The Significance of Focal Global Sclerosis in Idiopathic Nephrotic Syndrome

ABSTRACT. The clinical course of five pediatric patients with idiopathic nephrotic syndrome associated with focal global sclerosis in renal biopsy was analyzed retrospectively. The condition was defined as complete obsolescence of more than 15 % of glomeruli associated with tubular atrophy and interstitial fibrosis. At onset, all children had a steriod-sensitive relapsing nephrotic syndrome. Two became steroid-dependent and one steroid-resistent. Cyclophosphamide or chlorambucil treatment was initially followed by remission in all patients; a second course was successful in one of two patients. After 12 to 18 years of observation, four patients are in remission for periods of 2 to 12 years. Glomerular filtration rate is slightly reduced in only one patient. This study suggests that the clinical course of children with idiopathic nephrotic syndrome associated with focal global sclerosis is similar to that observed in patients with minimal glomerular changes but different from that in patients with focal segmental sclerosis.     

The significance of focal global sclerosis in idiopathic nephrotic syndrome. Long-term clinical observations

The clinical course of five pediatric patients with idiopathic nephrotic syndrome associated with focal global sclerosis in renal biopsy was analyzed retrospectively. The condition was defined as complete obsolescence of more than 15% of glomeruli associated with tubular atrophy and interstitial fibrosis. At onset, all children had a steroid-sensitive relapsing nephrotic syndrome. Two became steroid-dependent and one steroid-resistant. Cyclophosphamide or chlorambucil treatment was initially followed by remission in all patients; a second course was successful in one of two patients. After 12 to 18 years of observation, four patients are in remission for periods of 2 to 12 years. Glomerular filtration rate is slightly reduced in only one patient. This study suggests that the clinical course of children with idiopathic nephrotic syndrome associated with focal global sclerosis is similar to that observed in patients with minimal glomerular changes but different from that in patients with focal segmental sclerosis.     

Primary nephrotic syndrome in Iran: clinicopathological study of 310 cases

Three hundred and ten children with primary nephrotic syndrome were studied since 1972. 190 patients are classified as nephrosis (61%); including minimal glomerular lesions (22.9%), diffuse mesangial proliferation (6.77%) and focal and segmental sclerosis (31.6%). Corticoresponsivity was limited: 53.75% with a higher success rate in minimal glomerular lesions: 74% versus 38% of diffuse mesangial proliferation and 42.5% focal and segmental sclerosis. Immunosuppressive drugs were used for 96 patients corticodependent or resistant. They were more effective in dependent than resistant cases 94% versus 38%. A total of 149 cases were followed (mean: 3.9 years). In the last evaluation 67% were in remission, 8.10% in chronic renal failure and 24.8% with other abnormalities.     

Asymptomatic constant isolated proteinuria in children

The clinical features, renal biopsy findings, and subsequent course in 53 children with asymptomatic constant isolated proteinuria were studied retrospectively (1) to determine the prevalence of renal pathologic abnormalities among these children, (2) to identify those clinical characteristics that may enable recognition of children with an increased likelihood of having renal pathologic abnormalities, and (3) to assess the clinical course. All biopsy specimens were examined by light, immunofluorescence, and electron microscopy. Twenty-five patients (47%) had significant glomerular changes (15 had focal segmental glomerulosclerosis, 4 IgA nephropathy, 3 diffuse mesangial proliferative glomerulonephritis without IgA deposition, and 3 membranous glomerulonephritis), and 28 had minimal glomerular changes. There were no differences between the patients with significant glomerular changes and those with minimal glomerular changes with regard to clinical and laboratory findings except for a predominance of boys in the former group. At the latest follow-up, seven patients with significant glomerular changes, but none with minimal glomerular changes, had chronic renal impairment. Because of the high incidence of significant glomerular changes and the high rate of progression to chronic renal impairment, we believe that a renal biopsy is indicated for a child with asymptomatic constant isolated proteinuria.     

