Steroid-resistant Patients Research Articles

Cytokine and anti-cytokine therapies for inflammatory bowel disease.

Although the pathogenesis of inflammatory bowel disease (IBD) remains elusive, it appears that there is chronic activation of the immune and inflammatory cascade in genetically susceptible individuals. Current disease management guidelines have therefore focused on the use of anti-inflammatory agents, aminosalicylates and corticosteroids. These conventional therapies continue to be a first choice in the management of IBD. Immunomodulators, such as azathioprine, 6-mercaptopurine, methotrexate or cyclosporin, are demonstrating increasing importance against steroid-resistant and steroid-dependent patients. However, some patients are still refractory to these therapies. Recent advances in the understanding of the pathophysiological conditions of IBD have provided new immune system modulators as therapeutic tools. Other immunosuppressive agents including FK506 and thalidomide have expanded the choice of medical therapies available for certain subgroups of patients. Furthermore, biological therapies have begun to assume a prominent role. Studies with chimeric monoclonal anti-TNF-alpha antibody treatment have been reported with dramatic successes. However, observations in larger numbers of treated patients are needed to explicate fully the safety of or risks posed by this agent such as developing lymphoma, or other malignancies. Another anti-inflammatory cytokine-therapy includes anti anti-IL-6R, anti-IL-12 or toxin-conjugated anti IL-7R, recombinant cytokines (IL-10 or IL-11). Given the diversity of proinflammatory products under its control, NF-kappaB may be viewed as a master switch in lymphocytes and macrophages, regulating inflammation and immunity. Although some of them still need more confirmatory studies, those immune therapies will provide new insights into cell-based and gene-based treatment against IBD in near future.

Broadening the spectrum of diseases related to podocin mutations.

A total of 179 children with sporadic nephrotic syndrome were screened for podocin mutations: 120 with steroid resistance, and 59 with steroid dependence/frequent relapses. Fourteen steroid-resistant patients presented homozygous mutations that were associated with early onset of proteinuria and variable renal lesions, including one case with mesangial C3 deposition. Single mutations of podocin were found in four steroid-resistant and in four steroid-dependent; five patients had the same mutation (P20L). Among these, two had steroid/cyclosporin resistance, two had steroid dependence, and one responded to cyclosporin. The common variant R229Q of podocin, recently associated with late-onset focal segmental glomerulosclerosis, had an overall allelic frequency of 4.2% versus 2.5% in controls. To further define the implication of R229Q, a familial case was characterized with two nephrotic siblings presenting the association of the R229Q with A297V mutation that were inherited from healthy mother and father, respectively. Immunohistochemistry with anti-podocin antibodies revealed markedly decreased expression of the protein in their kidneys. All carriers of heterozygous coding podocin mutation or R229Q were screened for nephrin mutation that was found in heterozygosity associated with R229Q in one patient. Finally, podocin loss of heterozygosity was excluded in one heterozygous child by characterizing cDNA from dissected glomeruli. These data outline the clinical features of sporadic nephrotic syndrome due to podocin mutations (homozygous and heterozygous) in a representative population with broad phenotype, including patients with good response to drugs. The pathogenetic implication of single podocin defects per se in proteinuria must be further investigated in view of the possibility that detection of a second mutation could have been missed. A suggested alternative is the involvement of other gene(s) or factor(s).

Other immunosuppressive agents for focal segmental glomerulosclerosis

A prolonged course with corticosteroids represents the first therapeutic approach for nephrotic patients with focal segmental glomerulosclerosis (FSGS). In patients with contraindications to steroids or in those who do not respond to steroids or cyclosporine, cytotoxic agents, mycophenolate mofetil (MMF), plasmapheresis, and low-density lipoprotein (LDL) apheresis have been tried as alternative treatments. A short-term treatment with cytotoxic agents often is ineffective in steroid-resistant patients However, an aggressive and prolonged treatment with cytotoxic agents combined with corticosteroids proved to be effective in more than half of steroid-resistant children. In adults, the response to cytotoxic agents was good in steroid-responsive patients, but was poor in steroid-resistant patients. Better results were observed when cytotoxic therapy was prolonged for several months. The problem with these drugs is that long-term immunosuppression may be complicated by severe side effects including a major risk for cancer. Uncontrolled studies reported that MMF can induce some reduction of proteinuria , but complete remission of proteinuria was rare and no data on long-term follow-up evaluation with this drug are available. Good results have been reported with plasmapheresis, immunoadsorption, and lipopheresis. However, all the reports were uncontrolled, small sized, and with short-term follow-up evaluation. In conclusion, there are several therapeutic options for patients who respond to steroids and have further relapses of nephrotic syndrome, but how to treat steroid-resistant patients is still a matter of debate. Nevertheless, a 6-month trial with cytotoxic agents or MMF can be offered to steroid-resistant patients to identify the few patients who respond to these agents. The preliminary results with plasmapheresis or lipopheresis are promising but further studies are needed to assess the role of these treatments. © 2003 Elsevier Inc. All rights reserved.

