Cyclosporin in the treatment of idiopathic nephrotic syndrome in children

Thirty-five children (12 girls, 23 boys), aged from 1 year and 5 months to 14 years at the onset of idiopathic nephrotic syndrome, received cyclosporin A (CyA) because of steroid toxicity or failure to respond to steroids. The initial oral dose was 6 mg/kg per day and this was adjusted to obtain trough plasma levels of 50–150 ng/ml. The duration of treatment was between 2 and 8 months. In patients who responded to CyA treatment, the dosage was tapered off; treatment was stopped if found to be ineffective. Of the 35 children, 20 were frequent-relapsing steroid responders who suffered serious side-effects from steroid therapy. Seventeen of them either went into remission or did not relapse despite the withdrawal of prednisone. Prednisone doses could be lowered but not stopped in 1 patient and the remaining 2 patients relapsed when prednisone was tapered off. At the final examination, 10 of the 12 children in whom CyA was tapered off and who had initially responded to CyA had relapsed. A second course was given to these 10 patients and 3 failed to respond. Five children were partial steroid responders and CyA induced a remission in 1 and a partial remission in another. Among the 10 children who were steroid resistant, only 1 responded to CyA, 2 had a partial response and 7 failed to respond to CyA. A reduction of glomerular filtration rate occurred in 8 patients, 7 of whom had either persistent nephrotic syndrome or were in relapse, which suggests that factors other than CyA nephrotoxicity may have been operative. Complete reversal occurred in only 4 patients. Significant histological changes, likely to be related to CyA, were seen in 2 repeat renal biopsies out of the 11 performed.     

Skeletal effects of low-dose cyclosporin A therapy in children with nephrotic syndrome

Background. High doses of cyclosporin A (CsA) produce high-turnover osteopenia in rats. The aim of this study was to determine whether low-dose CsA affects the skeleton in children with nephrotic syndrome. Methods. Biochemical parameters of mineral and skeletal homeostasis, and bone mineral density (BMD) in eight boys with steroid-dependent, frequently relapsing minimal change nephrotic syndrome who had received low-dose CsA (between 1.6 and 3.1 mg/kg per day) for 2 years were compared with measurements in the same patients before CsA therapy and who had received glucocorticoids for long periods, and with measurements in age-matched controls. Results. It was possible to discontinue glucocorticoid therapy within 4 months after the start of CsA therapy. There was a significant increase in the mean serum alka-line phosphatase concentration in CsA therapy patients compared with the same patients before CsA therapy and the controls. Serum osteocalcin and tartrate-resistant acid phosphatase, and urinary deoxypyridinoline concentrations in CsA therapy patients did not differ from those in the controls. BMD in CsA therapy patients was increased significantly compared with values in the same patients before CsA therapy. BMD in CsA therapy patients was lower than that in the controls, but remained within 80% of the overall mean BMD value. Conclusions. Two years of low-dose CsA therapy without glucocorticoids does not appear to induce high-turnover osteopenia in children with steroid-dependent nephrotic syndrome. Received: February 7, 2000 / Accepted: May 10, 2000     

Expressing glomerular filtration rate in children

We have reviewed the studies that provide the current standards of reference for glomerular filtration rate (GFR) in normal children from 14 days to 12 years of postnatal age. These standards currently are presented as ml/min per 1.73 m², i.e., adjusted to average adult body surface area. Children from birth to 1 year of age have adjusted values below the adult range, making comparisons of observed to reference values difficult. Currently, there is no accepted way of obtaining reference values that vary smoothly with age. An analysis of the absolute GFR values in normal children taken from published studies led to an equation that estimates average GFR in relation to weight and term-adjusted age from-2 months (7 months gestational age) to 12 years in children at least 14 days post delivery. When these data are transformed to percentage of normal (% nl) for age and weight (i.e., percentage of the estimated average), it is possible to describe approximate apparent lower limits of normal GFR as is now done for adults and older children. For children with loss of renal mass, GFR expressed as % nl for age and weight provides a convenient standardization which has several useful applications. First, results expressed as % nl for children of different ages, particularly under 1 year of age, can be combined with those of older children for summary purposes. Second, the course of GFR measured serially in children is more appropriately described using this method for expressing GFR. Reporting GFR in absolute values is also useful, particularly in patients whose body mass is significantly distorted or whose absolute GFR is low.     

