Association of macrophage migration inhibitory factor −173C allele polymorphism with steroid resistance in children with nephrotic syndrome

The potential effects of macrophage migration inhibitory factor (MIF) on the natural immune response are due to the inhibition of immune cell activation, which is regulated by glucocorticoids. In this study, we investigated MIF –173G/C genotype and C allele frequency in 214 patients with idiopathic nephrotic syndrome (INS) and 103 healthy volunteers. We found significant increases in GC genotype (OR=3, p=0.0009) and C allele frequency (OR=2.5, p=0.0007) in INS. Upon classifying patients as steroid responsive (n=137) or resistant (n=77), a 20-fold over-expression of the CC-genotype was found in the steroid-resistant group (OR=20, p=0.0002). Moreover, a significant increase in C allele frequency in patients with focal segmental glomerulosclerosis (FSGS) has also been noted when compared with other histopathological groups (OR=3.2, p=0.0017). Furthermore, significant increases in the CC genotype (15.6% vs 3.3%) and C allele (75% vs 32%) frequencies have been found in patients with permanent renal function failure (p=0.013 and p=0.0002, respectively). Patients with the CC genotype were found to be at considerably increased risk of permanent renal failure (OR=5.43, p=0.013) and end-stage renal disease (OR=5.53, p=0.020). Additionally, there was a correlation between age of detection of proteinuria and CC genotype. We found an earlier age of onset of proteinuria in patients with the CC genotype (1.9±1.7 years) than in patients who were GC-heterozygous (3.7±3.1 years) and GG-homozygous (3.6±2.9 years, p=0.88). In summary, our results indicate that the MIF –173 C allele confers an increased risk of susceptibility to INS and plays a crucial role in glucocorticoid responsiveness.     

Has the incidence of childhood steroid sensitive nephrotic syndrome changed?

Nephrotic syndrome is among the most common types of pediatric kidney disease. However, there are few published data on its incidence and racial patterns. This study examines the incidence and racial patterns of childhood steroid sensitive nephrotic syndrome (SSNS). For the period 1/1/1996 to 12/31/2006, a retrospective chart review was performed of children less than 10 years of age who presented to Le Bonheur Children's Hospital in Memphis, TN with newly diagnosed SSNS. At the time of diagnosis, 38 children were found to reside in Shelby County, TN, with 31 children residing within the Memphis city limits. The annual incidence of SSNS in Shelby County was 2.4 cases/100,000 children. The incidence was higher in males (4.0/100,000) (p = 0.0002), children less than 5 years of age (3.6/100,000) (p = 0.007), and African Americans (3.7/100,000) compared to Caucasians (0.9/100,000) (p = 0.00006). These findings confirm that SSNS is a rare pediatric disease. They also suggest that the incidence of SSNS in Shelby County is comparable to that in prior reports. Our study is one of the first to show that SSNS may be more common in African Americans.     

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.     

Is there a role for rituximab in the treatment of idiopathic childhood nephrotic syndrome?

We each have nephrotic patients who become steroid dependent and in whom multiple immunosuppressive agents are employed. There is a need to balance possible therapeutic benefits with drug toxicity. This case report describes such a patient, who has suffered from nephrotic syndrome for over 11 years and had become resistant to the usual therapies. He was therefore given a single dose of the anti-CD20 drug rituximab, to which he showed a prompt response, leaving him free of proteinuria for the past 10 months.     

Association of IL-1β, IL-1ra, and TNF-α gene polymorphisms in childhood nephrotic syndrome

We investigated the association between IL-1, IL-1ra, and TNF- gene polymorphisms and childhood nephrotic syndrome (NS). We analyzed the genetic polymorphism of IL-1, IL-1ra, and TNF- genes in 152 patients with childhood NS and 292 healthy adult controls. The C to T exchange at position –511 of IL-1 and the G to A at –308 of the TNF- gene were genotyped. Five alleles of the IL-1ra gene were identified and designated as IL1RN*1, IL1RN*2, IL1RN*3, IL1RN*4, and IL1RN*5, according to the variable number of tandem repeats in intron 2. The allele frequencies of IL-11 (-511C), IL-12 (-511T), TNF1 (-308G), and TNF2 (-308A) were 53.0, 47.0, 92.1, and 7.9%, respectively, in the childhood NS group. This was not significantly different from normal controls. In the childhood NS group, the allele frequencies of IL1RN*1, IL1RN*2, IL1RN*3, IL1RN*4, and IL1RN*5 were 90.8, 7.6, 1.6, 0, and 0% [IL1RN*1 odds ratio (OR)=0.296, P=0.0001, IL1RN*2 OR=3.902, P=0.0002]. A high allele frequency of IL1RN*2 and a lower allele frequency of IL1RN*1 were found in childhood NS, although there was no association with IL-1 and TNF-. A high allele frequency of the IL1RN*2 allele may affect disease susceptibility in childhood NS.     