Cyclosporine in the treatment of idiopathic focal segmental glomerulosclerosis

Cyclosporine a known powerful immunosuppressive medication and has been used in the treatment of focal segmental glomerulosclerosis (FSGS) for over a decade. Its precise mechanism of action in this disorder is still debated and is likely at more than one level related to the pathophysiology of the disease. Multiple studies have been performed but the numbers of randomized trials of this drug in this disease are very limited. However, both the best studies in children and adults indicate in the steroid-resistant patients that 50% to 70% will have a response in terms of a significant reduction in proteinuria. Provided the total dose is kept to 5 mg/kg or less and duration to less than 12 months, the drug is safe but careful monitoring is required to maintain the blood pressure at ideal levels and to avoid nephrotoxicity. Relapses are common, but rather than considering this a failure of therapy the drug should be reintroduced because in most cases it will reestablish control of the proteinuria. Although in the past cyclosporine has been considered a second-line agent in FSGS, emerging data would suggest in the high-risk patients related to corticosteroid toxicity it should be considered primary therapy. © 2003 Elsevier Inc. All rights reserved.

Intra-arterial catheter directed therapy for severe graft-versus-host disease.

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), resulting in death in the majority of steroid-resistant patients. We assessed the efficacy of regional intra-arterial treatment in patients with resistant hepatic and/or gastrointestinal (GI) GVHD. In total, 15 patients with steroid resistant grade 3-4 hepatic (n = 4), gastrointestinal (GI) (n = 8) GVHD or both (n = 3) were given intra-arterial treatment. Patients with hepatic GVHD received methotrexate and methylprednisolone into the hepatic artery. Patients with GI GVHD were treated with infusions of methylprednisolone into the superior and inferior mesenteric arteries. Two patients with pronounced upper GI symptoms also received upper GI treatment. In total, 25 procedures were carried out (range 1-3 per patient). Hepatic response was observed in four out of seven (57%) patients with hepatic GVHD, three (43%) featuring good response. Complete responses were observed in nine (82%) GI GVHD patients, with median time to initial and complete response of 3 d (range 1-7) and 15.8 d (range 4-33) respectively. Regional treatment of severe GVHD with intra-arterial treatment appears to be effective and safe. GI treatment maybe more effective than intrahepatic treatment. Early administration of isolated intra-arterial therapy in high-risk patients may further improve the outcome and reduce untoward effects of systemic immunosuppressive treatment.

Prior bowel resections, perianal disease, and a high initial Crohn’s disease activity index are associated with corticosteroid resistance in active Crohn’s disease

OBJECTIVES: Some patients with Crohn’s disease (CD) do not respond to corticosteroid therapy. Furthermore, corticosteroids frequently cause side effects. Thus, predictive parameters for treatment refractoriness would be helpful for treatment decisions. METHODS: A total of 300 patients with active CD ( i.e., with a Crohn’s Disease Activity Index [CDAI] >200) entered the study. Treatment started with 60–100 mg/day prednisolone equivalent, which was then tapered to 10–15 mg/day within 6 wk and maintained at that dose for another 4 wk. After 10 wk of treatment, response to steroids was defined by a CDAI <150, steroid resistance by a CDAI always ≥150 and steroid dependency by a relapse after dose reduction. Of 239 eligible patients, 196 were responders, 26 were steroid resistant, and 17 were steroid dependent. RESULTS: Prior bowel resections, a high initial CDAI, and perianal disease were associated with steroid resistance. Of the steroid resistant patients 53.9% were bowel-resected compared to 20.4% of the responders (relative risk = 3.63; 95% CI = 1.79–7.36). Perianal disease was observed in 42.3% of steroid resistant patients versus 21.9% of responders (relative risk = 2.28; 95% CI = 1.12–4.66) and initial CDAI was 347 ± 91 in resistant patients versus 301 ± 81 in responders ( p < 0.05). Parameters for steroid dependent patients were not significantly different from those of responders. CONCLUSIONS: In this study (thus far the largest study for the evaluation of predictive factors for treatment refractoriness to corticosteroids in CD), only prior bowel resection, perianal disease, and a high initial CDAI were found to be predictive of resistance to steroid treatment.

