinine clearance (C _Cr) for estimation of glomerular filtration rate (GFR). Inulin clearance (C _in) was used as the reference standard for GFR. Thirty-nine concurrentC _in andC _Cr studies provided data for comparingC _in with the measuredC _Cr and with the calculatedC _Cr (calc-C _Cr). (Calc-C _Cr=k·L/P_Cr, where L=height in centimeters and k is the proportionality constant.) Thirty-one children 5.3–20.8 years of age, withC _in ranging from 2.8 to 138.8 ml/min per 1.73 m², participated in these studies at The Children's Mercy Hosptial. The measuredC _Cr was 16.7±10.3 ml/min per 1.73 m² (P<0.001) greater than theC _in, and the calc-C _Cr overestimatedC _in by a mean of 31.6±20.8 ml/min per 1.73 m² (P<0.001). Although there is good correlation betweenC _in andC _Cr (r=0.96), andC _in and calc-C _Cr (r=0.90), the 95% confidence intervals are quite broad. Hence, theC _Cr and the calc-C _Cr, derived using Schwartz values for k, consistently overestimate GFR. However, if the k value in the equation GFR=k·L/P_Cr is derived from k=C _in/L, rather than from k=C _Cr·P_Cr/L, a more accurate estimate of GFR may be obtained.     

Can the DOQI guidelines be met by peritoneal dialysis alone in pediatric patients?

DOQI guidelines recommend minimal standards for automated peritoneal dialysis (APD), with a weekly Kt/V of 2.1 and creatinine clearance (C _Cr) of 63 l/1.73 m². The purpose of this study was to assess if the DOQI guidelines could be met by dialysis alone in children on PD. Dialysis clearance studies were retrospectively analyzed in 20 pediatric patients on APD, all with a dwell volume of at least 1,000 ml/m². Mean dialytic Kt/V was 2.0; only 45% had a Kt/V above the recommended 2.1. Mean dialytic C _Cr was 43.5 l/week per 1.73 m²; only 10% achieved a C _Cr above the recommended 63 l/week per 1.73 m². Despite the significant correlation between total therapy volume (TTV) and both Kt/V and C _Cr, only 2 of 10 patients with a TTV over 10 l/m² per day reached the target C _Cr. All patients had currently recommended dwell volumes, therapy times, and nocturnal cycles, but DOQI guidelines were difficult to achieve with dialysis alone. Strict adherence to DOQI guidelines in anephric pediatric PD patients may result in changing dialysis modality. However, without evidence of a correlation between delivered dose of dialysis and improved outcome, adequate dialysis should not be assessed by only measuring Kt/V and C _Cr. Received: 24 June 1999 / Revised: 2 November 1999 / Accepted: 2 November 1999     

Clinical experience with icodextrin in children: ultrafiltration profiles and metabolism

Icodextrin use in adults provides sustained ultrafiltration (UF) in long-term dwells. No information is available on UF and metabolism in children. In 11 children, a volume of 1,049±138 ml/m² of the study fluid (1.36% glucose, 7.5% icodextrin, 3.86% glucose) was administered for 12 h. Net UF with icodextrin (339±147 ml/1.73 m²) did not differ from UF with 3.86% glucose (450±306 ml/1.73 m², P=0.53) and was higher than UF with 1.36% glucose (–87±239 ml/1.73 m², P=0.003). Icodextrin added 0.52±0.07 to the weekly Kt/V. Over 6 weeks, icodextrin was used for 12-h daytime dwell. Total icodextrin reached a steady-state level of 2.91±1.22 g/l at 2 weeks. The main icodextrin metabolites were maltose, maltotriose, and maltotetraose. After 2 weeks, steady state levels were 2.02±0.66 mmol/l, 1.46±0.35 mmol/l, and 0.45±0.12 mmol/l. No icodextrin or metabolites were detectable 4 weeks after the study. We conclude that 7.5% icodextrin is capable of maintaining UF during 12-h dwell in children and is comparable to UF obtained with 3.86% glucose. Steady-state levels of icodextrin and metabolites were reached at 2 weeks and disappeared after the study. Received: 11 November 1999 / Revised: 28 March 2000 / Accepted: 29 March 2000     

