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14 children with proven or presumably immunologically mediated tubulo-interstitial nephritis are presented. In 2 patients anti-tubular basement membrane antibodies were detected. In 6 immunofluorescence microscopy showed granular deposits of immunoglobulin and/or complement likely representing interstitial location of immune complexes. The findings by immunofluorescence were not significant in the remaining 6 patients. However, the association of renal disease to extra-renal disorders, namely chronic active hepatitis and ulcerative colitis, or uveitis or the presence of an epithelioid granuloma with multinucleated giant cells suggests that in such patients an immunologic disorder might be responsible for the tubulo-interstitial nephritis.

A new type of hereditary glomerulopathy was observed in ten children presenting with early and progressive glomerular symptoms, often associated with hypertension. Light microscopy showed a diffuse increase in the mesangial matrix and generalized widening of the capillary walls. Electron-microscopic examination of renal tissue, after phosphotungstic acid treatment, revealed the presence of fibrillar collagen within the mesangial matrix and the subendothelial aspect of the glomerular basement membrane, adjacent to normal lamina densa. Immunohistochemical studies identified the fibrillar collagen not usually present within the glomerular extracellular matrix as type III collagen. Clinical and family studies ruled out the diagnosis of nail-patella syndrome, an autosomal dominant disorder with typical extrarenal symptoms, which is also characterized by the presence of fibrillar collagen within the glomerular basement membranes. The poor renal outcome, the possible extrarenal haematological and pulmonary involvement and the transmission as an autosomal recessive trait strongly suggest that collagen type III glomerulopathy is a new type of hereditary disease. From the high incidence of superimposed haemolytic uraemic syndrome in patients or their siblings, it may be hypothesized that collagen type III glomerulopathy is the underlying defect in some of the familial cases of haemolytic uraemic syndromes.

Denys-Drash syndrome is a rare human condition in which severe urogenital aberrations result in renal failure, pseudohermaphroditism, and Wilms' tumor (nephroblastoma). To investigate its possible role, we have analyzed the coding exons of the Wilms' tumor suppressor gene (WT1) for germline mutations. In ten independent cases of Denys-Drash syndrome, point mutations in the zinc finger domains of one WT1 gene copy were found. Nine of these mutations are found within exon 9 (zinc finger III); the remaining mutation is in exon 8 (zinc finger II). These mutations directly affect DNA sequence recognition. In two families analyzed, the mutations were shown to arise de novo. Wilms' tumors from three individuals and one juvenile granulosa cell tumor demonstrate reduction to homozygosity for the mutated WT1 allele. Our results provide evidence of a direct role for WT1 in Denys-Drash syndrome and thus urogenital system development.

The founding of the European Society for Paediatric Nephrology (ESPN) in 1967 was the milestone for pediatric nephrology in Europe. Now, at the beginning of the 21st century, more than 2,000 European pediatricians in 46 European countries work in the field of pediatric nephrology, and approximately 500 of these meet regularly at the annual ESPN meetings. Half of these 2,000 pediatricians work in about 200 specialized pediatric nephrology centers in tertiary care units, whereas the other half work in secondary pediatric care, with a special interest in common renal diseases. In this article the founding and early years of the ESPN are outlined and include the structure of the first ten annual ESPN meetings from 1967–1976. Historical reports are given by five pioneers who were first-hand witnesses of the development of pediatric renal care in Europe.

Between 1980 and 1994, 38 children with severe forms of Schönlein-Henoch purpura glomerulonephritis were entered into a prospective study to evaluate methylprednisolone pulse therapy on the outcome of nephropathy in terms of clinical symptoms and histopathological changes. The patients were considered at risk of developing chronic renal failure when they presented with a nephrotic syndrome and/or had 50% or more crescentic glomeruli. Initial renal biopsies were obtained from all patients and revealed diffuse proliferative endocapillary glomerulonephritis in 2, focal and segmental glomerulonephritis in 4, and endo- and extracapillary glomerulonephritis in 32, 21 of whom had 50% or more glomeruli with crescents. Patients were treated with intravenous pulse methylprednisolone (3 days) followed by oral prednisone (3.5 months). At the latest follow-up, 1-16 years after initiation of therapy, 27 children had clinically recovered, 3 showed minimal urinary abnormalities, 4 persistent nephropathy, and 4 had progressed to end-stage renal failure. Sequential renal biopsies were obtained from 30 patients, 7-25 months after initiation of therapy. The clinical outcome correlated well with of the activity (hypercellularity, cellular and fibrocellular crescents, and interstitial edema with mononuclear cell infiltrates) and the chronicity (fibrous crescents, glomerular sclerosis, tubular atrophy, and interstitial fibrosis) indexes of post-therapy biopsies. Of particular interest were the post-therapy biopsies of the 18 patients who clinically recovered. They showed a significant decrease of the activity index from 5.1+/-1.1 to 0.4+/-0.8 with a decrease or even a disappearance of IgA deposits, while the chronicity index remained low (0.4+/-0.8 compared with 1.4+/-1). Although uncontrolled, our study suggests that methylprednisolone pulse therapy is effective in those patients at risk of progression of their nephropathy, especially if started early during the course of the disease before the crescents become fibrous.