Apolipoprotein E polymorphism in childhood nephrotic syndrome.

Recent clinical reports have demonstrated that the progression and prognosis of renal diseases are possibly influenced by apolipoprotein E (apoE) genotypes and alleles. In this study we investigated whether apoE genotypes and alleles can be a prognostic criterion for the steroid responsiveness in childhood nephrotic syndrome. One hundred and seven pediatric patients with primary idiopathic nephrotic syndrome and 83 healthy volunteers were enrolled in the study. Eighty-seven of the patients had steroid-sensitive nephrotic syndrome (SSNS) and 20 had steroid-resistant nephrotic syndrome (SRNS). The varepsilon2 allele frequency and varepsilon2/3 genotype frequency of the SNRS group were statistically higher when compared with SSNS and control groups ( P<0.05). The higher frequency of the varepsilon2 allele in steroid resistant nephrotic patients suggests that the varepsilon2 allele gives a possible genetic predisposition to steroid resistance in our population, but further studies are needed to clarify this subject.

Combined therapy of tacrolimus and corticosteroids in cyclosporin-resistant or -dependent idiopathic focal glomerulosclerosis: a preliminary uncontrolled study with prospective follow-up.

Cyclosporin has improved the outcome for steroid-resistant patients with focal glomerulosclerosis, but there is a proportion of patients that are either cyclosporin-resistant or suffer relapses, needing long-term therapy to sustain the remission. In these cases, preliminary reports suggest that tacrolimus could be an alternative therapy, but to date the evidence is limited to small series of patients with no long-term follow-up. In this study we analysed the efficacy and safety of a combined therapy of tacrolimus and steroids in 25 patients (mean serum creatinine= 1.24+/-0.49 mg/dl; mean proteinuria=10.2+/-9.5 g/day; mean serum albumin=2.4+/-0.58 g/dl) with idiopathic primary focal glomerulosclerosis and proven resistance to or dependence on cyclosporin A. After a 6 months trial of tacrolimus and steroids, proteinuria decreased in 17 patients (68%) (complete remission in 10 patients (40%), partial remission in two patients (8%) and a moderate reduction in proteinuria to levels <3 g/day was seen in five additional patients (20%)). The only predictor of response to tacrolimus was a previous response to cyclosporin and prednisone, either as a complete or partial remission (remission rate 75% vs 15.3; P=0.036). Mean time to remission was 112+/-24 days. After tacrolimus discontinuation, 13/17 patients (76%) relapsed and were treated with a second trial of tacrolimus for 1 year, achieving complete remission in five patients (38.4%), partial remission in four patients (30.7%) and reduction of proteinuria <3 g/day in four patients (30.7%). After 2 years of follow-up, 12 patients (48%) were on sustained remission. The main side effect was acute reversible nephrotoxicity (40%). Predictors of renal toxicity were age (P=0.037), baseline creatinine (P=0.046) and tacrolimus trough level (P=0.001). We conclude that combined therapy of tacrolimus and steroids induce sustained remission of proteinuria in a significant number of patients with idiopathic focal glomerulosclerosis whose disease was not controlled by the standard therapy of steroids and cyclosporin A.

Significantly Rapid Relief from Steroid-Resistant Nephrotic Syndrome by LDL Apheresis Compared with Steroid Monotherapy

Rapid amelioration of hypercholesterolemia by LDL apheresis (LDL-A) was performed for long-standing nephrotic syndrome (NS) with hyperlipidemia due to focal segmental glomerulosclerosis (FGS) and the clinical data and prognosis were compared between LDL-A-treated and nontreated groups. Seventeen steroid-resistant NS patients treated with LDL-A (LDL-A group) and 10 NS patients treated with steroids only (steroid-monotherapy (SM) group) were compared. Serum cholesterol and phospholipid levels were significantly lowered only in the LDL-A group (p < 0.01, respectively). The LDL-A group showed a significant decrease of urinary protein (UP, p < 0.01) and increase of serum albumin (p < 0.05). Average time needed to achieve a decrease of UP to less than nephrotic range (< 3.5 g/day) was significantly shorter in the LDL-A group than in the SM group (p < 0.01). Although this is not a prospective study, it is highly expected that a rapid improvement of hypercholesterolemia by LDL-A in steroid-resistant NS will provide more rapid relief from NS than steroid therapy alone.