特发性塌陷性肾小球病二例分析

目的分析和认识小儿特发性塌陷性肾小球病(ICG)的临床特征及病理特点。方法回顾性总结分析二例小儿特发性塌陷性肾小球病的临床资料、病理资料、治疗反应及随访结果。结果二例临床表现为典型的肾病综合征;化验结果有大量蛋白尿、高脂血症、低蛋白血症;病理可见肾小球毛细血管丛节段／全球性塌陷伴上皮细胞增生肥大变性及严重肾小管间质病变;治疗转归二例对激素耐药,其中1例用甲泼尼松和环磷酰胺冲击无效,迅速发展为肾衰竭,半年内死亡;另一例激素耐药。用环孢素A无改善,追踪8个月,持续高血压,蛋白尿无改善。结论小儿特发性塌陷性肾小球病临床以严重的肾病综合征伴迅速进展肾衰竭为特点;病理以肾小球的塌陷、上皮细胞增生肥大变性及严重肾小管间质病变为特点;本病治疗困难,预后不良。     

Hyporeninemic hypoaldosteronism in children with chronic renal failure

The syndrome of hyporeninemic hypoaldosteronism (SHH) is not infrequent in adults with chronic renal failure caused by chronic tubulointerstitial nephritis, but it has been reported rarely in children. We present a systematic study of the interrelation between renal excretion of potassium and the renin-aldosterone axis in 23 children with CRF of different and unselected causes. Twenty children with chronic renal failure never had hyperkalemia, and both renin and aldosterone were normally stimulated by intravenous administration of furosemide, whereas three patients had moderate hyperkalemia (serum potassium concentration between 5.3 and 5.6 mEq/L) and failed to raise plasma renin activity and aldosterone values in response to furosemide. There three patients with SHH had lower basal and stimulated values of fractional potassium excretion than did patients with normokalemic chronic renal failure. Fractional potassium excretion was curvilinearly related to glomerular filtration rate (GFR), but in all three patients with SHH it was lower than expected for the level of GFR present. Fractional sodium excretion was also related to GFR, but no abnormalities were found. Two patients had hyperchloremic metabolic acidosis. After furosemide administration, they excreted an acid urine with low ammonium content, features characteristic of type 4 or hyperkalemic renal tubular acidosis. Prostaglandin E2 excretion was also significantly related to GFR, and appeared appropriate in two patients with SHH. The identification of three patients with SHH among 23 with chronic renal failure of unselected causes suggests that this entity is not rare in childhood.     

Familial infantile nephrotic syndrome with ocular abnormalities

Two siblings born from consanguineous parents experienced infantile nephrotic syndrome with ocular and neurological abnormalities and a micropenis in the boy; both patients died before age 1. The opportunity to perform successively a renal biopsy and a two-step binephrectomy permitted a good histological follow-up. The lesions were characterized by mesangial involvement, followed by an extensive extracapillary proliferation and tubular dilatations with a high mitotic activity of the epithelium with anisocaryosis; the main features consisted in major ultrastructural changes of the glomerular basement membrane which were more significant and different from those previously described in the diffuse mesangial sclerosis. These 2 cases may either constitute a new entity or an extreme form of diffuse mesangial sclerosis, supported by recessive autosomal inheritance.     

C3 Deposition in Serially Biopsied Children with IgA Nephropathy

Twenty-five children with IgA nephropathy were studied by serial renal biopsy to investigate C3 deposition. The children were classified into three groups according to the immunofluorescent (IF) course of C3 deposition: group I (N = 9): unchanged or slightly decreased; group II (N = 4): changed to segmental deposition; and group III (N = 12): changed to negative deposition. Histological changes were scored semiquantitatively as an activity index (cellular proliferation, necrosis, interstitial cell infiltration and cellular crescents) and a chronicity index (mesangial sclerosis, segmental and global glomerular sclerosis, adhesion, fibrous crescents and tubulo-interstitial change). The IF findings were scored semiquantitatively and laboratory data were also studied. The following results were obtained: 1. Normal urinalysis was often observed in group III; 2. The IF scores of IgA and IgG were decreased at the second biopsy in all groups, most notably in group III; 3. The activity indices at second biopsies were decreased in all groups, most notably in groups II and III, consistently with our previous study which showed that C3 deposition increases in accordance with histological activity; 4. The chronicity index was unchanged in all groups and C3 deposition did not reflect histological chronicity. Thus, this study indicates that C3 deposition occurs as the disease progresses and reflects histological activity.     