Acute leucoencephalopathy during cyclosporin A therapy in a patient with nephrotic syndrome

A 13-year-old girl with nephrotic syndrome (NS) developed acute leucoencephalopathy during combination therapy with cyclosporin A (CyA) and prednisolone (PSL). The patient had a generalized motor seizure followed by coma at 19 days after CyA administration. Magnetic resonance scanning performed on the 1st hospital day revealed white matter lesions in the subcortices of the parietal and occipital lobes, brain stem and cerebellum. These lesions had completely resolved on the 10th hospital day. This episode might be caused by CyA because the clinical course and laboratory data revealed neither inflammation nor other causative factors. To our knowledge, this is the first report of acute leucoencephalopathy during combination therapy with CyA and PSL in a patient with NS.     

Convulsion during cyclosporin A therapy for nephrotic syndrome

A 10-year-old boy with nephrotic syndrome developed convulsions 6 weeks after the start of cyclosporin A (CyA) therapy. Generalized tonic-clonic convulsion occurred during relapse of nephrotic syndrome after influenza A infection. T2-weighted magnetic resonance imaging (MRI) showed high signal intensities in bilateral parieto-occipital lobes. He recovered from the convulsions and the MRI findings returned to normal early without neurological sequelae. CyA was discontinued for 1 week and then restarted. He has had no further convulsions or recurrence of nephrotic syndrome since that time. He had no evidence of high blood level of CyA, hypertension, electrolyte abnormalities, or renal or hepatic dysfunction. He was diagnosed with CyA-related reversible posterior leukoencephalopathy syndrome based on the rapid recovery of clinical symptoms and the characteristic MRI finding. Influenza A infection may have damaged the blood-brain barrier, paving the way for central nervous system toxicity. Received: December 3, 1998 / Accepted: June 7, 1999     

Estimating absolute glomerular filtration rate in children

Normal values of glomerular filtration rate (GFR) in children are often expressed in a value adjusted to adult ideal body surface area. These values work well for many clinical situations, but in infants and children, especially those with atypical body mass, they may not accurately reflect renal function. Most body composition values in children are expressed in developmentally appropriate ranges. Absolute GFR (ml/min) also changes during childhood increasing rapidly in infancy and then gradually with age and body size. Previously, we developed a bedside equation for estimating GFR (ml/min) in children that accounted for changes with age and body size, and which correlated well with steady-state cold iothalamate GFR (ml/min) measurements: GFR (ml/min) = k_*sqrt[(age(months) + 6)*wt (kg)/serum Cr (mg/dl)], where k=0.95 for females and 1.05 for males. In the present study GFR (ml/min) measured by iothalamate infusion was compared by correlation analysis with estimates calculated from the above equation in 566 children. This equation provides clinicians with a simple bedside method to estimate absolute GFR (ml/min).     

Increased cystatin C concentration in urine of nephrotic children

The aim of this study was to evaluate changes in urine and plasma concentrations of cystatin C in children with a relapse of the idiopathic nephrotic syndrome (INS). The study group comprised 12 children with INS with proteinuria and 12 children in an 8-week remission, both treated with steroids. Twelve healthy children served as controls. Cystatin C was detectable in the urine of children with proteinuria. The study suggests that massive proteinuria may influence renal cystatin C handling.     

Central neurotoxicity of cyclosporine in two children with nephrotic syndrome

The central neurotoxicity of cyclosporin A (CsA) has been abundantly documented in pediatric and adult recipients of bone marrow or organ transplants, with variations in the rate of occurrence from 0.5% to 35%. We report two cases of central neurotoxicity ascribable to CsA in children with nephrotic syndrome due to lipoid nephrosis. The manifestations of CsA-related central neurotoxicity include confusion, aphasia, dystonias, akinetic mutism, parkinsonism, palsies, seizures, catatonia, coma, brain hemorrhage, and cortical blindness. Decreased density of the cerebral white matter is visible by computed tomography (CT) in 50% of cases, with the most commonly involved sites being the occipital cortex, the cerebellum, the periventricular substance, and the brainstem. Magnetic resonance imaging is more sensitive and more specific than CT for investigating the white matter. High-signal lesions are seen on T2-weighted sequences in the areas that are abnormal by CT. Many risk factors have been reported, including hypomagnesemia, hypocholesterolemia, high-dose glucocorticoid therapy, arterial hypertension, and infections. We present two patients with central neurotoxicity both of whom have elevated cholesterol levels.     