Renal function during and after childhood acute poststreptococcal glomerulonephritis

It is still debatable whether acute poststreptococcal glomerulonephritis (APSGN) can lead to permanent renal impairment. The clinical, immunological, and histological findings during the acute disease have been described thoroughly, however, the hemodynamic events are still poorly understood. In this retrospective study, the inulin and p-aminohippurate clearances were measured to evaluate glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) within a month of onset of the disease (acute stage) in 26 children, and 2–12 months after onset (follow-up) in 22 children with APSGN. During the acute stage, the mean GFR was 77±23 (SD) ml/min per 1.73 m², the mean ERPF 537±138 ml/min per 1.73 m², and the filtration fraction (FF) 14%±3%, compared with values for controls of 115±11 ml/min per 1.73 m², 607±72 ml/min per 1.73 m², and 19%±2%, respectively (n=42). At follow-up, GFR was 114±15 ml/min per 1.73 m², ERPF 600±68 ml/min per 1.73 m², and FF 19%±3%. Thus, during the disease both GFR and ERPF fell below values for controls, but later were restored. The GFR, however, was more reduced than the ERPF, as indicated by the reduced FF. This might reflect a relative hyperperfusion of individual nephrons, which might start processes later deleterious to the nephrons. This finding, however, needs to be further investigated and we have therefore started a long-term follow-up of these patients. Received: 24 June 1998 / Revised: 4 December 1998 / Accepted: 7 December 1998     

Plasma atrial natriuretic peptide and endothelin levels in acute poststreptococcal glomerulonephritis

Plasma levels of atrial natriuretic peptide (ANP) and of endothelin (ET) were significantly elevated (87.7±13.9 pg/ml and 79.7±10.8pg/ml, respectively) during the acute phase of acute poststreptococcal glomerulonephritis (APSGN). Plasma renin levels were normal, fractional excretion of sodium (FE_Na) was 0.5±0.1% and creatinine clearance (C _Cr) averaged 82.2±18.3 ml/min per 1.73 m². In the recovery phase of the disease (n=12), levels of ANP (23.6±6.7 pg/ml) and ET (43.1±2.4 pg/ml) fell and were not significantly different from those measured in 11 control subjects. FE_Na increased to 1.3±0.1% andC _Cr to 113.5±12.1 ml/min per 1.73 m² (all values mean ± standard error). ANP did not correlate with PRA, blood pressure,C _Cr or FE_Na. There was an inverse relationship between the ET level and FE_Na in the acute phase of the disease (r=0.489,P<0.05), but no significant correlation between ET and blood pressure, PRA,C _Cr or ANP was found. We suggest that, despite the sodium retention, the increased ANP level in APSGN indicates unresponsiveness of the kidneys to ANP; the increased ET levels may contribute to this.     

Validation of the Center for Medicare and Medicaid Services algorithm for eligibility for dialysis

The Center for Medicaid and Medicare Services (CMS) has recently revised their end-stage renal disease (ESRD) Medical Evidence Report, Medicare Entitlement, and Patient Registration CMS 2728 Form. The modified algorithm calls for the use of formulae to estimate glomerular filtration rate (GFR). The new criterion is defined as estimated GFR of less than 20 ml/min per 1.73 m². GFR is either estimated by Schwartz formula (C_SCH) in children or Modification of Diet in Renal Disease formula (C_MDRD) in adults. The purpose of this communication is to test the validity of the new CMS GFR algorithm in detecting children who need renal replacement therapy. We evaluated two cohorts of children. Group I included single-center data from 626 ¹²⁵I-iothalamate clearance studies (C_IO) that were compared with the simultaneous estimation of GFR by C_SCH. Group II included data on 659 children from the patient incidence registry obtained from the ESRD Network of Texas between February 1996 and October 2003. In group I there were 76 children (76 C_IO) with C_SCH less than 20 ml/min per 1.73 m² of whom 50 (67%) had C_IO less than 15 ml/min per 1.73 m². Of children with C_IO less than 15 ml/min per 1.73 m², 62% had a C_SCH less than 20 ml/min per 1.73 m². The ability of C_SCH greater than 20 ml/min per 1.73m² to predict C_IO greater than 15 ml/min per 1.73 m² (negative predictive value) is 0.95. The number of children who were started on dialysis in Texas within the study period was 659 (group II). The mean C_SCH±SD was 10.8±7.7 ml/min per 1.73 m². Of the patients who were initiated on dialysis, 94% had C_SCH less than 20 ml/min per 1.73 m². The results were sustained when race, gender, age range, and type of diagnosis were considered. The new CMS algorithm provides a good negative predictive estimate of GFR less than 15 ml/min per 1.73 m². Disclaimer The analyses upon which this publication is based were performed under contract number 500–03-NW14 entitled End-Stage Renal Disease Networks Organization for the State Texas, sponsored by the Centers for Medicare and Medicaid Services, Department of Health and Human Services. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The authors assume full responsibility for the accuracy and completeness of the ideas presented. This article is a direct result of the Health Care Quality Improvement Program initiated by the Centers for Medicare and Medicaid Services, which has encouraged identification of quality improvement projects derived from analysis of patterns of care, and therefore required no special funding on the part of this contractor. Ideas and contributions to the author concerning experience in engaging with issues presented are welcomed.     

