Nephrotic syndrome in children: from bench to treatment.

Idiopathic nephrotic syndrome (INS) is the most frequent form of NS in children. INS is defined by the association of the clinical features of NS with renal biopsy findings of minimal changes, focal segmental glomerulosclerosis (FSGS), or mesangial proliferation (MP) on light microscopy and effacement of foot processes on electron microscopy. Actually the podocyte has become the favourite candidate for constituting the main part of the glomerular filtration barrier. Most cases are steroid sensitive (SSINS). Fifty percents of the latter recur frequently and necessitate a prevention of relapses by nonsteroid drugs. On the contrary to SSINS, steroid resistant nephrotic syndrome (SRINS) leads often to end-stage renal failure. Thirty to forty percents of the latter are associated with mutations of genes coding for podocyte proteins. The rest is due to one or several different circulating factors. New strategies are in development to antagonize the effect of the latter.

[Takayasu arteritis: a chronic vasculitis that is rare in children]. / Takayasu-arteriitis: een chronische vasculitis, zeldzaam bij kinderen.

Takayasu arteritis was diagnosed in two children, a 15-year-old girl and a 10-year-old boy. The girl had suffered from fatigue, malaise, abdominal pain and weight loss for several months, but no clear cause could be found. A few weeks later, when a blood pressure of 222/155 mmHg was measured, the possibility of renal artery stenosis was considered and imaging studies revealed indications for Takayasu's disease. The patient was given methylprednisolone followed by a combination of prednisone and, initially, cyclophosphamide, later methotrexate. This resulted in a clinical remission of the inflammatory process. The boy presented with increasing fatigue and variable episodes of fever. After 3 years, sarcoidosis or Castleman's disease were considered. Imaging studies revealed aortic stenosis. He underwent stenting of the involved vessel segment. Takayasu arteritis is a chronic vasculitis of unknown origin, affecting mainly the aorta and its main branches. As a result of the inflammation, stenosis, occlusion or dilatation of the involved vessels may occur and cause a wide range of symptoms. Especially in the early phase, the symptoms often are non-specific. One should look for hypertension, blood pressure differences between the two arms, decreased peripheral pulsation or bruits over the aorta and its major branches. Radiological examination may consist ofangiography, magnetic resonance imaging or CT-scans. Treatment consists of corticosteroids and other immunosuppressants, such as cyclophosphamide, methotrexate, azathioprine, and antagonists of tumour-necrosis factor alpha. In addition, balloon dilatation or stenting is often necessary.

Skin manifestations in vasculitis and erythema nodosum.

Cutaneous lesions are frequent in medium-sized and small vessel systemic vasculitides. The classic cutaneous manifestation of vasculitis is palpable purpura; however the clinical manifestations greatly depend on the size of the vessels affected. They usually do not affect prognosis but relapsing or intractable forms have been described. When skin manifestations are only one of the clinical signs of vasculitis, treatment with corticosteroids and, when indicated, an immunosuppressant, is mandatory, which usually leads to the rapid disappearance of cutaneous lesions. Conversely, when skin lesions are isolated, the diagnosis can be more challenging, but initial treatment may be less aggressive, e.g., dapsone or colchicine, reserving corticosteroids only for those patients in whom the former are ineffective. Erythema nodosum (EN) is the most frequent septal panniculitis. In general it is characterized by the sudden eruption of one or more erythematous and tender nodules or plaques located mainly over the extensor sides of lower extremities. EN resolves with complete "restitutio ad integrum" of the skin in 3-6 weeks. Relapses are uncommon but in patients with idiophatic, streptococcal or EN associated with other upper respiratory tract infections they are more frequent. The main treatment of EN is that of the underlying associated conditions, if demonstrated. Aspirin and other NSAIDs in full doses are often sufficient.

EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides.

BACKGROUND: There has been a lack of appropriate classification criteria for vasculitis in children. OBJECTIVE: To develop a widely accepted general classification for the vasculitides observed in children and specific and realistic classification criteria for common childhood vasculitides (Henoch-Schönlein purpura (HSP), Kawasaki disease (KD), childhood polyarteritis nodosa (PAN), Wegener's granulomatosis (WG), and Takayasu arteritis (TA)). METHODS: The project was divided into two phases: (1) the Delphi technique was used to gather opinions from a wide spectrum of paediatric rheumatologists and nephrologists; (2) a consensus conference using nominal group technique was held. Ten international experts, all paediatricians, met for the consensus conference. Agreement of at least 80% of the participants was defined as consensus. RESULTS: Consensus was reached to base the general working classification for childhood vasculitides on vessel size. The small vessel disease was further subcategorised into "granulomatous" and "non-granulomatous." Final criteria were developed to classify a child as HSP, KD, childhood PAN, WG, or TA, with changes introduced based on paediatric experience. Mandatory criteria were suggested for all diseases except WG. CONCLUSIONS: It is hoped that the suggested criteria will be widely accepted around the world because of the reliable techniques used and the international and multispecialist composition of the expert group involved.