Glomerular volume and renal function in children with different types of the nephrotic syndrome

Glomerular hypertrophy has been suggested to be an important factor in the pathogenesis of focal glomerular sclerosis. The aim of the present study was to analyse retrospectively the renal biopsies of 58 children (0.2–16.1 years of age) with different types of the nephrotic syndrome, minimal change nephrotic syndrome (MCNS), diffuse mesangial proliferation (DMP) and focal segmental glomerulosclerosis (FSGS). Glomerular surface area was measured and glomerular volume was calculated and related to steroid responsiveness and to renal function, measured by clearances of inulin and para-aminohippuric acid. Glomerular volume correlated with body surface area (BSA) and age. Because of this, patients with FSGS and DMP were matched according to BSA and age, with corresponding MCNS patients. Glomerular volumes of FSGS and DMP patients were significantly larger than those of MCNS patients. In the MCNS patients, significant correlations were found between glomerular volumes and glomerular filtration rate and effective renal plasma flow. Steroid-dependent and steroid-resistant patients showed larger glomeruli than the steroid-responsive children. We suggest that hyperfiltration and hyperperfusion, among other factors, may contribute to glomerular hypertrophy, mesangial proliferation and glomerulosclerosis.     

血糖水平对糖尿病患者肾小球滤过率估算公式的影响

目的 评价糖尿病患者血糖水平对肾小球滤过率（GFR）公式估算结果的影响;比较不同血糖水平Cockcroft-Gault（CG）公式和MDRD公式法估算GFR对诊断肾功能不全的差异。 方法 选取1210例糖尿病患者,同步检测99mTc-GFR（iGFR）、Scr和糖化血红蛋白（HbA1c）。运用CG和MDRD公式计算GFR估计值（eGFRCG、 eGFRMDRD）。依据肾脏病透析预后质量指南（K/DOQI）的建议将糖尿病患者分为iGFR正常组589例[NGFR组,iGFR≥90 ml&#8226;min-1&#8226;(1.73 m2)-1],iGFR轻度下降组[GGFR组,60≤iGFR<90 ml&#8226;min-1&#8226;(1.73 m2)-1]470例,iGFR中度下降组[MGFR组,30≤iGFR<60 ml&#8226;min-1&#8226;(1.73 m2)-1]151例。根据HbA1c的四分位点（7.1%,10.5%）分为4组（<7.1%、7.1%~8.6%、8.7%~10.4%、≥10.5%）,其中HbA1c<7.1%者定义为血糖控制较好组,HbA1c≥10.5%定义为血糖控制差组。采用Spearman相关分析、t检验、Bland-Altman分析、受试者工作特征（ROC）曲线等评估方程的偏离度、准确度,以及血糖对估算结果的影响。 结果 eGFRMDRD在各GFR亚组中均高估GFR;eGFRCG在NGFR组中低估GFR,差异有统计学意义。Bland-Altman分析结果显示,血糖控制较差组的eGFRMDRD的偏差高于血糖控制较好组的eGFRMDRD;血糖控制较差组的eGFRMDRD15%和30%准确性低于血糖控制较好组的eGFRMDRD,差异有统计学意义。血糖控制较差组和较好组间eGFRCG偏差及准确性差异均无统计学意义;而eGFRCG的偏差高于eGFRMDRD,差异有统计学意义。血糖控制良好组CG公式和MDRD公式在诊断肾功能不全患者的ROC曲线下面积差异无统计学意义。血糖控制较差组eGFRMDRD ROC曲线下面积显著大于eGFRCG曲线下面积,差异有统计学意义。 结论 糖尿病患者采用MDRD和CG公式法可导致GFR估计差误。MDRD公式的eGFR估计值受到血糖的影响较大,MDRD公式法高估GFR。MDRD公式在血糖控制较差的患者对肾功能不全患者的估算效应要优于CG公式。     

Effect of cyclosporin A on patients with lupus nephritis: a review of the literature