Adequate use of allele frequencies in Hispanics—a problem elucidated in nephrotic syndrome

Previous studies in children with focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome (NS) in the USA have revealed inter-ethnic differences in their clinical presentation and outcome. However, ethnicity was based on self-identification rather than on molecular genetic data. Here, we show that genetic heterogeneity exists in self-identified Hispanic (Spanish-American) patients with steroid-resistant nephrotic syndrome (SRNS), as patients may be either of Caucasian or Mesoamerican (Native-American) genetic background. Twenty-one self-identified Hispanic patients with SRNS from 18 families were initially evaluated for mutations in the NPHS2 and WT1 genes. All patients resided and were cared for in the USA. We performed a total genome search for linkage in all Hispanic patients using 250K single nucleotide polymorphism microarrays, comparing Caucasian with Mesoamerican allele frequencies to determine regions of homozygosity by descent and to establish the correct allele frequency for each family. We found that only ten families (56%) of the 18 self-identified Hispanic families are genetically of Mesoamerican descent, whereas the other eight families (44%) are of Caucasian descent. Due to the small number of families examined, we were unable to draw any conclusion on the prevalence of NPHS2 and WT1 in this ethnic group, but the data do suggest that self-identification of ethnicity in Hispanic-American patients is not an adequate basis for genetic studies, as this cohort may represent not only patients of Mesoamerican origin but also patients of Caucasian origin. Thus, one needs to critically review previous studies of FSGS/SRNS patients that involved Hispanic patients as a group. Future larger studies may employ a total genome search for linkage to test self-identified Hispanic ethnicity for true Mesoamerican versus Caucasian ethnicity in order to generate valid genetic data.     

Should hyperlipidemia in children with the nephrotic syndrome be treated?

 The pathogenesis, clinical significance, and treatment options of the disturbances in lipid metabolism in children with persistent nephrotic syndrome are reviewed. The lipoprotein profile is characterized by elevations of total plasma cholesterol and often triglycerides, elevated very low-density lipoprotein and low-density lipoprotein cholesterol, whereas high-density lipoprotein-cholesterol levels are variable; plasma levels of the atherogenic and thrombogenic lipoprotein(a) are also elevated. The pathophysiology of nephrotic dyslipoproteinemia is multifactorial, including both an increased hepatic synthesis and a diminished plasma catabolism of lipoproteins. There is a rationale for treatment, since dyslipidemia may contribute to the development of atherosclerosis and the progression of chronic renal failure. However, the benefits of treatment with lipid-lowering drugs have not been proven. Short-term studies in adults with nephrotic syndrome have documented safety and efficacy of lipid-lowering drugs, including hydroxymethylglutaryl-CoA reductase inhibitors (”statins”), bile acid sequestrants, fibric acids, fish oil, and probucol. Statins are the most-effective medication, resulting in a decrease of total cholesterol levels by about 30%–40%. Prospective controlled studies in children evaluating efficacy and safety of lipid-lowering drugs are needed. Received: 23 March 1998 / Revised: 15 June 1998 / Accepted: 15 June 1998     

Clinical features and outcome of childhood minimal change nephrotic syndrome: is genetics involved?

The pathogenesis of minimal change nephrotic syndrome (MCNS) is still unknown. We performed a clinical and genetic evaluation of 104 adults (mean age 35 years) who presented with MCNS in childhood (mean follow-up 30 years). Clinical data and the present health status were evaluated. Also, the genes encoding the four major slit diaphragm proteins, nephrin, podocin, Neph1 and CD2-associated protein were sequenced in 38 patients with MCNS of varying severity. MCNS presented at the mean age of 5 years, and 80% of the patients relapsed 1–28 (median 3) times during childhood. The 14 subjects (14%) who had proteinuric episodes still in adulthood had a refractory disease already as children. The participants did not show a strong tendency for allergy or immune diseases, and no familial clustering of MCNS was observed. The genetic analyses revealed heterozygous amino acid changes in nephrin and podocin in 10 of the 38 patients studied. On the other hand, the genes coding for Neph1 and CD2AP were highly conserved and no amino acid substitutions were detected. In conclusion, MCNS is a multifactorial disease, in which genetics play a minor role. Allelic variants of the podocyte proteins may, however, modify the phenotype in occasional individuals.Anne-Tiina Lahdenkari and Maija Suvanto contributed equally     

Obturator hip dislocation with intrapelvic migration of the femoral head in Ehlers–Danlos syndrome