Clear peritoneal effluent in a child on CCPD with a phlegmonous appendicitis.

Peritonitis as a result of a perorated appendicitis is a rare but life-threatening situation in a patient on peritoneal dialysis (PD). As far as we are aware, the combination of clear dialysate effluent and phlegmonous appendicitis in a patient on PD has not previously been described. We report a 16-year-old girl with acute onset of abdominal pain and vomiting who turned out to have phlegmonous appendicitis, despite having a clear dialysate effluent with normal cell count, and who subsequently developed E coli peritonitis after surgery.

[Kidney transplant survival rates and surgical complications in kidney transplants in children; experiences in the Emma Children's Hospital AMC]. / Niertransplantaatoverleving en chirurgische complicaties bij kinderniertransplantaties; ervaringen in het Emma Kinderziekenhuis AMC.

OBJECTIVE: To describe surgical complications, and patient and kidney transplant survival rates in children who have had a kidney transplant. DESIGN: Retrospective. METHOD: Data were analysed concerning the children who had been treated with a renal transplantation in the period 1985-2001 because of terminal renal insufficiency in the Emma Children's Hospital of the Academic Medical Centre in Amsterdam, The Netherlands, with arbitrary end date October 7, 2002. RESULTS: In the study period, 55 primary kidney transplantations were performed on 24 girls and 31 boys. 13 living related and 42 post mortem transplantations were performed. The extra-peritoneal approach was performed in all recipients. Up to October 7, 2002, 14 surgical complications (25%) developed: 4 cases of renovascular thrombosis, 4 urinary leakages, 6 urethral strictures, 1 urethral necrosis, 5 haematomas and 3 lymphoceles. 6 patients lost their grafts due to surgical complications (11%); 4 due to thrombosis, 1 due to urethral necrosis and 1 due to haemorrhage or haematoma. Due to hypertension secondary to the underlying kidney disease 2 patients died within one year after transplantation from hypertensive encephalopathy and cerebral bleeding respectively. The one- and five-year graft survival was 83% and 74% for living related transplantations respectively, and for post mortem transplantations 78% and 68% respectively. The main causes of graft loss were chronic rejection (9/21; 43%), acute rejection (4/21; 19%), thrombosis (4/21; 19%) and surgical complications (2/21; 10%). Primary nonfunction was the only factor with a negative prognostic value for graft survival.

Levamisole in steroid-sensitive nephrotic syndrome of childhood: the lost paradise?

Among the different drugs used for sparing steroids in steroid-sensitive nephrotic syndrome (SSNS) with frequent relapses and steroid dependency, levamisole is the least toxic and the least expensive. However, it is neither approved for this indication nor widely used in Europe. This may be explained by the difficulty in obtaining levamisole in some countries and the lack of good quality evidence for its effectiveness. Evidence is limited to three clinical trials that all suffered from methodological limitations. Statistical synthesis of these trials showed that levamisole reduces the risk of a relapse during treatment (relative risk 0.60, 95% confidence interval 0.45-0.79). From the available information, no conclusions can be drawn on the steroid-sparing effect, the long-term efficacy, and safety, as well as possible differences in efficacy in different subgroups of SSNS patients. The confirmation of a favorable effect of levamisole on the reduction of the frequency of relapses and on sparing steroids in an adequately powered, double-blind, placebo-controlled, randomized, multi-center clinical trial will promote consensus on the place of levamisole in the treatment of SSNS of childhood. Follow-up should be at least 1 year to evaluate long-term efficacy and side effects. If the results of such a clinical trial confirm the beneficial effects of levamisole in nephrotic syndrome, this may allow registration for this indication and interest companies other than Jansen-Cilag, which only recently has decided to stop its production.

Children with chronic renal failure have reduced numbers of memory B cells.