During the period from January 1973 to December 1990, 774 renal transplantations in 698 children were performed in our renal unit. A total of 540 grafts were examined both by light and immunofluorescence microscopy at least once. Recurrent glomerulonephritis was diagnosed in 62 grafts, de novo glomerulonephritis in 68 and allograft glomerulopathy in 38 (7%). The term allograft glomerulopathy (AGP) refers to the very specific pattern of glomerular involvement unique to renal allografts and characterized by: (1) widespread reduplication of the glomerular basement membrane due to a widening of the subendothelial space associated with (2) moderate increase in mesangial matrix and (3) interposition of mesangial matrix and cells. AGP is a glomerular manifestation of chronic rejection and is almost always associated with obliterative vascular changes. In our experience it is present in 25% of long-standing grafts (more than 10 years), but may develop early in the post-transplantation period (5 cases within the first year). In 13 of 33 patients in whom early biopsies were available, a different pattern characterized by a hypercellularity and the presence of monocytes-macrophages in the mesangial areas was observed. We suggest that this hypercellular pattern might be the early stage of the disease and could be called "acute allograft glomerulopathy" as opposed to the pattern characterized by reduplication of the glomerular basement membrane which deserves the name of "chronic allograft glomerulopathy." The exact relationship between these two patterns remains to be determined. Clinicopathologic correlations showed that chronic AGP is often associated with marked proteinuria. However, in our series proteinuria was absent or minimal in 25% of the cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Among the various primary conditions which may be associated with a nephrotic syndrome at birth or within the 1st year of life, the best known is the congenital nephrotic syndrome of finnish type (CNF) characterized by irregular pseudocystic dilatation of proximal tubules. This disease, very frequent in Finaland, is often familial with an autosomal recessive mode of inheritance. Patients are steroid resistant, but the cause of death is usually not uraemia but infection or severe diarrhoea with electrolyte imbalance. The second condition is idiopathic nephrosis including minimal change disease, diffuse mesangial proliferation and focal segmental glomerular sclerosis. As opposed to CNF, infants with “early onset nephrosis” may respond to steroid therapy as older children do and may even recover. However, there are no histopathological criteria which allow the certain differentiation of idiopathic nephrosis from CNF. The third condition is diffuse mesangial sclerosis (DMS), a clinicopathological entity which can occur as an isolated finding or be associated with male pseudohermaphroditism and/or Wilms' tumour (Drash syndrome). From a morphological point of view, DMS is easy to differentiate from CNF because of the characteristic pattern of involvement of the glomeruli. From a clinical point of view, the nephropathy, almost always characterized by a nephrotic syndrome, has two distinct features: it is most often diagnosed in the first 2 years of life and it progresses rapidly to end-stage renal failure, which usually occurs before the age of 3 years. The clinical findings in 36 patients with DMS are presented. The nephropathy was isolated in 22 infants and associated with male pseudohermaphroditism and/or Wilms' tumour in 14. The early onset of the nephropathy, its familial incidence and its association with Drash syndrome suggests an antenatal dysgenetic process. Recent studies indicate a direct role of WT1 (a Wilms' tumour gene) in the aetiology of Drash syndrome, and mutations of this gene have been found in 3 patients herein reported. It remains to be demonstrated whether or not the WT1 gene is also altered in patients with isolated DMS.

Familial juvenile nephronophthisis (NPH) is a chronic autosomal recessive kidney disease responsible for 15% of end stage renal failure in children. NPH is frequently (16% of cases) associated with Leber amaurosis (termed Senior-Loken syndrome, SLS). Linkage analyses, performed in 22 multiplex NPH families (18 without and 4 with ocular abnormalities), have localized the gene to a region between D2S48 and D2S51 on chromosome 2p. This was confirmed using adjacent microsatellite markers, one of which (AFM220ze3 at the D2S160 locus) gave a lod score of 4.78 at theta = 0.05 in the 18 families with isolated NPH, whereas the same marker excluded linkage with SLS. These results demonstrate linkage of the purely renal form of NPH to chromosome 2p, and suggest that there may be genetic heterogeneity between NPH and SLS.

The treatment of children with idiopathic nephrotic syndrome who have multiple relapses or who are steroid-resistant is a difficult issue. Alkylating agents are often proposed but they have several side effects, including gonadal toxicity, which limit their use. Treatment with levamisole may be efficient in steroid-dependent patients, allowing prednisone to be tapered or stopped in approximately 50% of cases. Cyclosporine has proved to be effective in 85% of steroid-dependent patients, but most patients relapse when cyclosporine is tapered or withdrawn. Thus, in these patients, cyclosporine may be required for long periods of time. Conversely, cyclosporine alone is less effective in steroid-resistant patients, as only 28% of these patients respond to the treatment. Cyclosporine in association with prednisone may be a better alternative as, in our experience, 14 out of 31 patients went into remission with such treatment. It should be stressed that response to cyclosporine is better correlated with initial steroid responsiveness than with histological category. Eighteen out of 43 patients with serial renal biopsies developed significant tubulo interstitial lesions which could be attributable to cyclosporine nephrotoxicity. The risk of developing chronic nephrotoxicity appears to be higher in steroid-resistant patients. Cyclosporine nephrotoxicity is not related to the duration of treatment and may develop in patients with normal renal function.