Increased serum and urinary neopterin in nephrotic syndrome indicate cell-mediated immune dysfunction.

T-cell-mediated immune disturbances are likely but not certain to cause the nephrotic syndrome. Because neopterin (NP) production is closely related to activation of cell-mediated immunity, we addressed the question by measuring serum NP concentrations and urinary NP/creatinine (Cr) ratios, as well as by assessing interstitial lymphocyte and monocyte infiltration in the kidney and activation of the same cell types in peripheral blood. Finally, we observed whether urinary NP/Cr ratios in nephrotic syndrome are changed by steroid therapy. Seventy-four patients with primary glomerulonephritis were divided into 4 groups based on presence or absence of nephrotic syndrome and presence or absence of mesangial proliferation and expansion. Serum and urinary NP concentrations were measured chromatographically. Infiltrating cells in the kidney were identified by immunohistochemistry, and activation of peripheral blood cells was examined by fluorescent surface marker antibodies and flow cytometry. Irrespective of the pathohistology of glomeruli, nephrotic groups showed significantly higher urinary NP/Cr ratios and serum NP concentrations. Nephrotic groups also exhibited more activation of T cells in peripheral blood than did nonnephrotic groups or a healthy control group. Serum NP did not correlate with extent of interstitial renal infiltrates. Steroid therapy decreased urinary NP/Cr ratios in steroid-responsive patients, but not in steroid-resistant patients. Increased serum NP concentrations and urinary NP/Cr ratios may reflect disordered cell-mediated immunity in the nephrotic syndrome, irrespective of glomerular histology or interstitial cell infiltration.

Intravenous cyclosporin in ulcerative colitis: a five-year experience.

Cyclosporin (CSA) is a promising alternative for patients with severe steroid-refractory ulcerative colitis (UC) previously facing only surgical options. Concerns over the long term efficacy and side effects resulted in this investigation of the University of Chicago's 5-yr CSA experience in these patients. All steroid-refractory severe ulcerative colitis (UC) patients treated with IV CSA from 1991 to 1995 were identified by using the university's IBD database, with additional information from patient charts and physician files. A total of 42 patients with severe UC unresponsive to IV steroids were treated with IV CSA (4 mg/kg/day). Of 42 patients, 36 (86%) responded; 31 were continued on oral CSA (8 mg/kg/day) for an overall mean of 20 wk. Ten initial CSA responders had colectomies after a mean of 6 months. Of the 36 initial responders, 25 (69%) also received 6-mercaptopurine (6-MP) or azathioprine (aza), and CSA and steroids were tapered. A total of 20% required colectomy, vs 45% of those not receiving 6MP/aza. In all, 62% of all patients, 72% of initial CSA responders, and 80% of initial CSA responders receiving 6MP/aza have avoided colectomy, with a life table analysis of "noncolectomy survival" of 58%, 70%, and 71%, respectively, at 5.5 yr. All colectomies occurred within 18 months of CSA initiation. Complications, resulting in CSA discontinuation in six patients, were all reversible, with complete recovery. CSA successfully allows most severe steroid resistant UC patients to retain their colons, and provides time for "elective" colectomy in others, especially if 6MP/aza are also given. Careful monitoring for side effects, including PCP prophylaxis, should be part of the treatment protocol.