Background. Steroids have been used for patients with some histologic groups of lupus nephritis with/without nephrotic-range proteinuria. However, many patients exhibit steroid-resistance, steroid-dependence, and/or frequent relapse, and there are many adverse effects. Recently, cyclosporin (CsA) has been reported to be effective for steroid-resistant nephrotic syndrome; however, with high-dose use, it produces specific adverse effects, especially nephrotoxicity. Here, we report results with the administration of low-dose CsA to patients with systemic lupus erythematosus (SLE). Methods. We treated three patients with steroid-resistant lupus nephritis with CsA (80–100 ng/ml blood trough level) for 6 months, and investigated the effect of CsA on lupus nephritis and SLE activity. Results. Mean pretreatment and posttreatment values for both 24-h urine protein excretion and total protein improved after treatment. Furthermore, SLE disease activity index scores, and levels of complements, anti-unclear antibody (ANA), anti-DNA antibody, and immune complexes in the three patients also improved. Conclusions. Our results support the idea that low-dose CsA is effective for nephrotic-range proteinuria caused by lupus nephritis, and show that this treatment may decrease SLE activity, without producing severe adverse effects. Received: May 31, 1999 / Accepted: February 18, 2000     

Foot process fusion and glomerular filtration rate in minimal change nephrotic syndrome

Reduced glomerular filtration rate (GFR), not due to hypovolemia, has been reported in patients in the proteinuric phase of the minimal change nephrotic syndrome (MCNS). A group of children with MCNS was studied to investigate the possible relationship between the fusion of glomerular epithelial foot processes and the reduction in GFR. The degree of foot process fusion was estimated as the harmonic true mean of foot process width and the length density of epithelial slit pores as determined by quantitative electron microscopic stereology. In the patients investigated GFR ranged between 40 and 127 ml/min/1.73 m2 body surface area, the filtration fraction between 6.9 and 22.5%, and the serum albumin concentration between 14 and 46 g/liter. The mean foot process width, which varied between 330 and 870 nm, showed a close correlation with GFR (r = -0.859) and the filtration fraction (r = -0.812), as well as with the serum albumin concentration (r = -0.756). As expected, a reduction of epithelial slit pore length occurred concomitant with the broadening of the foot processes. These results agree with the hypothesis that the reduction in the total length of glomerular epithelial slit pores, due to the fusion of foot processes, results in a reduced glomerular capillary permeability to water and small solutes.     

Serial estimation of glomerular filtration rate in children after renal transplant

Evaluation of serial monthly estimated glomerular filtration rate (eGFR) may be useful for studying pediatric renal allograft outcome. To determine the validity of this approach, we reviewed our single-center experience in pediatric renal transplant recipients to determine the effect of risk factors for renal allograft failure on eGFR. Clinical parameters recorded monthly through 5 years post transplant allowed serial assessment of eGFR. Monthly clinical data included height, weight, serum creatinine, cumulative number of acute rejection episodes, cyclosporine dose, and cyclosporine trough levels. From these data, eGFR was calculated monthly for each patient using the Schwartz formula. Time post transplant was grouped in 6-month intervals and plotted against mean eGFR to compare eGFR in patients grouped by demographic and clinical factors; 1,786 monthly data sets from 6 months post transplant (n=76 patients) to 5 years post transplant (n=25 patients) were analyzed. Overall mean eGFR from 6 months to 1 year was 75 ml/min per 1.73 m² and from 4.5 to 5 years 46 ml/min per 1.73 m². eGFR was lower at all time intervals for recipients of cadaver versus living-related donor grafts, and patients with ≥1 versus 0 acute rejections (P<0.01). After 1 year, eGFR was lower in black patients compared with white or Hispanic patients (P<0.01). Cyclosporine dose greater than 5 mg/kg per day was associated with better early and worse late graft function. These results are similar to those reported in multi-center studies using the outcome variable of graft failure and suggest that serial eGFR may be valid as an outcome variable to study chronic renal allograft dysfunction in children. Received: 1 March 1999 / Revised: 7 June 1999 / Accepted: 10 June 1999     