Long-term plasmapheresis and protein A column treatment of recurrent FSGS

Transient or intermittent plasmapheresis with concurrent immunosuppressive therapy is thought to be beneficial in the treatment of recurrent focal segmental glomerulosclerosis (FSGS) in the early post-transplant period. The results of long-term (6-year) plasmapheresis therapy, in a 9-year-old female with an immediate recurrence of FSGS [urinary protein/urinary creatinine (UP/UC)=17.7] after cadaveric renal transplant, are presented. A 4-week plasmapheresis course induced a decline in the proteinuria, but a relapse occurred after cessation of plasmapheresis. Addition of protein A column therapy led to a further decrease in the proteinuria, to a non-nephrotic range. Long-term control of the nephrotic syndrome was established using a chronic treatment regimen consisting of a single-volume plasmapheresis, followed by a protein A column treatment, performed on sequential days every 3–4 weeks. Mean UP/UC values decreased to 1.15±0.9. A course of cyclophosphamide was successfully used to control a worsening of proteinuria 4 years post transplant. Although sequential renal biopsies demonstrated progressive glomerular sclerosis, the patient’s mean calculated creatinine clearance only modestly declined from 78.3 ml/min per 1.73 m², at the time of transplantation, to 62.7 ml/min per 1.73 m², 6 years later. This patient demonstrated dependence on plasmapheresis/protein A column therapy to maintain a clinical remission of her FSGS recurrence. While long-term plasmapheresis and protein A column therapy in combination with immunosuppressive therapy reversed the effects of uncontrolled nephrosis and possibly facilitated long-term renal allograft survival, the glomerular sclerosis continued to progress. Received: 4 April 2001 / Revised: 15 June 2001 / Accepted: 15 June 2001     

Renal functional reserve in children with a previous episode of haemolytic-uraemic syndrome

Renal function [creatinine clearance (C _Cr)] and renal functional reserve (RFR) was measured in 16 children who had had haemolytic-uraemic syndrome (HUS) an average of 6.6±0.72 years previously. All patients had normal plasma creatinine and blood pressure and only 3 had proteinuria, which was mild in every instance. Patients were studied whilst ingesting three diets which provided an average of 1.5, 2.1 and 3.1 g protein/kg body weight per day, respectively. Diets were administered over three consecutive periods of 7 days each andC _Cr was measured on the 7th day of each diet. Values tended to correlate with protein intake. They were in the normal range when patients were taking 1.5 and 2.1 g protein diets and increased markedly in 13 of the 16 patients (P<0.001) when they ingested the high-protein diet (3.1 g). The effect on glomerular filtration rate (GFR)-measured byC _Cr and inulin clearance (C _in)-of an acute oral protein load was studied in 12 of the HUS patients and four control subjects. In the control periods, prior to the protein load, values forC _Cr were similar in the HUS and control subjects (104.0±11.0 vs 121.6±10.1 ml/min per 1.73 m², NS). HoweverC _in values were significantly reduced in HUS patients (59.5±9.2 vs 102.7±12.4 ml/min per 1.73 m², (P<0.025). TheC _Cr/C _in ratio in the patients averaged 2.10 compared with 1.13 in controls. Acute protein loading was accompanied by an increase inC _in in all controls but in only 8 of the 12 patients. Baseline values forC _in did not correlate with the presence or absence of protein-stimulated enhancement ofC _in. TheC _Cr/C _in ratios after protein loading remained twice as high in HUS patients as in controls. The data indicate thatC _Cr is not an accurate indicator of GFR in children who have had acute renal injury. Tubular secretion of creatinine represents a greater proportion of excreted creatinine in these children, may maintain serum creatinine in the normal range and mask the decrease in GFR. The study also emphasizes the problems of measuring RFR in these children.     