Lessons learned from studies of the natural history of diabetic nephropathy in young type 1 diabetic patients

Diabetic Nephropathy (DN) remains the leading cause of end stage renal disease (ESRD) in the Western world, responsible for nearly half of all new ESRD cases in the USA (1). DN develops in 20-25% of patients with type 1 diabetes (T1DM) (2) and, although risk of DN is clearly related to glycemic control (3,4), other variables including genetic propensity (5) are needed to explain why only a minority T1 DN patients progress to ESRD. The clinical manifestations of DN including increasing levels of urinary albumin excretion (AER), rising blood pressure (BP) and falling glomerular filtration rates (GFR) are closely related to renal structural abnormalities of DN (5,6). These glomerular, tubular, vascular and interstitial lesions are strongly correlated with these functional abnormalities especially when non-linear analysis models are used (6,7). This is because DN's natural history is one of clinical silence for years to decades during which time serious underlying renal lesions may be developing. Once the clinical manifestations, including the development of persistent microalbuminuria [(MA); (AER 20-200 microg/min)] are present, the structural injury is often far advanced (8). Moreover the nature of the renal lesions changes following the development of overt proteinuria so that the further decline in GFR is now associated with focal and global glomerular sclerosis and tubulo-interstitial injury which probably accelerates the GFR decline towards ESRD (7). Since interventions at these late stages of disease may only slow but not completely arrest the inexorable progression towards renal failure (9), understanding early natural history becomes important. Since DN structurally and functionally is a progressive disease; it is reasonable to presume that patients that either do not develop the earlier lesions of DN or develop them very slowly will not progress within their lifetime to stages of advanced renal structural injury and ESRD. We therefore considered it important to understand the early natural history of diabetic nephropathy and formed the International Diabetic Nephropathy Study Group (IDNSG) in order to investigate the early stages of DN in young T1DM volunteers. The design of the Natural History Study (NHS) (9) has been reported. The IDNSG participating institutions included 3 university centers (McGill University, Montreal, Canada with affiliations with the University of Sherbrooke, Sherbrooke, Canada, the Ottawa Civic Hospital, and the Childrens Hospital of Eastern Ontario; the Department of Pediatrics, University of Minnesota Medical School with affiliations at St Paul Children's Hospital and the International Diabetes Center in Minneapolis; the Robert Debré H?pital in Paris with affiliations with H?pital Saint Louis). The data coordinating center for the NHS was in the Department of Epidemiology and Biostatistics at McGill University and light microscopy readings were carried out at INSERM Unité 192 at the H?pital Necker-Enfants Malades in Paris. Patients could be included if they had type 1 diabetes for 2-20 years, had onset of diabetes before age 31, had AER less than 100 mug/min and GFR > or = 90 ml/min/ 1.73m2 (9). Patients also had to be normotensive for their age and sex and have no other significant renal or systemic disease. Quarterly studies included measurements of blood pressure, (BP), urinary albumin excretion rate (AER), hemoglobin A1C (HbA1C), GFR, and renal plasma flow (RPF). Renal biopsies were performed at baseline and after 5 years in the study. The primary goal of the study was to determine the clinical predictors of the baseline biopsy and baseline clinical and renal structural predictors of the changes between the baseline and the 5 year biopsy. The longitudinal structural studies are still in analysis and this paper will mainly review the cross sectional studies that have been completed to date.     