Bias and precision of estimated glomerular filtration rate in children

Determining true glomerular filtration rate (GFR) using an exogenous marker is time-consuming and cumbersome. Therefore, creatinine-based estimates of GFR are used. Recent papers using new population-specific/local parameters in their prediction equations, standardizing creatinine determination or adding other endogenous surrogate markers of GFR, like cystatin C, could demonstrate an improvement of bias inherent in the results of the prediction equations. Precision, however, is still poor. Currently, we have to accept a precision (as defined in the so-called Bland-Altman plot) of ±20% in adults and ±30–40% in children. This problem of poor precision/uncertainty is especially bothering in the higher, near normal GFR range. Caution should be exercised when applying prediction equations in individuals in need of an accurate GFR determination. In that case, a real clearance procedure has to be performed. In the long run, the true clearance procedure should be simplified using new exogenous GFR markers and developing new devices, allowing GFR measurements to be performed, for example, transcutaneously. Such a procedure would be more acceptable for both patients and physicians.     

控制性低血压联合血液稀释对兔肾小球滤过率的影响

目的 观察急性等容血液稀释和控制性低血压联合应用对肾小球滤过功能的影响。方法 选择40只家兔，随机分为对照组，控制性低血压组，血液稀释组和血液稀释联合控制性低血压组。采用氟烷－芬太尼维持麻醉；静脉注射0.02%的硝普钠进行控制性低血压，将MAP维持在35－40mm Hg；通过动脉放血和静脉输注乳酸钠林格氏液进行血液稀释，将Hct降低至20%-25%；采用分光光度法测定血浆菊糖的血浓度，以菊糖清除率来反映肾脏的滤过功能。结果 与对照组比较，控制性低血压组的菊糖排泄率明显降低（P＜0.01)，而联合组则无明显差异（P＞0.05)。结论 单纯控制性低血压可使肾小球滤过率明显降低，而联用血液稀释则可改善控制性低血压下的肾脏微循环灌注。     

Beneficial effect of second courses of cytotoxic therapy in children with minimal change nephrotic syndrome

Therapeutic guidelines are not available for children with minimal change nephrotic syndrome (MCNS) who experience frequent relapses or develop steroid resistance after a course of cytotoxic therapy. The records of nine children with biopsy-proven MCNS who received two courses of cytotoxic therapy with either chlorambucil or cyclophosphamide were reviewed to evaluate the length of remission, associated side-effects and long-term outcome. Initial cytotoxic therapy was given to five frequent-relapsing patients and four steroid-resistant patients 2–48 months (mean 16 months) following diagnosis of nephrotic syndrome. The second drug was given 4–85 months (mean 27 months) after the first. Steroid-resistant patients attained remissions of 0–81 months (mean 23 months) following the first agent and 13–67 months (mean 32 months) following the second. Frequent-relapsing patients experienced remissions of 0.5–24 months (mean 7.4 months) following the first cytotoxic drug and 3–72 months (mean 22 months) after the second. Remissions following the second agent were equal to or longer than those following the first in the seven patients who received both chlorambucil and cyclophosphamide. In the 19- to 128-month follow-up (mean 66 months), all four steroid-resistant patients experienced infrequent relapses which responded to prednisone. One frequent-relapsing patient remains in remission, three have chronic proteinuria and one still has a frequent-relapsing course. For the select group of patients who become frequent relapsing or steroid resistant after one course of cytotoxic therapy, a second course of cytotoxic therapy may allow time for catch-up growth, as well as improve steroid responsiveness once relapses occur.     

应用血清西司他汀浓度测定肾小球滤过率的相关研究

目的：提供临床上准确，简便测定肾小球滤过率的方法。方法：应用乳胶颗粒增强比浊法（PET）测定79例有肾脏损害患者血清西司他汀（cystatin C)浓度，同时测定血尿素氮（BUN），血肌酐（Scr),24h肌清除率（24h Ccr)和采用Cockcroft-Cault公式计算肌酐清除率（Ccockcroft)，结果除BUN外，以上指标与cystatin C均有相关关系，并有显著性意义。结论：cystatin C浓度检测在临床上提供一种快速，准确和简捷的测定肾小球滤过率的方法，能发现早期肾脏损害和肾功能改变。     