With the worldwide use of immunofluorescence microscopy, idiopathic IgA nephropathy (Berger's disease) has been recognized as a distinct form of primary glomerular disease. IgA nephropathy is the most common form of GN in many parts of the world. However, since the criteria for diagnosis are exclusively based on the findings of predominant IgA in the mesangium, the boundaries of this “entity” are not well delineated and it has become clear that several different clinical conditions share this common immunopathology. IgA nephropathy should, therefore be regarded as a syndrome. Schonlein-Henoch purpura (SHP) and Berger's disease represent the primary form of this syndrome. The clinical features of both diseases in children are reviewed. Although the clinical symptoms may appear different there is a close relationship between SHP and IgA nephropathy. They share the same pathology, the same pathogenesis, and they may both recur on a transplanted kidney. Moreover, both diseases can occur in a single family. When pathologic mechanisms are more defined, SHP may prove to be 1 end of a spectrum of diseases associated with microvascular immune deposits in which IgA is the predominant immunoglobulin seen, the other end being Berger's disease.

1. Diets deficient in phosphorus have been shown to preserve the renal function of uraemic rats, but the role of concomitant alterations in the intake of other nutrients caused by such diets was not elucidated. 2. Five groups of uraemic rats were compared. Three (A, B, C) received (ad libitum) diets deficient (0·03%), low (0·2%) or normal (0·5%) in P. Two groups (D, E) received restricted amounts of 0·2% and 0·5% P diets by pair-feeding with group A rats. 3. Phosphorus deficient diet resulted in marked anorexia, growth arrest, low P and high calcium plasma levels and severe rickets, but renal function became stabilized. Groups B and C had both higher total food intake and weight gain but a significantly higher mortality rate. After 36 weeks, mortality was 90% in these groups, and was 19%, 28% and 44% in groups A, D and E rats respectively, despite a higher P consumption in group E than in group B rats. 4. Normal P diet was associated with severe renal calcium deposits and high calcium heart content, which were related to the degree of hyperparathyroidism evaluated by bone histology. 5. Preservation of renal function was mainly mediated by reduction in some other components of the diet and not by P restriction itself. Normal P diet with restricted dietary allotments had little adverse effect on survival, and its influence on renal histology is not easy to explain. 6. Restriction in P sufficient to cause moderate hypophosphataemia, disappearance of phosphaturia and to prevent hyperparathyroidism without causing anorexia and other severe side effects, had little or no beneficial effect on renal deterioration.

The clinical course and outcome of 91 children less than 15 years of age at onset and followed for at least 1 year have been retrospectively analyzed. The course has been characterized by recurrent macroscopic hematuria in 74 patients, by proteinuria-microscopic hematuria and a single episode of macroscopic hematuria occurring either at onset or a few months later in 8, by proteinuria-microscopic hematuria in 7, and by proteinuria only in 1. Lastly, one patient showed rapidly progressive renal failure. Four groups were identified by light microscopy: minimal glomerular changes (26), focal and segmental glomerulonephritis (41), pure mesangial proliferation (3) and proliferative glomerulonephritis with crescents (21). A good correlation was found between the glomerular lesions observed by light microscopy and the outcome. In this series we have not observed a dramatic clinical deterioration suggesting a transformation from one histologic type to another, as reported by others. None of the 70 patients belonging to the first three groups has impaired renal function but two with focal and segmental glomerulonephritis have developed hypertension. Although the clinical course is benign, many patients have, at the last observation, an abnormal urinalysis characterized by microscopic hematuria and/or mild proteinuria; the proteinuria is over 1 g/24 h in six patients with focal and segmental glomerulonephritis. Ten patients remained in clinical remission for several years, but mesangial IgA deposits were still present in the only patient who had a repeat biopsy while in remission. In contrast, none of the patients with proliferative glomerulonephritis with crescents has had a prolonged remission. Six patients developed terminal renal failure 0.7, 0.11, 2, 4, 8 and 10 years after onset. Two additional patients are in moderate chronic renal failure with hypertension 10 and 12 years after onset. Most children show a persistent nephropathy, (in five proteinuria is over 1 g/24 h), and two of them have developed hypertension. Therapeutic trials using drugs with side-effects should, therefore, be used only in this group of patients.