Reduced serum IgG and subclass levels have been demonstrated in children with chronic renal failure. To study possible causes of this reduction, we analysed B cell subset composition, T helper cell frequencies and immunoglobulin (Ig) production capacity in vitro in children with chronic renal failure, with or without dialysis treatment. B cell subsets were characterized by determining CD27, IgM, IgD and CD5 expression within the CD19(+) population. Intracellular expression of interferon (IFN)-gamma, interleukin (IL)-2 and IL-4 in PMA/ionomycin-stimulated peripheral blood mononuclear cells (PBMC) was used to evaluate T helper frequencies. The capacity of B cells to secrete Ig in vitro was determined by measuring IgG(1), IgG(2) and IgM in culture supernatants of anti-CD2/CD28 monoclonal antibody (MoAb)- or SAC/IL-2-stimulated PBMC. Memory B cell numbers (identified as percentage or absolute number of CD19(+) IgM-IgD- or CD19(+)CD27(+) lymphocytes) were lower in children treated with haemodialysis (HD), peritoneal dialysis (PD) and children with chronic renal failure before starting dialysis treatment (CRF) compared to healthy controls (HC) (P < 0.05). Compared with HC, CD5(+) (naive) B cells were reduced in HD-treated patients but not for PD or for children with chronic renal failure before starting dialysis treatment (CRF). No significant differences in CD4(+) T helper cell subsets were found between the groups. However, CRF children had a higher percentage of IFN-gamma producing CD8(+) T lymphocytes compared to HC (P = 0.02). Finally, IgG(1), IgG(2) and IgM production in vitro was similar in the four groups. In conclusion, significantly lower numbers of memory type B cells were found in children with chronic renal failure compared to healthy controls. This reduction may contribute to the low Ig levels found in these children.

What is the difference between IgA nephropathy and Henoch-Schönlein purpura nephritis?

Henoch-Schönlein purpura nephritis (HSPN) and IgA nephropathy (IgAN) are considered to be related diseases since both can be encountered consecutively in the same patient, they have been described in twins, and bear identical pathological and biological abnormalities. Apart from the presence of extrarenal clinical signs found only in HSPN, other differences are noticed between the two diseases. The peak age ranges between 15 and 30 years for a diagnosis of IgAN, whereas HSPN is mainly seen in childhood. Nephritic and/or nephrotic syndromes are more often seen at presentation in HSPN. In contrast to IgAN, HSPN has been described in association with hypersensitivity. Endocapillary and extracapillary inflammations as well as fibrin deposits in the glomerulus are more frequent in HSPN. No major biological differences have been found between the two illnesses, except for a larger size of circulating IgA-containing complexes (IgA-CC) and a greater incidence of increased plasma IgE levels in HSPN. As tissue infiltration by leukocytes is a major feature of HSPN vasculitis, a possible role of a more potent activation of the latter cells by IgA-CC and/or circulating chemokines in HSPN should be considered. Further studies are required to elucidate this possible mechanism as well as the role of hypersensitivity in HSPN.

Henoch-Schönlein purpura nephritis: an update.

UNLABELLED: Henoch-Schönlein purpura (HSP) is a form of systemic vasculitis characterised by vascular wall deposits of predominally IgA typically involving small vessels in skin, gut and glomeruli and associated with purpura, colic, haematuria and arthralgia or arthritis. HSP nephritis (HSPN) leads to chronic renal failure in up to 20% of paediatric patients after 20 years of follow-up in selected series. The risk is related to the initial clinical presentation and the percentage of glomeruli presenting with epithelial crescents. The pathogenesis of HSPN might be related to an increased production of abnormally glycosylated IgA, which is not sufficiently cleared by the liver and leads to the formation of IgA macromolecules, accumulating in the circulation with subsequent deposition in vessel walls and in the glomerular mesangium. HSPN is related to IgA nephropathy. These two diseases can be encountered consecutively in the same patient, have been described in identical twins and bear similar pathological and biological abnormalities. No consensus about treatment has been reached up to now. Recent studies indicate that early treatment with methylprednisolone or a combination of steroids and cytotoxic drugs might prevent evolution to chronic renal failure. CONCLUSION: Despite numerous studies, the pathogeny of Henoch-Schönlein nephritis remains incompletely elucidated and controlled therapeutic trials are still needed.

Dialysate cancer antigen 125 levels in children treated with peritoneal dialysis.