Influence of serum albumin on renal function in nephrotic syndrome

 Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), determined by the clearances of inulin and para-aminohippuric acid, were evaluated in 119 children with different types of nephrotic syndrome and in different stages: the nephrotic stage (serum albumin <25 g/l), recovery stage (25–35 g/l), and remission (>35 g/l). GFR in the nephrotic stage was significantly lower than in remission and in controls, and was lowest at onset of the disease (84±6, 111±4, and 119±2 ml/min per 1.73 m²). ERPF was higher in the nephrotic stage than in recovery, especially in children with histological lesions. Thus the filtration fraction (FF) was greatly decreased in the nephrotic stage. In patients investigated both in the nephrotic and the remission phase, GFR and FF increased significantly. There was a direct correlation between the serum albumin concentration and FF and an inverse correlation between mean arterial pressure (MAP) and GFR and FF in all patients, a direct correlation between the serum albumin concentration and GFR in minimal change nephrotic syndrome patients, and an inverse correlation between ERPF and serum albumin in children with histological lesions. In conclusion, GFR and FF were decreased and ERPF increased in the nephrotic stage, normalizing in remission. The low GFR in the nephrotic stage was thus not dependent on hypoperfusion. We suggest that the low GFR is dependent on a very low ultrafiltration coefficient. The direct correlation between GFR and serum albumin and the indirect correlation between GFR and MAP suggest compensatory mechanisms that increase the ultrafiltration pressure to counteract the severely reduced ultrafiltration coefficient. Received: 19 November 1997 / Revised: 11 April 1998 / Accepted: 14 April 1998     

Two-year cyclosporin treatment in children with steroid-dependent nephrotic syndrome

 We describe a prospective study of 2-year moderate-dose cyclosporin (CS) treatment in 13 children with steroid-dependent minimal change nephrotic syndrome (MCNS). CS treatment was commenced at 100–150 mg/m² per day after remission was attained with prednisolone therapy, was adjusted to a target trough level of 100 ng/ml, and was administered for 2 years. The number of relapses during CS treatment significantly decreased compared with before CS treatment, all patients were able to discontinue prednisolone therapy, and steroid toxicity was reduced; 54% of patients remained in remission during CS treatment. Renal biopsies performed before CS treatment all showed MCNS without tubulointerstitial lesions. Creatinine clearance and urinary β₂-microglobulin levels during CS treatment were normal in all patients, but renal biopsies performed after CS treatment revealed chronic CS nephrotoxicity in 7 patients. Clinical data, including CS dose and CS trough blood levels, were not significantly different between patients with and without nephrotoxicity. In conclusion, 2-year moderate-dose CS treatment in children with steroid-dependent MCNS is effective in preventing relapse and decreasing steroid toxicity. This treatment can, however, result in a high incidence of chronic nephrotoxicity. Renal function is not a reliable indicator of chronic CS nephrotoxicity. Renal biopsy is therefore necessary to monitor chronic CS nephrotoxicity. Received: 4 March 1998 / Revised: 28 April 1998 / Accepted: 25 June 1998     

Effect of hyperfiltration on long-term follow-up of glomerular filtration rate in male Wistar rats

It has been suggested that a prolonged course of hyperfiltration could lead to progressive deterioration of renal function. In order to test this hypothesis, the following protocol was applied to 60 male Wistar rats. At 12 weeks of life, the rats were submitted to a surgical procedure: sham operation (25 rats), unilateral nephrectomy (25 rats) or 3/4 nephrectomy (10 rats). The three groups were again divided into two subgroups: one with high-protein intake (36%) and one with a low-protein intake (12%). In order to avoid any additional traumatic procedure which could shorten the animal's life, the glomerular filtration rate (GFR) was measured without blood sampling, using a previously validated technique based on an image recorded by a gamma camera between the 9th and the 10th min after intravenous injection of^99m technetium diethylenetriaminepentaacetate (DTPA). The sum of both kidneys and bladder activity was expressed as a percentage of the injected dose. The test was performed before surgery and every month thereafter. Six weeks after surgery, the highest filtration rate was found in the rats with two kidneys/high-protein diet, followed by the two kidneys/low-protein diet, the one kidney/high-protein diet, the one kidney/low-protein diet and the 1/2 kidney. The overall GFR in the one kidney/high-protein diet rat and in the 1/2 kidney rat was respectively 80% and 55% of the pre-operative values. Until 109 weeks of age, the survival rate was comparable in the five groups of rats. At 109 weeks of age, non-significant changes in renal function were observed, the follow-up slopes of the different subgroups being more or less parallel. At that age, the lesions of glomerular sclerosis were focal and discrete, without significant differences in the five groups.