Mycophenolate mofetil in steroid/cyclosporine-dependent/resistant nephrotic syndrome

Attempts to minimize the effects of prolonged steroid use in steroid-dependent nephrotic syndrome (SDNS) and the need to overcome steroid resistance (SRNS) justifies immunosuppressant therapy. We report our experience in a cohort of patients with SD/SRNS during the administration of mycophenolate mofetil (MMF) in a prospective protocol initiated in January 2001. Twenty-six children with idiopathic nephrotic syndrome were included (21 steroid dependent and 5 steroid resistant), whose response did not change after sequential treatment with cyclophosphamide (CPM) and cyclosporine (CsA). Histopathologic patterns were: 11 minimal change disease (MCD), 1 diffuse mesangial proliferation (DMP), 13 focal segmental glomerulosclerosis (FSGS) and membranous 1 glomerulonephritis (MGN). The median age of onset of NS was 2.8 years (range 1.2–12.5), and treatment with MMF was performed at a median age of 11.4 years (range 5–17) with an initial dose of 600 mg/m²/12 h, adjusted to maintain levels of mycophenolic acid (MPA) at 2.5–5 mcg/ml. The planned duration of study to assess treatment efficacy was 6 months. The mean MMF dose required was 624 (SD=136) mg/m²/12 h (range 415–970), which maintained mean C₀-MPA levels of 2.9 (SD=1.17) mcg/ml (range 1.2–5.9 mcg/ml). In the five patients with SRNS, only one achieved complete remission. In the patients with SDNS, steroid sparing was achieved in 15 and 9 remained in remission on MMF monotherapy. Withdrawal of MMF resulted in immediate relapse in 47%. In our study, MMF was a useful immunosuppressant due to its fewer undesirable effects and similar efficacy to other drugs used. It appears effective for the maintenance of remission in SDNS patients, with a response similar to that of CsA.     

A randomized cross‐over comparison of short‐term exposure of once‐daily extended release tacrolimus and twice‐daily tacrolimus on renal function in healthy volunteers

Calcineurin inhibitor nephrotoxicity remains an issue for transplant recipients. The pharmacokinetic profile (PK) of the once‐daily tacrolimus extended release (Tac‐ER) includes equivalent exposure [AUC_(0–24 h)] but lower C_max versus twice‐daily tacrolimus immediate release (Tac‐IR). We hypothesized that the unique PK profiles would result in pharmacodynamic differences in renal function. Nineteen healthy male subjects were allocated to once‐daily Tac‐ER and twice‐daily Tac‐IR in a prospective, randomized, two period, cross‐over study. Tacrolimus was titrated to achieve trough levels of 8–12 ng/ml. Twenty four hours ERPF and GFR estimated by para‐aminohippurate and sinistrin clearance were performed at baseline and at the end of each 10‐day dosing period. Mean Tac C₀ was 11.0 ± 2.2 and 11.3 ± 1.8 ng/ml for Tac‐ER and Tac‐IR, respectively. The mean Effective 24 h renal plasma flow (ERPF) was significantly higher with Tac‐ER compared with Tac‐IR (658 ± 127 vs. 610 ± 93 ml/min/1.73 m², P = 0.046). There was a trend to a greater mean GFR over 24 h for Tac‐ER at 114.5 ± 13.6 ml/min/1.73 m² compared with 108.9 ± 9.7 ml/min/1.73 m² for Tac‐IR, P = 0.116. Under controlled physiological conditions, ERPF was significantly improved with Tac‐ER compared with Tac‐IR, likely owing to the differing PKs of these tacrolimus preparations (ClinicalTrials.gov Identifier: NCT01681134).     