Immunofluorescence microscopy (IF) studies were carried out in 36 patients with Type I MPGN and showed the constant presence of deposits containing C3. Based on the presence or the absence of immunoglobulins (Ig), two main patterns were observed. Complement profiles (30 patients) and C3NeF activity (20 patients) were studied in the two groups defined by IF. Our findings indicate an activation of the complement system through the classical pathway even in the group characterized by the absence of Ig. Such an activation suggests the role of immune complexes in the pathogenesis of the disease. Because of the presence of C3NeF activity in occasional patients, a superimposed activation through the alternative pathway is not unlikely. In two additional patients, one with predominant IgA within the deposits and one with C2-deficiency, the complement system is probably activated through the alternative pathway.

Idiopathic nephrosis (IN), which includes minimal change (MCD), diffuse mesangial proliferation (DMP) and focal segmental glomerular sclerosis (FSGS), is classically characterized by the absence of significant deposits by immunofluorescence microscopy (IF), except for the focal lesions of segmental sclerosis and/or hyalinosis of FSGS, which fix IgM and C3 antiserums. Since IF is available in most centres, an increasing number of unexpected findings has been reported. In order to evaluate the clinical significance of the glomerular deposits revealed by IF in some instances, we reviewed the renal biopsy findings of 222 consecutive children presenting with IN and in whom IF microscopy was available. By light microscopy, 122 patients showed MCD, 10 DMP, and 90 FSGS with DMP (11 cases) or without (79 cases). By IF, 125 specimens were negative and served as controls; 54 showed mesangial IgM deposits, 24 mesangial IgG deposits (associated with Clq deposits in 16), 15 scattered granules of C3 and 4 predominant deposits of mesangial IgA. We correlated these findings with initial response to steroid therapy and outcome and could find no significant difference between the various categories defined by IF and the control group. Repeat biopsies, performed in 21 cases, showed the persistence of deposits in 11 and their transformation in 10. The particular problem raised by the patients who present with IN and mesangial IgA deposits is discussed. Our results demonstrate that patients presenting with IN and "positive IF", whether showing IgM, IgG and Clq, C3 or IgA, do not represent distinct clinicopathological entities.

Over a 15-year period we observed seven children (four girls, three boys) who presented within the first months of life with severe renal failure and acidosis, associated with hypertension in five patients and polyuria in four. In addition, one patient had a severe cholestatic liver disease. In two families, a similarly affected sibling had died previously. Four patients were referred with the clinical diagnosis of polycystic kidney disease because of moderate enlargement of kidneys, but renal imaging (intravenous pyelography and ultrasonography) did not confirm this diagnosis. A renal biopsy, performed in all patients, showed similar features characterized by a diffuse chronic tubulo-interstitial nephritis (TIN) and particularly by the presence of microcystic dilatation of proximal tubules and Bowman's space. Liver pathology was normal in two patients, including one with hepatomegaly. However, in the patient with cholestasis there was inflammatory portal fibrosis with mild duct proliferation. Progression of the renal disease was extremely rapid and all patients reached end-stage renal failure (ESRF) before the age of 2 years (11-22 months). Two children had successful renal transplants. Although this chronic TIN shares some features with nephronophthisis, we suggest that it represents a distinct entity both on clinical and morphological grounds. The specific clinical features of this disease are its early onset and rapid progression to ESRF. Pathologically, it differs from nephronophthisis by the absence of medullary cysts and thickened tubular basement membranes and by the presence of cortical microcysts.

Les auteurs rapportent 27 observations anatomo-cliniques, chez I’enfant, de «syndrome hemolytique et uremique» caracterise par la survenue simultanee d’une anemie hemolytique, d’une atteinte renale, d

The accidental death of a 13-year-old child with the syndrome of congenital bilateral oligonephronic renal hypoplasia with hypertrophy of nephrons ( oligomeganephronie ) provided an opportunity for morphologic study of the nephrons in the intermediate stage of this disease. Microdissection by the method of Oliver confirmed the existence of greatly hypertrophied glomeruli and proximal tubules, and permitted study of the abnormal configuration of the nephrons. Anatomic correlates of glomerulotubular balance in the reduced population of nephrons showed a markedly disproportionate enlargement of proximal tubules, relative to glomerular size. A brief description of the clinical and pathologic features of oligomeganephronie is included in the report.

Among the 2,052 children with renal disease admitted to a Pediatric Department during a period of 10 years, 270 developed chronic renal failure (CRF). Of these 270 patients, 147 (54%) were under 5 yea