Peritoneal mesothelial cells are important for local host defense and membrane integrity. Dialysate cancer antigen 125 (dCA125) has been shown to be a good marker for the mesothelial cell mass in adult peritoneal dialysis (PD) patients. In children on PD, no information is available yet. We measured dCA125 in 65 dialysate samples from 24 PD children with a median age of 9.2 years (range: 2-18 years) and a median treatment time of 2.6 years (range: 0.1-9.3 years) on PD. The median dCA125 concentration was 8 U/mL (range: 2.3-30.7 U/mL), and the CA125 appearance rate (CA125AR) was 66.5 U/min/1.73 m2 (range: 18-282 U/min/1.73 m2). On cross-sectional analysis, a negative correlation was found between dCA125 and duration of PD treatment (r = -0.3, p = 0.04). No relation was found between age and dCA125 or CA125AR when the first measurement from each child was considered. No correlation was found between dCA125 and the mass transfer area coefficient of creatinine (MTACcreat). Longitudinal analysis showed a negative trend in CA125AR with duration of PD treatment (p = 0.03). No relation was found between peritonitis incidence and dCA125 or CA125AR. In conclusion, no influence of age on dCA125 and CA125AR was found. Levels of dCA125 declined with the duration of PD treatment, reflecting mesothelial cell mass, but they did not correlate with the MTACcreat or the peritonitis incidence in stable PD children.

Immunoglobulins in chronic renal failure of childhood: effects of dialysis modalities.

BACKGROUND: It is not clear whether low serum levels of IgG (subclasses), previously demonstrated in children on peritoneal dialysis (PD), are related to the PD procedure or to factors associated with chronic renal failure (CRF). The aim of our study was to analyze the effect of PD on serum and PD effluent (PDE) IgG and subclass levels in children with end-stage renal failure. METHODS: We measured albumin, IgG, IgA, IgM, and IgG subclasses in serum and PDE from children on PD (N = 40) and compared the serum values with those of children treated with hemodialysis (HD, N = 23) or presenting with CRF but not yet dialyzed (CRF; N = 63), and with a group of healthy controls (HCs; N = 67). Sixteen PD children could be followed sequentially from before starting PD and eight during a peritonitis episode. RESULTS: Forty percent of the PD children showed reduced serum IgG2 levels (P = 0.0003) compared with 35% in HD (P = 0.006), 33% in CRF (P = 0.001), and 9% in HC children. IgG1 deficiencies were observed in 25% of PD patients (P < 0.0001), 4% of HD (P = NS), 16% of CRF (P = 0.0005), and 0% of HC children. IgG3 and IgG4 deficiencies were observed less frequently. Peritoneal clearances were similar for total IgG, IgG1, IgG2, and IgG4, but were lower for IgG3 (P < 0.05). No relationships were found between clearances and age or duration of PD treatment. Total IgG (P = 0. 003) and IgG1 (P = 0.002) levels declined just after starting PD. Peritonitis was associated with temporarily increased peritoneal loss of Ig, while the serum concentrations were unaffected. No significant relationship was found between the peritonitis incidence and reduced IgG or subclasses. However, all children with two or more peritonitis episodes per year had a reduced Ig level. CONCLUSIONS: Although the mean serum concentrations of immunoglobulins were normal in all studied groups, a deficiency of one or more IgG subclasses was present in all groups with renal failure, suggesting inhibition of their synthesis by the uremic state. Ig deficiencies were more frequently found in PD, likely caused by protein loss in PDE. A high peritonitis incidence was associated with reduced serum Ig levels.

Characteristics of peripheral and peritoneal white blood cells in children with chronic renal failure, dialyzed or not.

OBJECTIVE: To explore further the mechanisms leading to immune deficiency in chronic renal failure and the role of dialysis treatment in these mechanisms. DESIGN: Cross-sectional and longitudinal analysis. PATIENTS: We studied 39 children treated with peritoneal dialysis (PD), 23 children treated with hemodialysis (HD), 33 children not yet dialyzed [chronic renal failure (CRF)], and 27 healthy children. Peritoneal cells were also obtained from PD children for analysis. METHODS: White blood cells (WBCs) were isolated from blood and peritoneal dialysis effluent by centrifugation. The number of CD2+, CD4+, and CD8+ T cells, B cells, and natural killer cells were measured by flow cytometry. RESULTS: The total peripheral blood lymphocyte count was lower in PD children (2.6 x 10(9)/L), HD children (2.1 x 10(9)/L), and CRF children (2.0 x 10(9)/L) compared with healthy children (3.1 x 10(9)/L, p < 0.05). The B lymphocyte count was also lower in PD children (0.34 x 10(9)/L), HD children (0.22 x 10(9)/L), and CRF children (0.33 x 10(9)/L) compared with healthy children (0.52 x 10(9)/L, p < 0.01). Numbers of CD4+ T cells were not different, but numbers of CD8+ T cells were lower in PD children (0.56 x 10(9)/L), HD children (0.63 x 10(9)/L), and CRF children (0.53 x 10(9)/L) compared with healthy children (0.77 x 10(9)/L, p < 0.05). The count of natural killer cells was lower in PD children (0.21 x 10(9)/L), HD children (0.17 x 10(9)/L), and CRF children (0.18 x 10(9)/L) compared with healthy children (0.50 x 10(9)/L, p < 0.0001). The CD4/CD8 ratio of lymphocytes in peritoneal effluent was 0.8 versus 1.9 in peripheral blood (p < 0.001). The CD2/CD19 ratio was not different. The cell subsets remained stable during the first year of PD treatment. The CD2/CD19 ratio in peritoneal effluent was higher in children with a peritonitis incidence > or = 1 per year. CONCLUSIONS: The reduced numbers of B lymphocytes, CD8+ T cells, and natural killer cells found in CRF children, dialyzed or not, may favor the frequent occurrence of infections.

