Renal transplantation for fibromuscular dysplasia.

This is the first report that presents renal transplantation after bilateral nephrectomy as the final treatment for severe renovascular hypertension due to fibromuscular dysplasia (FMD). We describe the history of a 1-year-old girl who suffered from renovascular hypertension due to FMD. Imaging revealed multiple bilateral stenoses of the renal artery extending into the distal branches. The hypertension proved unresponsive to pharmacologic treatment and the intrarenal peripherally located stenoses rendered a conventional approach such as transluminal or surgical angioplasty not feasible. At the age of 5 years, a unilateral nephrectomy of the most affected kidney was performed, but she remained hypertensive and developed progressive cardiomyopathy and retinopathy. At the age of 6 years the remaining kidney was removed, followed by a living related renal transplantation with a kidney donated by her mother. Posttransplantation, she developed mild hypertension due to a postanastomotic stenosis, which was easily controlled with antihypertensives. Now 8 years after transplantation, she has experienced no further blood pressure related problems. Although there is a risk of recurrence of FMD after performing a living related transplantation, our report suggests that this procedure is relatively safe, provided appropriate preoperative evaluation and follow up is performed.

Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis--a review.

This review deals with podocyte proteins that play a significant role in the structure and function of the glomerular filter. Genetic linkage studies has identified several genes involved in the development of nephrotic syndrome and contributed to the understanding of the pathophysiology of glomerular proteinuria and/or focal segmental glomerulosclerosis. Here, we describe already well-characterized genetic diseases due to mutations in nephrin, podocin, CD2AP, alpha-actinin-4, WT1, and laminin beta2 chain, as well as more recently identified genetic abnormalities in TRPC6, phospholipase C epsilon, and the proteins encoded by the mitochondrial genome. In addition, the role of the proteins which have shown to be important for the structure and functions by gene knockout studies in mice, are also discussed. Furthermore, some rare syndromes with glomerular involvement, in which molecular defects have been recently identified, are briefly described. In summary, this review updates the current knowledge of genetic causes of congenital and childhood nephrotic syndrome and provides new insights into mechanisms of glomerular dysfunction.

[From gene to disease; Dent's disease caused by abnormalities in the CLCN5 and OCRL1 genes]. / Van gen naar ziekte; de ziekte van Dent veroorzaakt door afwijkingen in CLCN5- en OCRL1-genen.

Dent's disease is an X-linked disorder, characterized by generalized proximal tubular dysfunction, nephrolithiasis, nephrocalcinosis and the development ofend-stage renal disease, generally occurring after the age of thirty. In the majority of cases, the disease is caused by mutations in the CLCN5-gene. The pathogenesis of the disease has not yet been clarified. Defective recycling of multi-ligand proximal tubular receptors megalin and cubilin is considered responsible for the defective reabsorption of low molecular weight proteins, albumin, hormones and vitamins. Treatment with thiazide diuretics to diminish the hypercalciuria in combination with citrate supplements might prevent renal stone formation and deterioration of renal function. In the laboratory ofDNA diagnostics in the Radboud University Nijmegen Medical Centre, the molecular analysis of the CLCN5-gene in patients suspected with this disease is performed.

Focal segmental glomerulosclerosis in a patient homozygous for a CD2AP mutation.

Focal segmental glomerulosclerosis (FSGS) is a histologic diagnosis in several kidney diseases characterized by proteinuria and a severe decrease in kidney function. Mutations in several genes were found in patients with primary FSGS, one of which is a CD2-associated protein CD2AP (originally referred to as CMS). This gene encodes an adaptor protein that plays a role in endocytosis, cell motility, and cell survival. Mice deficient in Cd2ap (the mouse homolog) die due to kidney failure, while heterozygous mice develop lesions similar to those of FSGS patients. In the kidney, CD2AP regulates the actin cytoskeleton. The only previously described patient with CD2AP mutation had a severely truncated protein. In this study, we describe a patient with a novel mutation resulting in a premature stop codon yielding a protein truncated by only 4%. This shortened CD2AP protein displays a significantly decreased F-actin binding efficiency in vitro with no expression of the mutated allele in the patient's lymphocytes. Heterozygous expression of the CD2AP mutation in both parents did not lead to any kidney pathology, as both have normal glomerular filtration rates and no proteinuria.

[From gene to disease; 'apparent mineralocorticoid excess' syndrome, a syndrome with an apparent excess of mineral corticoids]. / Van gen naar ziekte; 'apparent mineralocorticoid excess'-syndroom, een syndroom met ogenschijnlijke overmaat aan mineralocorticoïden.