Hypermobility of the joints is a cardinal feature of Ehlers-Danlos syndrome (EDS) and joint dislocation as a result of no or minor trauma, is a relatively frequent complication of any form, because of ligamentous laxity [1-3]. Hip dislocations are usually the result of high-energy trauma in young adults, with most being posterior [4-6]. Obturator hip dislocations are relatively rare injuries, accounting for no more than 7% of all traumatic hip dislocations [6, 7]. No obturator hip dislocation as a result of minor insult in EDS has yet been reported. We report an unusual case of obturator hip dislocation by minor insult in EDS, complicated by femoral neck fracture and intrapelvic migration of the femoral head occurring during closed reduction, and also suggest management relevant to this rare injury.     

Successful (?) therapy of hemolytic-uremic syndrome with factor H abnormality

We report a patient with continuously recurring hemolytic-uremic syndrome due to factor H deficiency. First at the age of 3 months he showed signs of hemolytic anemia, thrombocytopenia and renal insufficiency, often recurring concomitantly with respiratory tract infections, despite weekly to twice weekly plasma substitution (20 ml/kg body weight). Now at the age of 3.5 years glomerular filtration rate is approximately 50 ml/min/1.73 m² and psychomotoric development is normal. Since factor H is mainly synthesized in the liver, hepatic transplantation has been proposed as curative treatment. Before justification of liver transplantation as the ultimate treatment for these patients, an international registry should be developed to optimize and standardize therapeutic alternatives.     

The heart of children with steroid-resistant nephrotic syndrome: is it all podocin?

Mutations in the gene NPHS2 encoding podocin are responsible for a recessive form of steroid-resistant nephrotic syndrome (SRNS). The common phenotype is of massive proteinuria in early childhood that tends to progress to end-stage renal failure. Extrarenal manifestations have not been described. Twenty-two children with SRNS from six unrelated Arab families were found to be homozygous for the R138X mutation in NPHS2. Eighteen patients underwent cardiac evaluation at diagnosis of SRNS while they had normal BP and preserved renal function. Cardiac anomalies were detected in 16 (89%) children: Left ventricular hypertrophy in eight, pulmonary stenosis in six, discrete subaortic stenosis in two, and Ebstein anomaly and ventricular septal defect in one each. The remaining four affected individuals were assessed only once they had end-stage renal failure. They had severe left ventricular hypertrophy and experienced repeated episodes of heart failure. Two control groups were equally evaluated. The first consisted of 37 siblings without nephrotic syndrome, of whom only one carrier had a cardiac defect (P < 0.001). None of the second group, which included 22 children with persistent nephrotic syndrome as a result of other causes, had a cardiac anomaly (P < 0.001). Cardiac disorders in homozygotes for mutations in NPHS2 cannot be attributed to an association by chance or to a state of persistent nephrotic syndrome. Because human podocin mRNA is expressed in fetal heart, it is speculated that it may have a role in normal cardiac development. Cardiac evaluation is recommended at the time of diagnosis of SRNS due to mutations in podocin.     

Quantitative evaluation of the transplanted lin− hematopoietic cell migration kinetics

Stem cells take part in organogenesis, cell maturation and injury repair. The migration is necessary for each of these functions to occur. The aim of this study was to investigate the kinetics of transplanted hematopoietic lin⁻ cell population (which consists mainly of the stem and progenitor cells) in BALB/c mouse contact hypersensitivity model and quantify the migration to the site of inflammation in the affected foot and other healthy organs. Quantitative analysis was carried out with the real-time polymerase chain reaction method. Spleen, kidney, bone marrow, lung, liver, damaged and healthy foot tissue samples at different time points were collected for analysis. The quantitative data normalization was performed according to the comparative quantification method. The analysis of foot samples shows the significant migration of transplanted cells to the recipient mice affected foot. The quantity was more than 1000 times higher, as compared with that of the untreated foot. Due to the inflammation, the number of donor origin cells migrating to the lungs, liver, spleen and bone marrow was found to be decreased. Our data shows that transplanted cells selectively migrated into the inflammation areas of the foot edema. Also, the inflammation caused a secondary migration in ectopic spleen of hematopoietic stem cell niches and re-homing from the spleen to the bone marrow took place.     