In 1957 Rich [1] presented observations in 20 children with the nephrotic syndrome who died between several months and five years after the onset of edema. One-half of these children died from infection. He described a progressive sclerosis of glomeruli starting in the juxtamedullary region of the kidney and suggested that this was the usual way in which lipoid nephrosis progressed. A few years later, studies of renal biopsy specimens from patients with the idiopathic nephrotic syndrome revealed a particular group that was characterized by the presence of focal sclerosing glomerular lesions as distinct from others with minimal or diffuse glomerular lesions [2–4]. It is only in recent years that a clear correlation has been established between these focal lesions and a specific clinical course. A high incidence of microscopic hematuria, corticosteroid resistance and developing renal insufficiency in nephrotic patients with this finding has now been reported by most authors [5–17]. Since the lesions under discussion are characterized by focal involvement of glomeruli and by the sclerotic changes which take place in affected glomeruli, the terms focal glomerular sclerosis (FGS) or focal sclerosing glomerulonephropathy [17] seem appropriate. Other names such as focal sclerosing glomerulonephritis [4, 16] or focal glomerulosclerosis [11, 15, 20] have been proposed. In our opinion the word ‘glomerulonephritis' should be avoided because of the confusion it may introduce in reference to focal and segmental glomerulonephritis [9]. The term ‘focal gbmerulosclerosis' is also confusing since, for decades, the word ‘glomerulosclerosis' has been used for the small sclerotic glomeruli often found in infant kidneys [18, 19]. The frequent histologic finding of FGS in nephrotic patients whose clinical presentation at onset could not be distinguished from that of ‘nephrosis,' or who might have exhibited minimal glomerular lesions on a previous biopsy specimen [3, 5, 8, 13, 14, 16, 17], raises an important question as to the relationship between ‘minimal lesion nephrotic syndrome' (M LNS) and this ‘disease' (FGS). A recent report of the possible recurrence of the nephrotic syndrome and the focal lesion in transplanted kidneys suggests that a humoral factor may be operative which antedates the glomerular structural changes. Accurate diagnosis of FGS in nephrotic patients may therefore be of considerable practical importance.

The role of amount and nature of carbohydrates in the course of experimental renal failure. The renal effects of carbohydrates (CHO) were studied in two experiments. 1) The effects of CHO-energy restriction was evaluated by comparing uremic growing rats (initial weight: 80 g) fed “ad lib” (L rats) or CHO-restricted (starch and glucose) but receiving identical amounts of all other nutrients (R rats). R rats showed reduced growth, slower increase in plasma creatinine, lower mortality rate, and less histological renal damage than L rats. 2) Two types of CHO restriction, low glucose (R1 rats) or low starch (R2 rats) were compared to “ad lib” feeding (L1 rats) in adult rats (initial weight: 130 g). Growth was identically reduced in R1 and R2 rats. Mean plasma creatinine levels at week four was lower in R1 than in L1 rats. The overall rate mortality was higher for L1 and R2 than in R1 rats (79%, 81%, 53%) but included deaths from other causes than renal failure. Actuarial survival excluding these deaths was 27%, 83% and 10% in L1, R1 and R2 rats, respectively. Diffuse renal lesions were found in 25 of 30L1, 5 of 15R1, and 12 of 15R2 rats (R1 vs. R1 and R2, P < 0.01). The results show that CHO restriction may preserve the renal parenchyma, and suggest that restriction of “simple” rather than “complex” CHO restriction may be beneficial, a finding which could be of clinical importance if confirmed by further investigations.

Early renal changes in hemizygous and heterozygous patients with Fabry's disease. Renal biopsy specimens were obtained for light and electron microscopy in 12 patients with Fabry's disease (9 hemizygous males and 3 heterozygous females), ranging in age from 7 to 51yr. Renal function and blood pressure were normal in all patients. In hemizygous patients, diffuse glycolipid accumulation was observed early in life in every glomerular, vascular, and interstitial cell; tubules were involved irregularly, predominantly in distal convoluted tubules and Henle's loop. In heterozygous females, the glycolipid storage had the same morphological features but was found irregularly, being absent in one patient and present patchily in the 2 others: some cells were normal, others were involved massively. Associated degenerative renal changes were present in all patients but one (a heterozygous female) and were clearly age-related. They first affected vessels as round fibrinoid deposits resulting from necrosis of severely involved smooth muscle cells. In older patients, intimal thickening was superimposed, and degenerative glomerular and tubular changes were noted. They may have been related partly to ischemic damage. In addition, mesangial cell necrosis could have contributed to the development of glomerular sclerosis. Our findings in heterozy-gotes are consistent with Lyon's hypothesis of X chromosome inactivation in each female cell. They suggest that renal glycolipid involvement and urine a-glactosidase activity are closely related. They provide theoretical evidence against the possible benefits of enzyme replacement therapy. Lesions renales precoces chez les sujets hemizygotes et heterozygotes atteints de maladie de Fabry. Les biopsies renales de 12 malades âges de 7 a 51 ans (9 sujets hemizygotes et 3 heterozygotes) ont ete etudiees en microscopie optique et electronique. Tous avaient une fonction renale et une pression arterielle normales. Chez les sujets de sexe masculin, hemizygotes, l'accumulation de glycolipides est precoce et diffuse, presente dans toutes les cellules glomerulaires, interstitielles et vasculaires. Dans les tubes la surcharge est irreguliere et predomine sur les tubes contournes distaux et les anses de Henle. Chez les femmes transmettrices l'aspect est moins monomorphe: la surcharge est absente chez une malade, elle est presente chez les deux autres mais touche irregulierement les cellules tant glomerulaires, interstitielles et vasculaires que tubulaires. Les lesions degeneratives du parenchyme renal, associees a la surcharge, sont presentes dans tous les cas sauf chez une des transmettrices, leur severite est correlee avec l'âge des malades. Elles touchent d'abord les vaisseaux sous la forme de depots fibrinoides arrondis presents dans la paroi musculaire des arteres; ces depots sont la consequence de la necrose des cellules musculaires surchargees de glycolipides. Chez les sujets plus âges, aux lesions de la media s'associe une endarterite, et des alterations degeneratives glomerulaires et tubulaires apparaissent, probablement secondaires aux alterations vasculaires. La necrose des cellules mesangiales peut egalement intervenir dans la genese des lesions glomerulaires. Nos observations chez les heterozygotes sont compatibles avec l'hypothese de M. Lyon concernant l'inactivation d'un chromosome X dans chaque cellule feminine. Elles suggerent l'existence d'une correlation etroite entre l'importance de la surcharge du parenchyme renal et le taux urinaire d'α-galactosidase. Elles jettent un doute sur le benefice qu'on peut attendre des therapeutiques enzymatiques substitutives.