Intravenous cyclosporin in ulcerative colitis: a five-year experience

OBJECTIVE: Cyclosporin (CSA) is a promising alternative for patients with severe steroid-refractory ulcerative colitis (UC) previously facing only surgical options. Concerns over the long term efficacy and side effects resulted in this investigation of the University of Chicago’s 5-yr CSA experience in these patients. METHODS: All steroid-refractory severe ulcerative colitis (UC) patients treated with IV CSA from 1991 to 1995 were identified by using the university’s IBD database, with additional information from patient charts and physician files. RESULTS: A total of 42 patients with severe UC unresponsive to IV steroids were treated with IV CSA (4 mg/kg/day). Of 42 patients, 36 (86%) responded; 31 were continued on oral CSA (8 mg/kg/day) for an overall mean of 20 wk. Ten initial CSA responders had colectomies after a mean of 6 months. Of the 36 initial responders, 25 (69%) also received 6-mercaptopurine (6-MP) or azathioprine (aza), and CSA and steroids were tapered. A total of 20% required colectomy, vs 45% of those not receiving 6MP/aza. In all, 62% of all patients, 72% of initial CSA responders, and 80% of initial CSA responders receiving 6MP/aza have avoided colectomy, with a life table analysis of “noncolectomy survival” of 58%, 70%, and 71%, respectively, at 5.5 yr. All colectomies occurred within 18 months of CSA initiation. Complications, resulting in CSA discontinuation in six patients, were all reversible, with complete recovery. CONCLUSIONS: CSA successfully allows most severe steroid resistant UC patients to retain their colons, and provides time for “elective” colectomy in others, especially if 6MP/aza are also given. Careful monitoring for side effects, including PCP prophylaxis, should be part of the treatment protocol.

Intravenous immune globulin (i.v.IG) therapy in steroid-resistant atopic dermatitis.

Many trials have been done on steroid-resistant atopic dermatitis. Recently, intravenous immune globulin (i.v.IG) was reported to be effective in the treatment of steroid-dependent atopic dermatitis. The aim of this study was to clarify whether i.v.IG therapy is effective in steroid-resistant atopic dermatitis. Forty-one steroid-resistant atopic dermatitis patients were tested in this study. Patients who weighed less than 30 kg were administered 500 mg/kg of i.v.IG. Patients who weighed 30 kg or more were administered 15 g of i.v.IG. Patient evaluations and laboratory tests with peripheral bloods such as eosinophil percentages and serum IgE levels were performed at days 0, 1, 7, and 21. In the present study, patients who responded to i.v.IG therapy were classified as Group A. Twelve patients who showed transient effects with lower clinical significance were classified as Group B (29.3%). Remaining 12 patients (29.3%) in Group C showed no improvement at all. Serum IgE levels and blood eosinophil percentages were markedly decreased in Group A. I.v.IG therapy may be recommended in the treatment of atopic dermatitis with extremely high serum IgE levels.

Long-term results of cyclosporine-induced remission of relapsing nephrotic syndrome in children.

Twenty-nine children with nephrotic syndrome were treated with cyclosporine (CsA), 100 mg/m2/day for 6 months and prednisone, 2 mg/kg every other day for 1 month and then subsequently 1 mg/kg every other day for 5 months. A renal biopsy had shown minimal change disease (MCD) in 18 children, focal segmental glomerulosclerosis (FSGS) in 3 children, membranous glomerulonephritis (MGN) in 4 children, membranoproliferative glomerulonephritis (MPGN) in 2 children, and IgA nephropathy in 2 children. All MCD patients went into complete remission during therapy. Five out of 11 steroid-sensitive patients (45.5%) remained in complete remission, while the remaining 6 (54.5%) had 2 to 3 relapses, 19 to 47 months after CsA discontinuation. Two out of 7 steroid-resistant patients (28.6%) were still in complete remission and 5 (71.4%) had 1 to 6 relapses 25 to 49 months after CsA withdrawal. The mean number of relapses in the steroid-sensitive group before and after CsA treatment decreased more (8.5 vs 1.4) than in the steroid-resistant group (8.1 vs 2.4) (p < 0.05). At the most recent examination, 1 of 3 FSGS patients achieved complete remission and 2 had a partial response. Three of 4 MGN patients were in complete remission and 1 was in partial remission. One of 2 MPGN patients achieved complete remission and 1 showed partial remission. Two patients with IgA nephropathy were in partial remission. We compared MCD patients in sustained remission and relapse; the mean CD4/CD8 ratio decreased from 1.5 to 0.9 in the remission group, in comparison with no change in the relapsed group (p < 0.05). The posttreatment renal biopsy showed lesions of nephrotoxicity in 3 of 18 children with MCD whose renal function did not alter after CsA treatment. We concluded: 1) A 6-month treatment of CsA, in combination with a low-dose alternate-day steroid, proved to be effective in maintaining the remission of steroid-sensitive and steroid-resistant MCD patients. 2) The CD4/CD8 ratio can be used as a index to predict remission or relapse after CsA therapy.