The role of dietary protein in progressive renal disease

Recently, a renewed interest in the role of dietary protein intake in the treatment of progressive renal disease has occurred. Early investigators suggested that high protein intake had a deleterious effect on renal function. Animals fed a high protein intake had more proteinuria and more-extensive glomerular sclerosis compared with animals fed a normal protein intake. More recent investigations have revealed that not only will a high protein intake exacerbate renal disease but a low protein intake will slow and/or prevent decline in renal function and the severity of renal histologic changes. These studies have provided the stimulus for investigations involving humans. Such studies suggest that patients with progressive renal disease of various causes, when placed on low-protein diets (0.6 g/kg/d), exhibit a slowing of the decline in renal function. The mechanism of the halting of such progression has been suggested to be a reduction in the hyperfiltration that occurs in the remaining nephrons after renal injury is established. Micropuncture studies have indicated that after the kidney has suffered injury, either through disease process or surgical removal, the unaffected nephrons try to maintain overall function, with individual nephrons increasing their filtration. This increase in single-nephron glomerular filtration rate (GFR) is accompanied by increases in single-nephron blood flow and an increase in transcapillary pressure, with altered membrane permeability, resulting in increased proteinuria. This increase in filtered albumin is taken up by the mesangium, with resulting mesangial expansion and glomerular sclerosis, with impingement on the glomerular filtering surface area, ultimately resulting in further decreases in GFR. Lowering protein intake will prevent this hyperfiltration, albuminuria, and the histologic changes. Furthermore, whether reduced protein intake is needed during times of physiologic increases in GFR (pregnancy, unilateral nephrectomy) is not clear. The processes that occur from the time after ingestion of protein to changes in GFR are not known but are probably mediated by systemic or intrarenal hormones. When adjusting protein intake, the minimum recommended dietary allowance for daily protein requirements must be considered. In adults, this level is 0.5 g/kg/d, with lower intakes requiring supplementation with essential amino acids. Requirements for children vary according to age--the younger the child, the higher the requirement. Minimum requirements for children with renal insufficiency have not been established.(ABSTRACT TRUNCATED AT 400 WORDS)     

Idiopathic mesangial IgA-glomerulonephritis in childhood

Nineteen out of 83 children with asymptomatic haematuria were classified as having IgA glomerulonephritis, characterized by diffuse mesangial deposition of IgA in the absence of systematic disease. Different histological patterns were observed: i.e., minor glomerular lesions (5 cases), focal and segmental proliferative glomerulonephritis (8 cases) and diffuse proliferative glomerulonephritis (6 cases). Recurrent gross haematuria is the clinical hallmark of the disease. Proteinuria was present in 14 children and exceeded 1 g/m²/day in 3 patients. Clinico-pathological correlations showed a close relation between the degree of proteinuria and the histological lesions. Serum IgA levels were elevated in 3 children. Glomerular filtration rate remained above 80 ml/min/1.73 m² in a 1 to 9 year follow-up.Dedicated to Prof. W. Doerr (Institute of Pathology, University of Heidelberg) on the occasion of his 65th birthday     

肾小球系膜区IgM沉积在儿童原发性肾小球疾病中的意义

目的：探讨肾小球系膜区IgM沉积在儿童原发性肾小球疾病中的意义。方法：选取2005年6月至2011年6月于北京大学第一医院儿科住院并行肾穿刺活检的原发性肾小球疾病患儿作为研究对象。根据免疫荧光下肾小球系膜区有无IgM沉积进行分组,将肾小球系膜区IgM沉积≥+且IgM免疫荧光强度≥其他免疫球蛋白荧光强度的患儿作为IgM沉积组,其余患儿为对照组。回顾性分析两组的临床、病理特点和随访等情况。结果：125例原发性肾小球疾病患儿进入分析,其中IgM沉积组76例,对照组49例。①两组在发病年龄、血总蛋白、血白蛋白、血总胆固醇、肌酐清除率、肾早期损伤指标、高血压和肾功能不全发生率等方面差异无统计学意义。IgM沉积组24 h尿蛋白定量及血IgM水平显著高于对照组（P分别为0.025和0.038）。②IgM沉积组肾小球硬化及小动脉病变发生率显著高于对照组(P分别为0.002和0.039),基底膜增厚发生率显著低于对照组（P=0.000）。③对激素治疗反应两组差异无统计学意义（P=0.364）。④随访2~78个月,两组肾功能不全及ESRD发生率差异无统计学意义。⑤IgM沉积组3/76例男性患儿行重复肾活检。除1例首次肾活检已诊断为局灶节段性肾小球硬化外,余2例在第2次肾活检时均由系膜增生性肾小球肾炎转化为局灶节段性肾小球硬化。结论：伴系膜区IgM沉积的原发性肾小球疾病患儿蛋白尿程度更重,肾脏病理改变亦更突出。对于伴系膜区IgM沉积的原发性肾小球疾病患儿应格外关注并密切随访,警惕其进展为局灶节段性肾小球硬化的可能。     