1. Bunn HF, Haney DN, Kamin S, et al: The biosynthesis of human hemoglobin A~c: Slow glycosylation of hemoglobin in vivo, J Clin Invest 57:1652, 1976. 2. Koeulg RJ, Peterson CM, Jones RL, et al: Correlation of glucose regulation and hemoglobin AI0 in diabetes mellitus, N Engl J Med 295:417, 1976. 3. Widness JA, Rogler-Brown TL, McCormick KL, et al: Rapid fluctuations in glycohemoglobin (hemoglobin A~) related to acute changes in glucose, J Lab Clin Med 95:386, 1980. 4. McDonald M J, Shapiro R, Bleichman M, et al: Glycosylated minor components of human adult hemoglobin, J Biol Chem 253:2327, 1978. 5. Haney DN, and Bunn HF; Glycosylation of hemoglobin in vitro: Affinity labeling of hemoglobin by glucose-6-phosphate, Proc Natl Acad Sci 73:3534, 1976. 6. Stevens VJ, Vlassara H, Abati A, and Cerami A: Nonenzymatic glycosylation of hemoglobin, J Biol Chem 252:2998, 1977. 7. Garrick LM, McDonald M J, Shapiro R, et al: Structural analysis of the minor human hemoglobin components: Hb A~I Hb AI~ 2 and Hb A~b, Eur J Biochem 106:353, 1980.

In 1983 the Council of the American Society of Nephrology instituted the John P. Peters Award to recognize individuals who have made outstanding contributions to clinical nephrology. The Award was named for John P. Peters, Professor of Medicine and Director of Metabolism and Renal Diseases at Yale, who was a leader in establishing the specialty of nephro/ogy in the United States by his training of many leading academic nephrologists. The first recipient of the Award in 1983 was Donald W. Se/din, and subsequent Awards were given to Jean Hamburger and John P. Merrill in 1984, to Franklin H. Epstein in 1985, to Be/ding H. Scribner in 1986, and to Conrad L. Pirani and Jacob Churg in 1987. The John P. Peters Award of the American Society of Nephrology was presented, at the 1988 Annual Meeting of the American Society of Nephrology, by Dr. A. F. Michael and Drs. Henry L. Barnett and Renee Habib. The following are Dr. Michael's Introductions for Dr. Barnett and Dr. Habib.

Serial determinations of complement components (C1q, C4, C3, C5 and factor B) were performed in 32 children with acute glomerulonephritis. Low levels of C3 were found in 30 patients and low levels of C5 in 26. The findings of reduced C1q and/or C4 levels (25 patients) in the first days of the disease suggest activation of the classical pathway. Depressed Factor B levels were found rarely (4 patients). In all patients, the presence of a C3 splitting activity and/of a C3 nephritic factor-like activity was investigated. Both activities were demonstrated in 7 patients whereas in another patient, only C3 splitting activity was noted. A disappearance of both activities was observed in all patients. In 3 patients tested, the C3 nephritic factor-like activity was heat-labile and was therefore not related to true C3 nephritic factor. Both pathways are implicated in the early phases of the disease but continued C3 depression is probably through alternate pathway.

Several immunologically mediated mechanisms may lead to injury of renal tubules and interstitial tissue resulting in tubulointer-stitial nephritis (TIN). The distinguishing features of these mechanisms are based upon their immunofluorescent microscopic (IF) pattern. Tubular linear deposits of immunoglobulins (Ig) suggest the presence of circulating antitubular basement membrane (TBM) antibodies. Granular deposits of Ig and/or complement (C) are likely related to the presence of immune complexes (IC). In the absence of deposits, a cell-mediated reaction may be suggested. These mechanisms have been well studied in experimental models. They may also be observed in man. We report about 14 children with proven or presumed immunologically mediated TIN.