Comparison of noninvasive methods for distinguishing steroid-sensitive nephrotic syndrome from focal glomerulosclerosis

Although renal biopsy is the definitive investigation in kidney disorders and is particularly helpful in distinguishing steroid-responsive nephrotic syndrome (SRNS) from focal glomerulosclerosis (FGS), it is attended by a small risk to the patient. Accordingly, noninvasive tests have been used to predict the response to steroids and the underlying renal histologic diagnosis in nephrotic syndrome. The performance of these tests has, however, not been encouraging. We have therefore compared the reliability of the conventional selectivity index (SI) of serum and urinary transferrin and immunoglobulin G (IgG) against other tests of urinary proteins, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE), and isoelectric focusing (IEF). SI, SDS PAGE, and IEF were carried out in children with nephrotic syndrome within 2 months of clinical presentation. Thirty-one children who had SRNS were compared with 26 who had biopsy-proved FGS and who were steroid resistant. SDS PAGE and IEF revealed excretion of albumin and transferrin only, with homogeneous anionic charge, respectively, in SRNS but unrestricted excretion of additional proteins IgG, β 2-microglobulin, and lysozyme with heterogeneity of electrical charge in FGS. With SDS PAGE and IEF we were able to predict all children who had SRNS and FGS; the SI test predicted all steroid-resistant patients with FGS but was able to predict only 41.7% of the patients with SRNS. Therefore the negative predictive value for steroid response was 58.8% by SI and 100% by SDS PAGE and IEF; the positive predictive value was 100% by SI, SDS PAGE, and IEF. We illustrate the value of SDS PAGE in guiding management in a further seven children with FGS in whom there was either an initial discordance between renal biopsy results and steroid responsiveness or when biopsy was delayed. Accordingly, SDS PAGE and IEF of urinary proteins appear to be useful tests in the diagnosis and management of SRNS and FGS.

Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma.

Glucocorticosteroids are a very effective treatment for asthma and other chronic inflammatory diseases. However, a small proportion of patients is resistant to the therapeutic effects of glucocorticoids. Pharmacokinetic and ligand binding studies suggest that the molecular abnormality in steroid resistance lies distal to nuclear translocation. We have previously reported that there is a decreased ability of glucocorticoid receptors (GR) to bind to the DNA-binding site in peripheral blood mononuclear cells (PBMC) after dexamethasone treatment. This reduced DNA binding was due to a decrease in the number of receptors available rather than an alteration in affinity for DNA. To study this reduced DNA binding, we examined the ability of the nuclear translocated transcription factors activator protein 1 (AP-1), nuclear factor kappa B (NF-kappa B) and cyclic AMP response element-binding protein (CREB) to bind to their DNA-binding sites and to interact with GR in PBMC from patients with steroid-sensitive and steroid-resistant asthma. There was a significant reduction in the interaction between GR and AP-1 in these steroid-resistant patients, although interaction with other transcription factors activated in inflammation (NF-kappa B and CREB) was unaffected. An increase in the basal levels of AP-1 DNA binding was also detected in the nuclei from steroid-resistant asthmatic patients. There were no differences in the amount of messenger RNA detected for the components of AP-1, c-Fos and c-Jun, nor in the sequences of these messenger RNAs. These results suggest either that the ability of the GR to bind to glucocorticoid response elements and AP-1 is altered in steroid-resistant patients or that increased levels of AP-1 prevent GR DNA binding, and that this may be the molecular basis of resistance to the antiinflammatory effect of steroids in these cells.

Management of the Difficult Nephrotic Patient

Most children with nephrotic syndrome do well, usually with multiple relapses and remissions. Some children require high doses of oral steroids to sustain a remission and develop significant steroid toxicity. These patients frequently can be managed with oral alkylating agents or with cyclosporine. A few nephrotic children to not respond to oral prednisone. The most common biopsy finding in steroid-resistant patients is focal segmental glomerulosclerosis. Many patients with this condition progress to chronic renal failure. Evidence suggests that the outcome is improved with either cyclosporine or with a protocol using pulse intravenous methylprednisolone and oral alkylating agents.