Apparent mineralocorticoid excess (AME) is an autosomal recessive disease caused by deficiency of the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). 11beta-HSD2 converts cortisol into inactive cortisone and prevents the stimulation of the mineralocorticoid receptor by cortisol. In patients with AME, an enhanced stimulation of mineralocorticoid receptors by cortisol in the distal nephron causes an elevated sodium reabsorption and increased potassium excretion. Sodium retention leads to severe low renin hypertension. The diagnosis of AME is based on the detection of an increased concentration of cortisol metabolites and a low or undetectable concentration of cortisone metabolites in urine. Molecular analysis of the HSD11B2 gene confirms the diagnosis. AME is successfully treated by potassium-sparing diuretics, sometimes in combination with loop diuretics (furosemide). Mild forms of AME might occur more frequently than is currently known and should be suspected in patients with hypertension, hypokalemia and decreased plasma renin concentration. Since liquorice can induce the clinical symptoms of AME due to reversible inhibition of the 11beta-HSD2 enzyme by glycyrrhetinic acid, the active ingredient of liquorice, patients suspected of having AME should not consume liquorice.

[From gene to disease; the haemolytic uraemic syndrome can be caused by mutations in regulating factors of the alternative route of the complement system]. / Van gen naar ziekte; het hemolytisch-uremisch syndroom als gevolg van mutaties in de regulatie van de alternatieve route van het complementsysteem.

Defective control of the alternative route of the complement system is an important cause of the non-diarrhoea haemolytic uraemic syndrome (HUS). On the endothelial surface, mutations in HF1, MCP and IF predispose to development ofHUS. Uncontrolled complement activation on the surface of endothelial cells will damage these cells extensively. Plasmapheresis can be an effective, although temporary, treatment for mutations in HF1 and IF. HUS frequently recurs after renal transplantation in patients with HF1 or IF mutations but not in patients with a mutation of MCP. These genetic defects can be detected by routine diagnostics.

Renal transplant nephrectomy in children: can an aggressive approach be recommended?

BACKGROUND: A patient with a failed renal graft is generally approached conservatively, especially when graft failure occurs more than 1 month after transplantation. This approach was the cause of extensive morbidity in our institution and therefore we evaluated the correctness of our approach towards transplanted children. PATIENTS AND METHODS: Case histories of 182 renal transplants in 145 patients, performed between 1977 and 1999 were reviewed. RESULTS: A total of 63 renal grafts failed: 19 between 0-1 month (group 1), 22 between 1 month and 1 yr (group 2) and 22 later than 1 yr after transplantation (group 3). Fifty-three grafts (84%) were removed: 100% of group 1, 86% of group 2 and 68% of group 3. The symptoms that indicated the need for graft removal were fever without a clear infection focus (n = 12), abdominal pain in the transplant area (n = 14), macroscopic hematuria (n = 10) and severe hypertension (n = 22). After transplant nephrectomy pain, fever and macroscopic hematuria completely resolved in all and hypertension resolved in 36% of patients. Transplant nephrectomy-associated morbidity was observed in 38% of the patients with 100% recovery. CONCLUSION: The clinical outcome confirmed the indications for transplant nephrectomy. Our future approach will be more aggressive: as soon as symptoms such as unexplained fever, local pain or macroscopic hematuria appear, graft removal will be performed without delay.

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.

[From gene to disease: cystinosis]. / Van gen naar ziekte; cystinose.

Cystinosis is an autosomal recessive disorder caused by an impaired transport of cystine out of lysosomes. The most severe infantile form of cystinosis starts with Fanconi syndrome at the age of 3-6 months. Untreated patients develop renal failure before the age of 10. The cystinosis gene (CTNS) maps to chromosome 17p13, spans 23 kb and is composed of 12 exons. CTNS encodes a 367 amino acid protein, cystinosin, which is a H(+)-driven lysosomal cystine transporter. It is enigmatic how lysosomal cystine accumulation induces the clinical symptoms. ATP depletion was demonstrated in an experimental model consisting of loading lysosomes with cystine dimethylester. The amino-thiol cysteamine depletes lysosomal cystine content by a disulfide-exchange reaction with cystine. Therapy with cysteamine should be administered as early as possible and continued after a renal transplantation as the extra renal damage still progresses. Improved life expectancy of cystinotic patients requires the attention of internists with a special interest for this rare disorder.

Is biopsy required prior to cyclophosphamide in steroid-sensitive nephrotic syndrome?