The relationship between the TGF-β1 gene −509C/T polymorphism and tubulointerstitial damage resulting from primary nephrotic syndrome

Background: The aim of this study was to investigate the correlation between the transforming growth factor (TGF)-β1 gene ?509C/T polymorphism and the susceptibility to primary nephrotic syndrome (PNS), and in particular to the severe degree of tubulointerstitial damage (TID) seen in Chinese. Methods: Ninety-eight PNS patients and 128 normal controls were studied. The extent of tubulointerstitial changes was evaluated and patients were divided into two groups according to the severe or mild degree of TID. The TGF-β1gene ?509C/T polymorphism was detected with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique, and the serum level of TGF-β1 was determined by enzyme-linked immunosorbent assay (ELISA). Results: No statistical differences in genotype or allele frequency of the TGF-β1 gene ?509C/T were found between PNS and normal subjects. However, T allele and CT + T?T genotype frequency were higher in the PNS with severe TID than the mild TID and controls. Additionally, the serum concentration of TGF-β1 was significantly higher in the PNS with severe TID group than the other two groups and in the T?T genotype individuals than the CC and CT genotype individuals. A logistic regression analysis demonstrated that TGF-β1 gene ?509C/T genotype was the risk factor of TID in PNS patients [OR (odd ratio) 2.34, confidence interval (CI) 0.98–3.46, p = 0.012]. Conclusion. TGF-β1 gene ?509C/T polymorphism was associated with severe TID. The higher value in serum concentration of TGF-β1 was also associated with severe TID and the T?T genotype/T allele. T allele gene might be the important risk factor for susceptibility.     

Crescentic post-streptococcal glomerulonephritis with nephrotic syndrome in the adult: is aggressive therapy warranted?

The prognosis for adults with acute post-streptococcal glomerulonephritis (PSGN) who present with crescentic glomerulonephritis and nephrotic proteinuria is not known. We report a patient with rapidly progressive glomerulonephritis and nephrotic-range proteinuria following acute pharyngitis, in whom serologic and kidney biopsy findings led to a diagnosis of PSGN. The patient was treated with corticosteroids and anti-hypertensive medications resulting in improvement in renal function and decrease in proteinuria. These results suggest that aggressive treatment of crescentic PSGN with nephrotic syndrome can result in a favorable outcome.     

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

Several of the drugs currently used for the treatment of glomerular diseases are prescribed for their immunotherapeutic or anti-inflammatory properties, based on the current understanding that glomerular diseases are mediated by immune responses. In recent years our understanding of podocytic signalling pathways and the crucial role of genetic predispositions in the pathology of glomerular diseases has broadened. Delineation of those signalling pathways supports the hypothesis that several of the medications and immunosuppressive agents used to treat glomerular diseases directly target glomerular podocytes. Several central downstream signalling pathways merge into regulatory pathways of the podocytic actin cytoskeleton and its connection to the slit diaphragm. The slit diaphragm and the cytoskeleton of the foot process represent a functional unit. A breakdown of the cytoskeletal backbone of the foot processes leads to internalization of slit diaphragm molecules, and internalization of slit diaphragm components in turn negatively affects cytoskeletal signalling pathways. Podocytes display a remarkable ability to recover from complete effacement and to re-form interdigitating foot processes and intact slit diaphragms after pharmacological intervention. This ability indicates an active inside-out signalling machinery which stabilizes integrin complex formations and triggers the recycling of slit diaphragm molecules from intracellular compartments to the cell surface. In this review we summarize current evidence from patient studies and model organisms on the direct impact of immunosuppressive and supportive drugs on podocyte signalling pathways. We highlight new therapeutic targets that may open novel opportunities to enhance and stabilize inside-out pathways in podocytes.     

A case of minimal change nephrotic syndrome with acute renal failure complicating Hashimotoâs disease

A 63-year-old man was admitted to our hospital for evaluation of generalized edema. Coexistence of severe hypothyroidism and nephrotic syndrome was detected by laboratory examination. High titer of both antimicrosomal antibody and antithyroid peroxidase antibody indicated Hashimotoas disease. Renal biopsy showed minimal change glomerular abnormality, but no findings of membranous nephropathy. A series of medical treatments, including steroid therapy, thyroid hormone and human albumin replacement therapy, were administered. However, acute renal failure accompanied by hypotension, was not sufficiently prevented. After 9 sessions of plasmapheresis therapy, the severe proteinuria and low serum albumin levels were improved. Even after resting hypotension was normalized, neither renal function nor thyroid function were fully recovered. After discharge, renal function gradually returned to normal, and the blood pressure developed into a hypertensive state concomitant with the normalization of thyroid function. This report is a rare case of autoimmune thyroid disease complicated with minimal change nephrotic syndrome. In most cases of nephritic syndrome, acute renal failure (ARF) has been reported to coexist with hypertension. Although pseudohypothyroidism is well-known in nephrotic pathophysiology, complications of actual hypothyroidism are uncommon. It is suggested that the development of hypotension and ARF could be enhanced not only by hypoproteinemia, but also by severe hypothyroidism.