Delayed renal failure with extensive mesangiolysis following bone marrow transplantation. Within two years we have had the opportunity of observing seven leukemic children who were referred to our Pediatric Nephrology Unit for delayed renal failure following bone marrow transplantation (BMT). These children (3 to 12 years old), six with acute lymphoblastic leukemia (ALL) and one with acute non-lymphoblastic leukemia (ANLL), underwent BMT (4 autologous BMT, 3 allogeneic BMT) after the first remission in two, and after the second remission in five. Preparative regimen for BMT included cyclosphosphamide in three, cyclosphosphamide, vepeside and cytosine A in four, and a total body irradiation in a single dose of 10 grays (1000 R) in all of them. Three children were treated immediately after grafting with low dose cyclosporine for four to six months. Five to 10 months after BMT, four patients developed a hemolytic uremic syndrome with severe hypertension. The remaining three were found to have isolated renal insufficiency several months post-BMT. In the seven patients, renal biopsy showed a uniform pattern of severe glomerular involvement characterized by extensive lesions of mesangiolysis associated with severe arteriolonecrosis. A repeat biopsy performed one year later in two patients showed severe scarring of the renal parenchyma with minor lesions of mesangiolysis. The similarity of the pathologic features observed suggests that the same mechanism might have been operative in the seven patients. It is very likely that the nephropathy is related to total body irradiation enhanced by chemotherapy. We conclude that current treatments of high risk leukemia might become a new cause of chronic renal failure. Further investigations are needed to know the exact incidence of this complication.

Children with idiopathic nephrosis are usually treated with corticosteroids and, in the vast majority of cases, nephrosis is steroid responsive. However, some 60% of cases relapse as soon as steroid therapy is withdrawn or when the dosage is decreased. This constitutes steroid dependant nephrosis where patients may develop serious side effects of steroid therapy. Immunosuppressive drugs, mainly alkylating agents, are effective in these situations but their long term toxic effects also limit their use. Few children with idiopathic nephrosis fail to respond to steroids. In these patients, the effectivness of immunosuppressive drugs have not been demonstrated. In the past few years, several reports have claimed that ciclosporine (CSA) could be beneficial in such patients (17–7). We shall report here our experience with Ciclosporine in 51 children, 37 steroid dependant and 14 steroid resistant.

The glomerular pathology of 634 transplant specimens (526 biopsies and 108 transplantectomies) from 410 children was studied. Three types of glomerulopathies were observed: (1) recurrent glomerulonephritis (GN) (40 of 142 patients with glomerular nephropathy), (2) de novo GN (52 grafts), and (3) transplant glomerulopathy (29 grafts). The study of recurrent GN is considered of great interest because of the possible insight into the nature of the original disease and the opportunity to observe the evolution of the disease in sequential biopsies of the transplant. The two major forms of de novo GN were membranous GN and IgG linear deposits along glomerular and tubular basement membranes. Transplant glomerulopathy, although distinctive morphologically, may resemble membranoproliferative GN (MPGN) or thrombotic microangiopathy.

Twenty-four biopsies of renal allografts, generally cadaveric, from 20 patients with cystinosis were examined by light, polarization, phase contrast, and electron microscopy. The unusual dark cells previously reported in the native kidneys and livers of patients with cystinosis were observed in 12 of the 24 biopsies. The cells were present in the interstitium in all of these 12 biopsies, in glomeruli in one biopsy, and in the tubular lumen in two biopsies. They were evident by light and electron microscopy in stained and unstained ultrathin sections, and could be discerned solely in Epon sections. The dark appearance resulted from the presence of dark, fine granular material in the cytoplasm and nucleus and in cytoplasmic inclusions. The cells were judged to be macrophages. They were present as early as 3 months following transplantation and bore no relationship to interstitial crystals or inflammation. The dark cells have two important implications: cystine storage may not be limited to lysosomes, and dark cells are a morphologic alternative to the traditional identifying configuration of cystine in tissues, namely crystals.

It has been demonstrated in previous studies that there are several morphological variants of membranoproliferative glomerulonephritis (MPGN) [1–3]. In most cases mesangial cell proliferation and an increase in mesangial matrix are associated with capillary wall thickening ("classical MPGN"). In some cases, in addition to the previous findings, there is an accentuation of lobulation of glomerular tufts due to the presence of sclerotic nodules in most of the centrilobular areas. This is accompanied by peripheral displacement or obliteration of capillary lumens (lobular GN or "MPGN with lobular pattern"). More or less abundant epithelial crescents may be seen in both variants. However, analysis of the capillary wall thickening by light and electron microscopy reveals two types of involvement: In the first, thickening of the capillary walls is due to an interposition of mesangial matrix between the endothelium and a normal basement membrane, producing a "double contour" appearance. Electron microscopy, as well as immunofluorescence microscopy, reveals in all cases the presence of abnormal subendothelial deposits. This variety is called MPGN with subendothelial deposits (SED) . In the second, the thickening of the capillary walls is due to the presence of an abnormal dense refractile material located in the basement membrane itself. "Double contours" here are an inconstant finding. This variety warrants the name of MPGN with dense intramembranous deposits (DIMD) ; it has recently been called laminal glomerulonephritis [4]. These two varieties of MPGN are at present not distinguished one from another in most clinical studies because it may be difficult to recognize MPGN with DIMD on light microscopy. Therefore, with one exception [5], there are no extensive studies dealing with this specific entity. We observed 44 cases of this variety of MPGN and report here detailed clinical and complement studies, together with histological data in these cases for comparison with 84 cases of MPGN with SED seen during the same period of time.