AIM: The present studywas designed to retrospectively evaluate the use of renal biopsies prior to cyclophosphamide therapy. The aim of the study was to determine in how many cases histological outcome of the biopsies had subsequently changed the decision to treat or refrain from treatment. PATIENTS AND METHODS: Between January 1980 and September 2001, 85 children with steroid-sensitive nephrotic syndrome (SSNS) underwent a renal biopsy in the University Hospitals of Utrecht and Nijmegen before the start of an 8-week cyclophosphamide treatment. MCNS was suspected in all children because of the following criteria: edema, proteinuria, hypoalbuminemia, absence of macroscopic hematuria and in rare cases microscopic hematuria, no permanent hypertension, normal C3 serum level, a normal glomerular filtration rate as determined by creatinine clearance and age > 1 year. Cyclophosphamide therapy was indicated because of a frequently relapsing (FR) course of illness in 8 children, because of steroid dependence (SD) in 22 children and because of combined FR and SD in 55 children. Steroid-resistant children were excluded from this study. RESULTS: Histology confirmed the diagnosis MCNS in 84 out of 85 children. In addition to MCNS, IgA deposits were observed in renal specimens of 2 children. In 1 SD child, the initial diagnosis MCNS was changed 3 years later when a repeated biopsy showed progression into focal segmental glomerulosclerosis (FSGS). CONCLUSION: In summary, no renal biopsy is required prior to cytotoxic therapy in children with uncomplicated steroid-sensitive nephrotic syndrome.

Defective proximal tubular function in a patient with I-cell disease.

A girl with a proven diagnosis of I-cell disease is presented. Proximal tubular dysfunction was characterized by increased excretion of low molecular proteins, aminoaciduria, hyperphosphaturia, and high/slightly increased urinary calcium. The concentration of 1,25-dihydroxycalciferol in serum was increased. Rickets were present on X-rays. As the proximal tubular dysfunction resembles the dysfunction in Dent disease, one can speculate about a common pathogenesis. Impairment of acidification in lysosomes due to loss of function of the chloride-5 channel impairs intralysosomal protease activity in Dent disease, while in I-cell disease the intralysomal protease activity is lacking.

WT-1 and NPHS2 mutation analysis in patients with non-familial steroid-resistant focal-segmental glomerulosclerosis.

BACKGROUND: Familial forms of steroid-resistant nephrotic syndrome with the histologic findings of focal-segmental glomerulosclerosis have frequently a genetic basis. For the non-familial forms this is still unresolved. PATIENTS AND METHODS: Ten children with non-familial steroid-resistant nephrotic syndrome along with focal-segmental glomerulosclerosis were tested for mutations in the WT-1 and NPHS2 genes. RESULTS: In 1 patient, a mutation in intron 9 of the WT-1 gene and in 1 patient a heterozygous NPHS2 mutation could be detected. Both abnormalities are important for the treatment modalities and prognosis. CONCLUSION: Additional studies will have to provide a solid basis for the recommendation of mutation analysis in non-familial steroid-resistant focal-segmental glomerulosclerosis.

Perinatal rupture of the uropoietic system.

AIMS: Ruptures of the uropoietic system resulting in either urinary ascites or urinoma are rare complications in the neonate. Although ruptures without clear predisposing factors are described, in most cases they are associated with obstructive uropathy. The diagnosis is often delayed and the prognosis is related to the degree of renal damage. There is discussion about possible protective mechanisms of the rupture for renal function in patients with obstructive uropathy. METHODS: We retrospectively analyzed the clinical presentation, predisposing factors and the renal function before and after treatment of 10 neonates with a rupture of the pyelum or urinary bladder in our hospital. RESULTS: The group consisted of 9 boys and 1 girl. The average birth weight was 3,880 g. The patients presented with distended abdomen (n = 10), abdominal mass (n = 2), ascites (n = 5), oligohydramnion (n = 2), hypertension (n = 1) and anuria (n = 1). Underlying diagnosis included obstruction of the ureteropelvic junction (UPJ obstruction) in 3 children and posterior urethral valves in 7 children. Five children presented with urinoma, 3 children had a urinoma in combination with ascites and 2 children had isolated ascites. All children had reduced renal function at the time of diagnosis. In all 10 cases, the serum creatinine decreased after treatment. Scintigraphic investigation with mercapto-acetyltriglycerine (MAG III) demonstrated diminished function and perfusion of all 3 kidneys with UPJ obstruction and isolated urinoma even after treatment. Children with posterior urethral valves and urinoma revealed better function of the ruptured kidney and diminished function of the kidney which was not ruptured. One child with a rupture of the urinary bladder and urinary ascites showed good function and perfusion of both kidneys. CONCLUSION: Perinatal ruptures of the uropoietic system are rare. The clinical presentation is aspecific. One should consider a rupture of the urinary bladder or pyelum in a neonate with a distended abdomen, hydronephrosis and ascites. The long-term prognosis depends on the underlying diagnosis and the location of the rupture. Probably, a UPJ obstruction with an isolated urinoma is associated with irreversible renal damage of the ruptured kidney. A rupture resulting in urinary ascites apparently provides better decompression with better function of the ruptured kidney. Scintigraphic investigation is necessary for a separate evaluation of the single kidney function.

