Cornelis H. Schröder

The cognitive development of pre-school children treated for chronic renal failure

Chronic renal failure in young children is associated with impaired cognitive development, but recent studies present a more optimistic perspective. An important question is whether the earlier initiation of renal replacement therapy (RRT) might prevent the reported developmental retardation. The cognitive development of 31 patients (age <5 years with a serum creatinine clearance of <20% of normal) undergoing different treatment modalities was monitored by repeated measurements during a prospective 3-year study. Fifteen patients received conservative treatment and 16 patients were on dialysis treatment at the start of the project. We were able to evaluate the effect of the onset of RRT on 12 patients who were transferred from conservative treatment to dialysis. At the beginning of the study, the cognitive development of the total group was significantly delayed (mean developmental index=78.5, SD=19.5) compared with a normal population. Patients undergoing conservative treatment scored significantly higher (P<0.01) than those on dialysis. The effect of starting dialysis treatment appeared to be positive, but only a significant short-term improvement was observed. Follow-up evaluation of 7 patients on conservative treatment and of 9 dialysis patients over a 2-year period did not show any significant change in a positive or negative direction. The present study revealed that pre-school dialysis patients are at risk with respect to their cognitive development. This is particularly true for the group with concomitant disorders. Less severe disease in the group on conservative treatment may be assumed to be a positive contributing factor to the more normal performance of these patients. No evidence was found to support the hypothesis that the earlier initiation of dialysis treatment will have a beneficial effect on development.

The development of anti-glomerular basement membrane nephritis in two children with Alport's syndrome after renal transplantation: characterization of the antibody target

Two children with Alports syndrome are described, who developed anti-glomerular basement membrane (GBM) antibody-mediated nephritis after renal transplantation. The reactivity of antibodies in their serum with collagenase-solubilized normal GBM was examined by SDS-PAGE with one- and two-dimensional immunoblotting. The specificity was compared with that of antibodies present in serum from a patient with Goodpastures syndrome, and a mouse monoclonal antibody (MCA-P1), directed against the Goodpasture antigen. All reacted in a similar way with collagenase-solubilized GBM. Since abnormalities in the composition of the GBM are present in Alports syndrome, it is proposed that differing antigen composition of GBM in the host compared with the donor kidney, together with transplant rejection, may have provoked the development of post-transplant anti-GBM antibodies.

The glycosaminoglycan content of renal basement membranes in the congenital nephrotic syndrome of the Finnish type

A decrease in the concentration of heparan sulphate proteoglycan (HSPG) in the glomerular basement membrane (GBM) is supposed to cause the increased GBM permeability in the congenital nephrotic syndrome (CNS). Therefore, we analysed the glycosaminoglycan (GAG) content and composition of the GBM and tubular basement membrane (TBM) from 3 patients with CNS of the Finnish type (FCNS) and 16 control infants. The GAG content, determined by spectrophotometric assay after papain digestion, was not significantly different in FCNS patients compared with controls. In addition, the GAG composition was comparable in the two groups, with heparan sulphate (HS) constituting at least 75% of the total GAG content. The urinary GAG content (expressed as mg GAG/mmol creatinine) was age dependent, but similar in both groups. Indirect immunofluorescence studies on kidney tissue from normal human infants, using monoclonal or polyclonal antibodies against the core protein of human GBM HSPG, showed linear staining of almost all renal basement membranes. A monoclonal antibody directed against the HS chain of HSPG showed strong GBM and a weak TBM staining. Kidney tissue from three patients with FCNS displayed no discernible differences in the distribution or quality of staining with the same antibodies. These biochemical and immunohistochemical results are in contrast to the decrease in anionic sites (by polyethyleneimine staining) and the replacement of GBM HS by chondroitin sulphate, observed by others in CNS of the diffuse mesangial sclerosis type.

Proteomic profiling and identification in peritoneal fluid of children treated by peritoneal dialysis

BACKGROUND Proteomic technologies offer a high-throughput analysis of the expression of proteins in biological samples. The global analysis of the proteins in peritoneal dialysis (PD) fluid will provide a better understanding of the biological processes of the peritoneal membrane. METHODS The dialysate of nine paediatric PD patients was collected from peritoneal equilibrium tests with 3.86% glucose. Proteins were separated on a 10% SDS-PAGE gel and in-gel digested with trypsin. Peptide mixtures were analysed using nanoLC-MS/MS and results were searched against the NCBI database. RESULTS A total number of 189 proteins were identified in the PD fluid of nine patients, with 88 proteins shared by all patients. These 88 proteins accounted for 47% of the identified proteins and >90% of the total protein content in the analysed samples. Proteins were subdivided into eight different classes according to function. CONCLUSIONS This study gives a representative overview of the proteins present in PD fluid. The proteins in PD fluid reflect plasma proteins as well as local peritoneal processes. Potentially interesting proteins are revealed.

Fungal peritonitis in children on peritoneal dialysis

Fungal peritonitis is a rare but serious complication in children on peritoneal dialysis (PD). In this study, risk factors were evaluated, and therapeutic measures were reviewed. A retrospective, multi-centre study was performed in 159 Dutch paediatric PD patients, between 1980 and 2005 (3,573 months). All peritonitis episodes were reviewed. Fungal peritonitis episodes were evaluated based on possible risk factors and treatment strategy. A total of 321 episodes of peritonitis occurred, with 9 cases of fungal peritonitis (2.9%). Candida peritonitis occurred most frequently (78%). Seven patients (78%) had used antibiotics in the prior month. Fungal peritonitis patients had a higher previous bacterial peritonitis rate compared to the total study population (0.13 versus 0.09 episodes/patient*month), with twice as many gram negative organisms. In all fungal peritonitis patients, the PD catheter was removed. In four patients restart on PD was possible. Fungal peritonitis is a rare complication of PD in children, but is associated with high technique failure. The most important risk factors are a high bacterial peritonitis rate, prior use of antibiotics, and previous bacterial peritonitis with gram negative organisms. The PD catheter should be removed early, but in children, peritoneal lavage with fluconazole before removal may be useful to prevent technique failure.