Glycosaminoglycan excretion in children with nephrotic syndrome

Although most childhood nephrotic syndromes respond to steroid treatment, steroid resistant nephrotic syndrome (SRNS) is also common and is particularly difficult to treat. This study investigated the role of glycosaminoglycans (GAG) in the pathogenesis and clinical course of nephrotic syndrome in children. Thirty-four children (21 males and 13 females, mean age 3.7±1.6 years) with steroid-sensitive nephrotic syndrome and 20 children with steroid-resistant nephrotic syndrome (12 males and 8 females, mean age 10.9±3.8 years; of the twenty, four had primary SRNS (FSGS) and the others had secondary SRNS) were included the study. Mean urine levels of GAG relative to creatinine (U_GAG/U_Cr) in patients with SRNS (n=20, 113.01±78.46 mg g^–1 Cr) and in patients experiencing the nephrotic period of steroid-sensitive nephrotic syndrome (n=34, 132.15±101.55 mg g^–1 Cr) were both significantly higher than mean U_GAG/U_Cr for control subjects (n=30, 51.83±47.66 mg g^–1 Cr) (P<0.01 for both). Patients excreted significantly more GAG during the nephrotic period of steroid-sensitive nephrotic syndrome than during remission (132.15±101.55 vs 39.11±42.73 mg g^–1 Cr, respectively; P<0.01). There was, however, no significant difference between U_GAG/U_Cr for patients with steroid-resistant nephrotic syndrome and U_GAG/U_Cr in the nephrotic period of steroid-sensitive nephrotic syndrome. Urine GAG excretion correlated significantly with the severity of proteinuria. The results suggest that GAG play a significant role in the pathogenesis of nephrotic syndrome but that GAG excretion is not a marker for response to steroid treatment in pediatric patients with this condition.     

The performance of three estimates of glomerular filtration rate before and after live donor nephrectomy

Serum creatinine‐based estimates of glomerular filtration rate (GFR) are inaccurate in healthy individuals. Therefore, their use in assessment prior to live donor nephrectomy has been restricted. There are less data on their use postdonor nephrectomy. This study assessed three GFR estimates against Cr⁵¹ EDTA radioisotope GFR (iGFR) in the same cohort of patients before and after donor nephrectomy. A total of 206 patients underwent iGFR measurement prior to donor nephrectomy and this was repeated in 187 patients 6–8 weeks postsurgery. The iGFR was compared with the modification of diet in renal disease (eGFR), Cockcroft–Gault (cgGFR) and Mayo Clinic equation (mcGFR) estimates of GFR. Preoperatively, all GFR estimates performed poorly against iGFR; however, mcGFR provided the most reliable estimate. The eGFR underestimated iGFR by 23.60 ± 16.43 ml/min/1.73 m², cgGFR by 15.54 ± 18.13 ml/min/1.73 m² and mcGFR overestimated by 0.72 ± 18.11 ml/min/1.73 m². Postdonation, all estimates again performed poorly, but eGFR and mcGFR outperformed cgGFR. The eGFR underestimated iGFR by 9.13 ± 10.11 ml/min/1.73 m², mcGFR by 9.44 ± 13.80 ml/min/1.73 m² and cgGFR overestimated by 6.42 ± 14.49 ml/min/1.73 m². No GFR estimate performed sufficiently well to supersede iGFR measurement prior to donor nephrectomy. Performance postdonation was little better. In addition, there was no correlation between fall in iGFR and fall in GFR estimates postdonation.     