Necrotizing arteritis in acute poststreptococcal glomerulonephritis: report of a recovered case.

A patient with biopsy documented acute poststreptococcal glomerulonephritis and arteritis recovered completely with supportive therapy. Illness was preceded by group A streptococcal pharyngitis. At the time of presentation, serum creatinine concentration was 11.5 mg/dl. Serum cryoglobulins containing IgG and C3 were present. The first biopsy, performed during the acute illness, contained glomeruli with typical features of acute PSGN. Medium-sized arteries had extensive necrosis and leukocytic infiltration, and contained IgG, C3, and fibrin. Glomerular filtration rate returned to normal within three weeks; proteinuria cleared by three months, and microscopic hematuria by 11 months. Renal biopsy one year later showed minimal mesangial hypercellularity and no arteritis.     

Acute reversible kidney failure in IgA nephritis

Four patients with acute renal failure during an acute course of IGA-nephritis are described. Percutaneous renal biopsies showed only minor glomerular lesions in all patients. Immunosuppressive therapy was not necessary. In all patients acute renal failure was completely reversible. The four patient showed further episodes of macrohematuria without acute renal failure. All patients had normal renal function, normotensive blood pressure and microhematuria during interval. In three of the patients we found erythrocytes casts and a mild protein excretion. IGA-nephritis is one of the most common types of glomerulonephritis in adolescents and adults. If acute renal failure occurs during a course of IGA-nephritis with macroscopic haematuria a percutaneous renal biopsy has to be performed. Only in case of severe crescents formation (greater than 75%) immunosuppressive therapy is necessary. Glomerular lesions are responsible for long time prognosis.     

91例儿童Alport综合征临床、病理特点及误诊分析

目的探讨儿童Alport综合征(AS)临床、病理特点和诊治情况,以提高对AS的认识。方法收集确诊的91例AS患儿临床资料进行回顾性分析。结果 91例患儿均有血尿,86例伴有蛋白尿。61例X连锁显性遗传AS(XL-AS)患儿有阳性家族史。肾活检的82例患儿中74例有轻度或轻-中度系膜增生,48例系膜区少量免疫复合物,53例肾小球基底膜(GBM)有变薄、增厚和撕裂。63例进行了肾组织Ⅳ型胶原α3、α5链免疫荧光检测,确诊AS 58例,其中53例符合XL-AS,5例符合常染色体隐性遗传AS。91例AS患儿中,58例通过肾组织Ⅳ型胶原α3、α5链免疫荧光确诊,21例通过电镜确诊,1例通过皮肤活检确诊;12例基因诊断确诊。发现6个COL4A5基因新突变。45例曾被误诊其他疾病,其中41例接受过激素和/或免疫抑制剂治疗。结论儿童AS临床表现缺乏特异性,特征性GBM电镜改变仅见于部分患儿,本区域儿童AS误诊误治率仍较高。COL4A5基因新突变比例较高。     

MICROANGIOPATHIC GLOMERULOPATHY IN CHILDREN WITH SICKLE CELL ANEMIA

We studied kidney biopsy specimens from three children with sickle cell anemia and microangiopathic glomerulopathy. One child also had cyanotic congenital heart disease. Laboratory evaluation revealed proteinuria and normal serum creatinine in all and normal serum complement in two of the three children at the time of biopsy. In all biopsies, glomeruli were enlarged with diffuse hypercellularity and focal segmental mesangial interposition; capillary loop lumens were congested with sickled erythrocytes. Immune labeling identified segmental immunoglobulin G, C3, and properdin over the glomerular capillary loop walls in each case. Ultrastructurally, the subendothelial zone of the glomerular basement membrane was widened with new lamina densa formation with focal mesangial interposition. The glomerular lesion we describe in these children may be due to endothelial injury related to the altered erythrocytes, glomerular hemodynamics, and the hypercoagulable state characteristic of sickle cell disease.     