[Pathogenesis of IgA nephropathies]. / Pathogénie des néphropathies à IgA.

The loss of kidney function in IgA nephropathy results from matrix overproduction by mesangial cells stimulated by IgA circulating complexes (IgA-CC) deposited in the mesangial area. High IgA-CC plasma concentrations are at least partly secondary to a genetically induced overproduction of undergalactosylated IgA molecules poorly cleared by the liver.

IgG glycation and function during continuous ambulatory peritoneal dialysis.

IgG in dialysate may have an important role in anti-infection mechanisms during continuous ambulatory peritoneal dialysis (CAPD). As Fc fragment oligosaccharidic chains are crucial for IgG effector functions, we have tested the hypothesis that IgG glycation might occur during CAPD and modify IgG properties. Purified normal IgG was incubated with glucose solutions of different concentrations and pH. Separation of glycated IgG was performed by affinity chromatography. Complement activation (C3c deposition) and phagocytosis by polymorphonuclear leucocytes (PMN) were studied in vitro using Staphylococcus aureus Wood (STAW) as antigen. In addition, we compared the percentages of glycated IgG in IgG purified from sera and dialysates of 12 CAPD patients. The percentage of glycated IgG after in vitro incubation of normal IgG with glucose solutions was directly proportional to glucose concentrations, incubation time and pH. Glycated IgG anti-STAW induced a higher C3c deposition than non-glycated IgG anti-STAW (C3c/IgG (mean +/- SD) 0.96 +/- 0.06 vs 0.79 +/- 0.08; P = 0.027). PMN phagocytosis was not affected by IgG glycation. The percentages of glycated IgG in dialysates of CAPD patients were greater than those in corresponding sera (5.38 +/- 2.36% vs 4.56 +/- 2.47%; P = 0.006). It is concluded that IgG glycation may take place in the peritoneal cavity during CAPD and lead to enhanced complement activation. This could explain the high degree of complement activation previously described in dialysate of CAPD patients and might theoretically result in a reduction of complement factors available in dialysate for adequate anti-infection mechanisms.

Do intestinal hyperpermeability and the related food antigens play a role in the progression of IgA nephropathy? I. Study of intestinal permeability.

Intestinal permeability was investigated by using 51Cr-EDTA as a probe molecule in 29 patients with immunoglobulin A nephropathy (IgA NP) and 20 healthy controls in 1990. Intestinal permeability was significantly higher in the IgA NP patients than in the controls (IgA NP, 3.86 +/- 0.29%; controls, 2.72 +/- 0.23%, p < 0.005). There was a significant relation between the manifestations of the disease (proteinuria and/or microhematuria) and the increased intestinal permeability (p < 0.05). By 1994, after an interval of 4 years, average intestinal permeability in the 21 patients available for study had not changed (3.80 +/- 0.36 vs. 4.57 +/- 0.63%) and was significantly higher than in the controls (p < 0.02). In patients with elevated serum IgA levels (serum IgA > 3.2 g/l; n = 15) there was a significant correlation between serum IgA levels and the degree of intestinal permeability (p < 0.02). During the 4-year period, the patients' kidney function deteriorated (n = 25; creatinine clearance in 1990, 92.4 +/- 6.1 ml/min; in 1994, 73.9 +/- 7.6 ml/min; p < 0.0002), the deterioration being greater in patients with increased intestinal permeability. There was no relation between the histologic grade of the biopsy specimen, hypertension and intestinal permeability. These data collected over a 4-year period suggest that in IgA NP increased intestinal permeability may play a role in the pathogenesis of the disease and adversely influence its progression.