Poor correlation between published methods to predict creatinine clearance and measured creatinine clearance in asymptomatic HIV infected individuals

The purpose of this study was to evaluate the predictive ability of six published creatinine clearance (C_Cr) equations in healthy human immunodeficiency virus (HIV) infected individuals. A 24-h urine collection to determine C_Cr was done on an out patient basis in 18 subjects. Predicted C_Cr was compared with the measured values, and the predictive performance was assessed with percentage mean error (bias) and percentage root mean error (precision). Mean ± standard deviation measured C_Cr was 107 ± 35 mL/min/1.73 M². C_Cr determined using each of the published equations correlated poorly with measured values. C_Cr determined using Hull methods was significantly different from the measured values. Though Cockcroft and Gault and Jelliffe methods had the lowest mean bias and greater precision, a significant range of difference from measured C_Cr was observed (-12 to + 28%). All methods over estimated the measured C_Cr in HIV-infected individuals. Until other approaches are developed, a 24 h urine collection may be the best approach for assessing renal function in HIV-infected individuals, especially in those receiving medications with narrow therapeutic indices that are cleared by the kidney.     

Comparison of cystatin C- and creatinine-based estimated glomerular filtration rates for predicting all-cause mortality in Japanese patients with type 2 diabetes: the Fukuoka Diabetes Registry

Background

There is little information about the predictive ability of cystatin C-based estimated glomerular filtration rates (eGFR_Cys) for all-cause mortality in Asian populations. We compared the discriminatory ability of eGFR_Cys for all-cause mortality with that of creatinine-based estimated glomerular filtration rates (eGFR_Cr) in Japanese patients with type 2 diabetes.

Methods

A total of 4869 participants were classified into four categories (eGFR ≤29, 30–59, 60–89, and ≥90 ml/min/1.73 m²) by eGFR_Cr and eGFR_Cys, and followed up for a median of 3.3 years.

Results

150 deaths were identified. The multivariable-adjusted risk of all-cause mortality was significantly increased in eGFR_Cr ≤29 ml/min/1.73 m² compared with eGFR_Cr ≥90 ml/min/1.73 m² [hazard ratio (HR) 2.4 (95 % confidence interval (95 % CI) 1.2–5.0)], whereas it was significantly increased in eGFR_Cys 59 ml/min/1.73 m² or lower [30–59 ml/min/1.73 m², HR 1.9 (95 % CI 1.1–3.5); ≤29 ml/min/1.73 m², HR 5.8 (95 % CI 2.8–12.0)]. Comparing eGFR_Cys with eGFR_Cr, the proportions of participants reclassified to lower and higher eGFR stages were 6.3 and 28.8 %, respectively. The multivariable-adjusted HRs for all-cause mortality were 1.8 (95 % CI 1.1–2.9) and 0.7 (95 % CI 0.4–1.1), respectively. The C statistic of the model including eGFR_Cys and other risk factors was significantly increased compared with the model including eGFR_Cr. The net reclassification improvement and the integrated discrimination improvement were significantly positive.

Conclusions

Our findings suggest that eGFR_Cys has a stronger association with all-cause mortality and is superior to eGFR_Cr for predicting all-cause mortality in Japanese patients with type 2 diabetes.

     

Effects of growth hormone on growth factors after renal transplantation

Growth retardation occurs frequently in renal transplanted children (RTx) and can be improved by growth hormone (GH) treatment. This study retrospectively examines the insulin-like growth factor-1 (IGF-1) and IGF binding protein (IGFBP) profile of ten growth-retarded children previously given renal allografts, after 1 year of GH treatment period. Ten prepubertal patients (nine boys and one girl) were investigated. They had a mean chronological age (CA) of 11.4±1.1 years and a mean bone age (BA) of 7.3±0.9 years. Mean height was –3.9±0.4 SD units below the mean for CA. The mean body mass index (BMI) was 16.9±0.6 and the mean inulin clearance was 36.5±4.9 ml/min/1.73 m². Recombinant hGH was given at 4 IU/m²/day. Plasma GH, total and free IGF-1, IGFBP-2 and -3 were measured by specific radioimmunoassay (RIA). IGFBPs were characterized by SDS PAGE techniques and ligand and immunoblot analyses. Mean velocity was markedly increased (P<0.01) after 1 year of GH therapy, expressed as SD score for BA. The range of growth response was wide. The total and free plasma IGF-1 increased (P<0.01) by about 100% (mean values after GH therapy: 95.9± 2.1 nM and 165±29 pM, respectively). Plasma IGFBP-3 concentrations increased by about 40% (mean value: 148±18 pM, P<0.01), with a concomitant increase in both intact IGFBP-3 and its 30-kDa proteolytic fragment. There was no change in plasma IGFBP-2 concentration. Both mean values of inulin clearance and BMI were unchanged during the treatment. In view of the IGF-1/IGFBP concentration changes, there should have been an even better growth response to GH therapy in these patients. This strongly suggests IGF-1 insensitivity, probably as a result of corticosteroid therapy. Received: 12 April 2000 / Revised: 31 July 2000 / Accepted: 1 August 2000     