Negligible urinary cysteamine loss in cystinosis patients with Fanconi syndrome.

Cystinosis is an inborn error of lysosomal cystine transporter, resulting in cystine accumulation in lysosomes of all cells. Renal Fanconi syndrome is an early sign of kidney involvement in cystinosis patients. Cysteamine, a small amino-thiol, depletes intralysosomal cystine content and reduces organ damage. However, it does not reverse renal Fanconi syndrome and only postpones the progression to renal failure. We examined whether cysteamine could be lost in the urine of cystinosis patients with Fanconi syndrome, which may explain the inefficiency of treatment. Urinary cysteamine loss was studied in 6 cystinosis patients with and without Fanconi syndrome and was less than I% of ingested dose in all patients.

Effective treatment of peritoneal dialysis-associated peritonitis with cefazolin and ceftazidime in children.

OBJECTIVE: To evaluate the use of the combination of cefazolin and ceftazidime for initial treatment of peritoneal dialysis (PD)-related peritonitis in pediatric patients. DESIGN: Retrospective nonrandomized study. SETTING: Pediatric dialysis units of the University Medical Center of Utrecht and Nijmegen, The Netherlands. PATIENTS: 40 children (median age 5.4 years) who were treated with PD during the study period of 4.5 years. INTERVENTIONS: All 50 episodes of peritonitis that occurred during the study period were evaluated by review of medical records. Patients were given intraperitoneal ceftazidime 500 mg/L dialysis fluid, and cefazolin 500 mg/L as a loading dose, followed by a maintenance dose of ceftazidime 125 mg/L and cefazolin 100 mg/L, intraperitoneally, 4 times daily. Antibiotics were continued for 14 days. RESULTS: After identification of the causative microorganism, one of the antibiotics was discontinued in 34 cases, and the antibiotic schedule was adapted in 2 cases. All cases were initially cured within 3 days. In 5 cases (10%), there was a peritonitis with the same organism recurring within 2 weeks after completion of treatment. There were 4 cases of PD-related peritonitis caused by pseudomonas, all of which were cured. CONCLUSIONS: The antibiotic combination of cefazolin and ceftazidime is effective for the initial therapy of PD-related peritonitis in children. The toxic complications of aminoglycosides are avoided with this combination.

[Kidney insufficiency and persistent hypotension following compromise of the renin-angiotensin system in a fetus and a young infant]. / Nierinsufficiëntie en persisterende hypotensie na beïnvloeding van het renine-angiotensinesysteem bij een foetus en een jonge zuigeling.

A newborn girl had chronic renal failure following prenatal exposure to an angiotensin-converting enzyme (ACE) inhibitor, and a young infant with congenital nephrotic syndrome, showed persistent hypotension with neurological complications following bilateral nephrectomy at the age of 4 months. Both died. The renin-angiotensin system (RAS) is well-known for its regulatory function with respect to blood pressure, renal haemodynamics, fluid balance and electrolyte balance. Furthermore, its role in growth and differentiation of the kidneys and urinary tracts is becoming clearer. The RAS is highly important for the foetus and young infant. Extreme caution should be exercised with prenatal exposure to ACE inhibitors or angiotensin receptor blockers and bilateral nephrectomy in young infants.

The molecular basis of Dutch infantile nephropathic cystinosis.

Infantile nephropathic cystinosis, an inborn error of metabolism with an autosomal recessive inheritance pattern, is characterized by lysosomal storage of the amino acid cystine due to an impaired transport of cystine out of the lysosomes. Initial clinical features consist of the renal Fanconi syndrome and crystals in the cornea. Oral therapy with cysteamine lowers the intracellular cystine content. Recently, the gene coding for the integral membrane protein cystinosin, which is responsible for membrane transport of cystine (CTNS), was cloned. Mutation analysis of the CTNS gene of Caucasian patients revealed a common 57-kb deletion, and several other mutations spread throughout the entire gene. In the present study, we developed an improved screening method for the detection of the common 57-kb deletion. By use of this method we detected the 57-kb deletion in 59% of the examined Dutch alleles. The remaining alleles were screened for other mutations by genomic sequencing of the different exons, revealing three previously described mutations. Furthermore, we studied a possible genotype-phenotype relation of the homozygous deleted patients, which could not be demonstrated in our study population. Next to biochemical determination of cystine in leukocytes or fibroblasts, molecular genetic analysis enables prenatal diagnosis and facilitates identification of carriers.