Thirty of 85 children with membranous glomerulonephritis (MGN) had associated extraglomerular disorders. The relation of these associations to membranous glomerulonephritis (MGN) is discussed. The causal relationship of acute hepatitis (5 cases), persistent hepatitis B antigenemia (6 cases), systemic lupus erythematosus (2 cases) and syphilis (1 case) may be ascertained; in similar conditions a definite antigen (Ag) has been found in MGN deposits. The association with SS or SA hemoglobinopathy (3 cases) ans with a preceding streptococcal infection (4 cases) raises the possible responsibility of renal tubular epithelium (RTE) Ag and of a streptococcal Ag. D-penicillamine therapy (1 case) is a well-known cause of MGN although the acting Ag remains unknown. Four children had serum sickness-like symptoms, two had hematologic disorders and two had proximal tubular dysfunction, one of them with proven anti-tubular and anti-alveolar basement membrane antibodies. A decrease in plasma C4, Clq, and factor B with normal C3 was frequently observed. The multiple Ag previously described as causative of MGN are recalled. The prevalent incidence of HBsAg is stressed, and the necessity for further investigations in patients with MGN in order to find an underlying disease is emphasized.

We report 27 patients who presented with segmental hypoplasia (SH) and hypertension. Twenty were girls and hypertension was rarely discovered before 8 years of age. Corticopapillary scarring was unilateral in 7 cases and bilateral in the remaining 20. Nephrectomy performed in 11 cases led to normalization of blood pressure (BP) in only 4. Death occurred in 2, BP was well controlled in 2 and poorly controlled in 3. The remaining 16 children were treated with hypotensive drugs. At latest followup, 8 had progressed to terminal failure and 6 had a well controlled BP with stable renal function. In one patient there was a decreased GFR while BP was well controlled and in the remaining one, renal function was stable while BP was poorly controlled.

Alagille syndrome is characterized by the association of chronic cholestasis with a paucity of interlobular bile ducts and a distinctive facies together with cardiovascular, skeletal and eye abnormalities. We examined the kidneys of 26 patients with this syndrome; 22 were under 3 years of age and 4 were 4, 6, 12 and 17 years old, respectively. Eighteen showed glomerular lesions of variable severity characterized by a mesangiolipidosis. In the 8 lesser affected patients light microscopy (LM) disclosed a fibrillar appearance of the mesangium, and electron microscopy (EM) showed lipid vacuoles widespread in the mesangial matrix. In the 10 patients who were affected to a greater degree LM and EM showed, in addition to the mesangial matrix changes, the presence of mesangial foam cells. Clinical signs of renal involvement were mild in all patients except for one who died from chronic renal failure at 8 months of age. The extent of mesangiolipidosis was not related to age but to the degree of cholestasis, the most severe lesions being observed in patients aged 3, 6, 8, and 14 months. The glomerular lesions observed in Alagille syndrome are strikingly similar to those observed in adults with lecithin-cholesterol acyl transferase deficiency and other conditions characterized by an increase in plasma lipoproteins rich in free cholesterol and in phospholipids. We conclude that glomerular involvement should be added to the characteristic features of Alagille syndrome. Also we found that the lipid deposition in the glomeruli of patients with Alagille syndrome is related to an abnormal lipid metabolism, which is the consequence of severe cholestasis. The most striking feature of our study is the early detection of the glomerular lesions, contrasting with the lack of overt clinical renal disease. Renal failure may be a major complication for patients with this syndrome in adulthood.

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.

Pathologic and clinical data concerning 50 children with extramembranous glomerulonephritis (EMGN) are reported. This type of glomerular lesion is characterized by thickening of the capillary walls, due to subepithelial deposits without endocapillary proliferation. EMGN occurred in all age groups including infancy. It was often latent and discovered by routine urinalysis. Nephrotic syndrome and hematuria were frequent but not constant. In no instance could a specific etiology be demonstrated. Corticosteroids as well as immunosuppressive drugs seemed ineffective. Remissions often occurred while patients received no treatment. Patients were followed for one to ten years. Twenty-six children had complete remissions, 17 of them without subsequent relapse. Twenty-four patients had persistent proteinuria. The only five patients who developed chronic renal failure presented with persistent biochemical changes of the nephrotic syndrome. EMGN is not an uncommon nephropathy in children, but seems to have a more benign course in children than in the older age groups hitherto reported.