Calcitriol pulse therapy is not more effective than daily calcitriol therapy in controlling secondary hyperparathyroidism in children with chronic renal failure

Calcitriol oral pulse therapy has been suggested as the treatment of choice for secondary hyperparathyroidism, but its efficacy and safety are still under discussion. The present randomized multicenter study compares the effect of an 8-week course of daily versus intermittent (twice weekly) calcitriol therapy on parathyroid hormone (PTH) suppression in 59 children (mean age 8.4±4.7 years) with chronic renal insufficiency (mean C_cr 22.4±11.6 ml/min per 1.73 m²) and secondary hyperparathyroidism. After a 3-week washout period, the patients were randomly assigned to treatment with daily oral calcitriol (10 ng/kg per day) or intermittent oral calcitriol (35 ng/kg given twice a week). The calcitriol dose was not changed throughout the study period of 8 weeks. At start of the study, the median intact PTH (iPTH) level was 485 pg/ml (range 83–2032) in the daily group (n=29) and 315 pg/ml (range 93–1638) in the intermittent group (n=30). After 8 weeks, the respective median iPTH concentrations were 232 pg/ml (range 63–1614) and 218 pg/ml (range 2–1785) (ns). The mean iPTH decrease from baseline was 19.2±57.8% and 13.7±46.7% respectively (not significant). Calcitriol reduced the iPTH concentration in 23/29 patients in the daily group and in 21/30 in the intermittent group. One episode of hypercalcemia (>11.5 mg/dl) was observed in both groups and a single episode of hyperphosphatemia (>7.5 mg/dl) was observed in the daily group. It is concluded that oral calcitriol pulse therapy does not control secondary hyperparathyroidism more effectively than the daily administration of calcitriol in children with chronic renal failure prior to dialysis. Received: 29 September 1999 / Revised: 2 February 2000 / Accepted: 9 February 2000     

Cystatin C: influence of perfusion and myocardial injury on early (<24 h) renal function after pediatric cardiac surgery

Background: Cardiopulmonary bypass (CPB)‐associated renal dysfunction following cardiac surgery is well recognized. In patients with renal disease, cystatin C has emerged as a new biomarker which in contrast to creatinine (Cr) is sensitive to minor changes in glomerular filtration rate (GFR). Aim: We utilized cystatin C to investigate the association of CPB perfusion parameters with acute renal injury after pediatric cardiac surgery. Methods: Twenty children, aged 4–58 months (AVSD, n = 7; VSD, n = 9; and ASD, n = 4), were prospectively studied. Glomerular filtration rate was quantified postoperatively by creatinine clearance (first and second 12‐h periods; CrCl_0–12 and CrCl_12–24). Serum cystatin C and Cr were measured preoperatively and on days 0–3. Recorded CPB parameters included bypass duration (BP), perfusion pressure (PP), lowest pump flow (Q_min), lowest hematocrit, and corresponding lowest oxygen delivery (DO_{2 min}). Myocardial injury was determined by troponin‐I. Results: Postoperatively, GFR remained unchanged (CrCl_0–12 63.6 ± 37.0 vs CrCl_12–24 65.1 ± 27.5; P = 0.51) and only correlated with cystatin C (CrCl_0–12 vs cystatin C_Day0 [r = 0.58, P = 0.018] and Cr_Day0 [r = 0.09, P = 0.735]). Cr and cystatin C increased postoperatively to peak on days 2 and 3, respectively (Cr_PreOp 31 ± 6.9 vs Cr_Day2 36.9 ± 12.2, P = 0.03; cystatin C_Day0 0.83 ± 0.27 vs cystatin C_Day3 1.45 ± 0.53, P = 0.02). Increased cystatin C was significantly associated with BP (P = 0.001), mean PP (P = 0.029), Q_min (P = 0.005), troponin‐I (P < 0.001), and DO_2min <300 ml·min^?1·m^?2 (P = 0.007). Receiver–operator cutoff >1.044 mg·l^?1 for cystatin C exhibited 100% sensitivity and 67% specificity for detecting renal dysfunction, defined as GFR <55 ml·min^?1·1.73 m^?2. Conclusions: Cystatin C is a sensitive marker of early renal dysfunction following pediatric heart surgery. Variations in bypass parameters, myocardial injury, and ultimately critical oxygen delivery are significantly associated with the degree of renal impairment.     