儿童C1q肾病10例临床与病理分析

目的探讨C1q肾病的临床与病理改变的关系。方法对10例经肾活检确诊为C1q肾病患儿临床表现、肾小球、肾小管及免疫病理特征进行分析比较,6例肾病综合征中环磷酰胺冲击治疗3例,环胞素、霉酚酸酯和甲泼尼龙冲击治疗各1例。结果临床表现为单纯性血尿2例,肾炎综合征、急性肾炎各1例,肾病综合征6例;病理类型为轻微病变、系膜增生性肾小球肾炎各2例,局灶节段性肾小球硬化5例,新月体肾炎1例;肾小管间质1例无改变,Ⅰ级和Ⅱ级各3例,Ⅲ级2例,Ⅳ级1例;免疫荧光:系膜区均有娃著的以C1q为主的沉积。10例患儿平均随访25.7个月;6例肾病综合征均对激素抵抗,加用免疫抑制剂治疗,5例缓解,1例无效,肾功能渐减退。结论C1q肾病临床病理改变多样化,临床以肾病综合征为主,病理以局灶节段性肾小球硬化为主,对激素多不敏感,预后与间质损害程度相关,与C1q沉积无相关性。     

The correlation between the clinical, laboratory and histopathological features of childhood membranoproliferative glomerulonephritis and response to treatment.

In this study, the clinical, laboratory and histopathological features of 50 children with membranoproliferative glomerulonephritis are reviewed. Age distribution varied from 5 to 15 years. The clinical presentation in the patients was nephrotic syndrome (24%), acute nephritic syndrome (20%) and nephritic/nephrotic syndrome (56%). Hypertension, macroscopic hematuria and hypocomplementemia were present in 40 percent, 58 percent and 34 percent of the patients, respectively. Light microscopic findings were as follows: glomerular lobulation (36%), mesangial sclerosis (20%), tubulointerstitial findings (36%), and crescents (26%). C3 (93%) was the most common immunofluorescence and IgM (86%), the most frequently encountered immunoglobulin. Response to treatment could not be anticipated by the initial clinical and laboratory features. Patients who did not have tubulointerstitial changes tended to have a greater response to therapy.     

Association of early-onset nephrotic syndrome and microcephaly. Apropos of 4 cases in 2 families

The authors report 4 cases in 2 different families of a syndrome characterized by nephrotic syndrome of early onset (during the first 2 years of life) and microcephaly. Such an association was previously reported in 5 cases. In 4 it was familial. The study of families suggests an autosomal recessive transmission. Microcephaly was associated with psychomotor retardation, sometimes dysmorphic facies and various neurologic abnormalities. The nephrotic syndrome was characterized by its early onset and prognostic severity. However, the renal histologic lesions were heterogeneous: either minimal glomerular changes with focal and segmental hyalinosis or mesangial sclerosis, or, so-called "microcystic dysplasia". This heterogeneity does not suggest a single genetically determined disorder.     

Reduced Glomerular Filtration and Elevated Urinary Protein Excretion in Diabetic Ketoacidosis

ABSTRACT. Glomerular filtration rate (GFR) was measured by two methods in 9 children with diabetic ketoacidosis (DKA), directly by true creatinine clearance and indirectly by means of serum beta-2-microglobulin levels. We found significantly reduced GFR in the first hours of DKA. The rapid improvement in GFR after fluid and electrolyte replacement indicates that volume depletion is the major cause of low filtration rate. In spite of the reduced GFR we observed pronounced albuminuria and low molecular weight (LMW) proteinuria. We conclude that the pathological albuminuria and microalbuminuria in DKA are caused not by glomerular hyperfiltration but by tubular dysfunction