Differences in binding of glucocorticoid receptor to DNA in steroid-resistant asthma.

Although glucocorticosteroids are a very effective treatment for asthma and other chronic inflammatory diseases, a small proportion of patients are resistant to their therapeutic effects. The molecular mechanism for this steroid resistance is unclear. Steroid resistance cannot be explained by pharmacokinetic mechanisms, by a defect in the binding of steroids to glucocorticoid receptors, nor by defective nuclear translocation of this receptor, thereby suggesting that the molecular abnormality lies distal to nuclear translocation. We examined the ability of nuclear translocated glucocorticoid receptors to bind to their DNA binding sites (GRE) using electrophoretic mobility shift assays in PBMC from patients with steroid-sensitive and steroid-resistant asthma. The binding of the glucocorticoid receptor to DNA in these patients was also studied using Scatchard analysis. Dexamethasone induced a significant rapid and sustained twofold increase in GRE binding in PBMCs from steroid-sensitive asthmatic patients and nonasthmatic individuals, but this was markedly reduced in steroid-resistant asthmatic patients. Scatchard analysis of glucocorticoid receptor-GRE binding showed no change in binding affinity but did show a reduced number of receptors available for DNA binding in the steroid-resistant patients. These results suggest that the ability of the glucocorticoid receptor to bind to GRE is impaired in steroid-resistant patients because of a reduced number of receptors available for binding to DNA.

Steroid-resistant, cyclosporine-responsive, relapsing nephrotic syndrome

Eighteen children with steroid-resistant nephrotic syndrome received cyclosporine A (CsA), including 7 patients with minimal change disease, 4 with focal segmental glomerulosclerosis and 7 with mesangial hypercellurarity. Doses were adjusted to maintain whole blood trough levels at 80-200 ng/ml and ranged from 5 to 10 mg/kg (mean 7 mg/kg). Fourteen patients responded after 2 months of therapy with either a complete or partial remission, and received a total of 12 months of CsA with low-dose corticosteroids. Remission rates were similar among the three histological types, although complete remissions occurred more commonly in minimal change disease, while the other two histological types tended to have partial responses. Serum creatinine values ranged from 0.3 to 1.2 mg/dl at the start of treatment and were stable in 17 of 18 patients during CsA therapy. CsA was discontinued after 12 months in 11 responders. Relapses were a significant problem. Nine patients had 16 relapses, all occurring within 6 months after discontinuing CsA; 13 of 16 relapses responded to CsA and corticosteroids. Five children had multiple relapses. Three patients who initially responded to treatment had CsA-resistant relapses. There were no differences among the histological types with respect to the occurrence of relapses or response to CsA after relapsing. Four patients developed chronic renal failure, including 2 of 4 who failed initial therapy and 2 of 3 who developed CsA-resistant relapses. In conclusion, initial therapy with CsA was effective in resolving nephrotic syndrome in steroid-resistant patients. However, CsA dependency, frequent relapses and the development of chronic renal failure presented significant problems.

Outcome in Idiopathic Childhood Nephrotic Syndrome

112 patients with idiopathic childhood nephrotic syndrome have been referred from 1970 through 1989 at the Department of Pediatrics, University of Berne. One patient remitted spontaneously without medication. Ninety-eight patients responded to prednisone: 15 had a single bout of nephrosis, 47 developed a tendency towards relapses and 36 steroid dependence. In 28 patients with tendency towards relapses cure took place on either prednisone alone or prednisone plus cyclophosphamide. In 18 patients with steroid dependency cure took place on prednisone alone or prednisone plus cyclophosphamide. Thirteen patients failed to respond to steroids. The course of the disease was more benign in 68 patients with minimal change disease as compared with 14 patients with focal and segmental glomerular sclerosis. Immunofluorescence studies demonstrated mesangial IgM deposits in 14 out of 54 patients, but this finding was not a marker for poor steroid response or progression to renal failure. The course of the disease was especially unfavourable in patients with persisting nephrosis on completion of the initial course of steroid therapy. In conclusion it appears appropriate to define the disease in terms of steroid responsiveness as steroid resistant patients sometimes show normal glomeruli, steroid responsive sometimes have focal and segmental glomerular sclerosis or mesangial IgM deposits, and decisions depend more on the steroid responsiveness than on the histological features.