Cyclosporine-A-induced nephrotoxicity in children with minimal-change nephrotic syndrome: long-term treatment up to 10 years

The impact of cyclosporine A (CsA) therapy in patients with steroid-dependent nephrotic-syndrome (SDNS) on long-term renal function is controversial. Data beyond 5 years are rare. Long-term renal function was evaluated in children with SDNS with and without CsA therapy, especially beyond 5 years. Twenty children were treated with CsA (study group) for a mean of 5.4 ± 2.2 years (ten patients for 5–11 years). Glomerular filtration rate (GFR) was calculated before and after 3 and 12 months and at latest follow-up of therapy. Fifteen children with cyclophosphamide-treated SDNS without CsA served as controls. In the study group, GFR decreased within 12 months from 136 ± 19 to 120 ± 31, to 114 ± 14 ml/min per 1.73 m² at latest follow-up (p < 0.0001). Patients with CsA > 5 years had a GFR of 111 ± 14 ml/min per 1.73 m² at latest follow-up without a GFR below 90 ml/min per 1.73 m². No CsA toxicity was found in biopsies. In the control group, GFR dropped within 3 months, from 137 ± 27 to 130 ± 24, to 126 ± 19 ml/min per 1.73 m² at latest follow-up (p = 0.1). Patients with and without nephrotoxic CsA therapy showed a drop in GFR. In CsA-treated patients, GFR was about 12% lower at latest follow-up compared with patients without nephrotoxic therapy but always remained within normal range. CsA seems to be safe, even in long-term treatment for more than 5 years.     

Pre‐ and postdonation kidney function in donors of a kidney paired donation with unique criteria for donor glomerular filtration rate – a longitudinal cohort analysis

Baseline predonation estimated GFR (eGFR) appears to predict the risk of postdonation chronic kidney disease in live donors. New KIDGO guidelines recommend an eGFR ≥90 ml/min/1.73 m² as an acceptable level of glomerular filtration rate (GFR) for kidney donation. In the Australian Paired Kidney Exchange (AKX) program, all donors with a raw measured GFR (mGFR) ≥80 ml/min are deemed suitable for donation, but the significance of this selection indicator is unclear. We analysed the first 129 live donors in the AKX program with at least 1‐year follow‐up linking records in the AKX database and ANZDATA. There were 73 male and 56 female donors; mean (±SD) age was 53 ± 11 years. Predonation eGFR was 94 ± 13 ml/min/1.73 m², mGFR 99 ± 17 ml/min/1.73 m² and raw mGFR 108 ± 18 ml/min. Baseline eGFR was <80 ml/min/1.73 m² in 19 donors, and <90 ml/min/1.73 m² in 42 donors. At 1 year postdonation eGFR was 68 ± 15 ml/min/1.73 m² and the predicted eGFR at 30 years postdonation was on average 50 (29–83) ml/min/1.73 m². The hypothetical mean age at end‐stage kidney disease was estimated to be 145 (95% CI 120–263) years. Over 30% of AKX live donors would have been excluded from donation using KDIGO guidelines. Using AKX donor guidelines, the majority of donors with predicted eGFR <30 ml/min/1.73 m² 30‐year postdonation were aged ≥50 years. Long‐term outcome data on AKX donors with low eGFR will need careful monitoring.