Solutions for peritoneal dialysis in children: recommendations by the European Pediatric Dialysis Working Group

The purpose of this article is to provide recommendations on the choice of peritoneal dialysis (PD) fluids in children by the European Pediatric Dialysis Working Group. The literature on experimental and clinical studies with PD solutions in children and adults was analyzed together with consensus discussions within the group. A grading was performed based on the international KDIGO nomenclature and methods. The lowest glucose concentration possible should be used. Icodextrin may be applied once daily during the long dwell, in particular in children with insufficient ultrafiltration. Infants on PD are at risk of ultrafiltration-associated sodium depletion, while anuric adolescents may have water and salt overload. Hence, the sodium chloride balance needs to be closely monitored. In growing children, the calcium balance should be positive and dialysate calcium adapted according to individual needs. Limited clinical experience with amino acid-based PD fluids in children suggests good tolerability. The anabolic effect, however, is small; adequate enteral nutrition is preferred. CPD fluids with reduced glucose degradation products (GDP) content reduce local and systemic toxicity and should be preferred whenever possible. Correction of metabolic acidosis is superior with pH neutral bicarbonate-based fluids compared with single-chamber, acidic, lactate-based solutions. Prospective comparisons of low GDP solutions with different buffer compositions are still few, and firm recommendations cannot yet be given, except when hepatic lactate metabolism is severely compromised.

Retinal abnormalities in Alport's syndrome

Abstract. The ophthalmological findings in 13 patients with Alports syndrome are reported. Special attention was given to the retina and retinal functions. Flecked retinopathy was present in 12 out of the 13 cases. Two cases showed tortuosity of the retinal vessels. Retinal function tests showed no significant abnormalities. This study suggests that in Alports syndrome, retinal lesions are more common than has been reported until now.

Heparan sulfate proteoglycan from human tubular basement membrane. Comparison with this component from the glomerular basement membrane.

Heparan sulfate proteoglycan (HSPG) was extracted from human tubular basement membrane (TBM) with guanidine and purified by ion-exchange chromatography and gel filtration. The glycoconjugate was sensitive to heparitinase and resistant to chondroitinase ABC, had an apparent molecular mass of 200-400 kDa and consisted of 70% protein and 30% glycosaminoglycan. The amino acid composition was characterized by its high content of glycine, proline, alanine and glutamic acid. Hydrolysis with trifluoromethanesulfonic acid yielded core proteins of 160 and 110 kDa. The heparan sulfate (HS) chains obtained after alkaline NaBH4 treatment had a molecular mass of about 18 kDa. Results of heparitinase digestion and HNO2 treatment suggest a clustering of sulfate groups in the distal portion of the HS side chains. These chemical data are comparable to those obtained previously on glomerular basement membrane (GBM) HSPG (Van den Heuvel et al. (1989) Biochem. J. 264, 457-465). Peptide patterns obtained after trypsin, clostripain or V8 protease digestion of TBM and GBM HSPG preparations showed a large similarity. Polyclonal antisera and a panel of monoclonal antibodies raised against both HSPG preparations and directed against the core protein showed complete cross-reactivity in ELISA and on Western blots. They stained all basement membranes in an intense linear fashion in indirect immunofluorescence studies on human kidneys. Based on these biochemical and immunological data we conclude that HSPGs from human GBM and TBM are identical, or at least very closely related, proteins.

Hereditary disorders of the glomerular basement membrane

Abstract. Increased knowledge of the biochemical composition of the glomerular basement membrane (GBM) and the introduction of molecular genetics has shed new light on the hereditary disorders of the GBM. In this review three disorders are highlighted. About 85% of the cases reported as Alport syndrome are transmitted as the X-linked form and are due to mutations of the COl4A5 chain localized at Xq22. The autosomal recessive form can be explained by mutations in the COl4A3 and COl4A4 gene. Anti-GBM nephritis leading to loss of the renal allograft in about 1% – 5% of transplanted Alport patients can be the tragic consequence of this disorder. Some patients with familial benign hematuria have an abnormality of COl4A4. The nail-patella syndrome is a rare autosomal dominant disorder defined by the association of nail dysplasia, bone abnormalities, and frequently renal disease. The gene is localized in region 9q34.1, COl5A1 is not involved. The Finnish type is the best known of the different forms of congenital nephrotic syndrome. The gene has been mapped to the long arm of chromosome 19. Diffuse mesangial sclerosis occurs in the isolated form and as part of the Denys Drash syndrome. Disturbances of the WT1 function in the epithelial cells can have a role in the renal abnormalities of the Denys Drash syndrome.

Reduction of potassium in drinks by pre-treatment with calcium polystyrene sulphonate.

Dietary potassium intake in patients with chronic renal failure is generally reduced by oral administration of potassium-binding resins. These drugs may cause disturbances of bowel function and have an unpleasant taste. Pre-treatment of drinks with these resins and their subsequent removal may prevent these inconveniences. In four formulas (whole milk, humanised infant formula, apple juice, and orange juice) we were able to lower the potassium content by 50% with calcium polystyrene sulphonate. No important increase of sodium content was observed, as was reported with the use of sodium polystyrene sulphonate. There was a, potentially beneficial, increase of the calcium concentration.