Chlorambucil treatment of frequently relapsing nephrotic syndrome

Chlorambucil, in combination with prednisone, was compared with prednisone alone in a randomized controlled trial in 21 children with either steroid-dependent or frequently relapsing nephrotic syndrome to assess its effect on the duration of remission and the rate of relapse. All control patients treated with prednisone alone continued to relapse at the same rate, with all patients experiencing a return of proteinuria by seven months. Conversely, those who received the same prednisone therapy along with chlorambucil for six to 12 weeks remained in complete remission, without further medication, during 12 to 34 months of follow-up observation. Complications were minimal. Immediate side effects commonly reported with cyclophosphamide were not seen with chlorambucil. Comparison with published reports also suggests that remission induced by chlorambucil is more stable than that after cyclophosphamide. Chlorambucil appears to be of value in the frequently relapsing nephrotic patient, adding an effect that is unattainable with prednisone alone.     

Fish oil therapy in IgA nephropathy

IgA nephropathy often progresses to endstage renal failure over a period of many years, and any therapy directed to IgA nephropathy will most likely have to be administered over an extended period of time. Therefore, optional therapy should be effective and free of long-term adverse effects. Besides fish oil, prednisone has also been investigated for treatment of IgA nephropathy, with a lack of consistent results; severe adverse effects are common with long-term use. Several studies have shown positive although not overly impressive results; therefore optimal therapy for slowing the progression of renal failure secondary to IgA nephropathy has not been established. Problematic issues with available studies included the following: (1) most of the clinical studies previously discussed were short-term, contained small numbers of patients, and most but not all were uncontrolled; (2) early reports involving fish oil therapy demonstrated conflicting results regarding its efficacy, including one study that observed increased progression of renal disease in patients treated with fish oil; however, recent studies have shown more promise for fish oil therapy for up to 2 years of treatment; and (3) since most of the studies were conducted over a short period of time, it is difficult to assess long-term effects and safety of oil treating IgA nephropathy, a disease that progresses to ESRD over 10-20 years. However, given the low number of adverse effects and apparent low risks associated with this relatively safe food supplement therapy observed in most clinical trials of up to 2 years duration, fish oil may slow the progression of renal failure in patients with IgA nephropathy. Therefore, with appropriate monitoring of renal function and blood tests, treatment with fish oil 6-12 g/d should be considered in patients with IgA nephropathy.     

Antihuman immunoglobulin affinity immunoadsorption strongly decreases proteinuria in patients with relapsing nephrotic syndrome

An in vitro study was undertaken to investigate the potential for cellular telephones to interfere with representative models of presently used ICDs. Digital cellular phones (DCPs) generate strong, amplitude modulated fields with pulse repetition rates near the physiological range sensed by the ICD as an arrhythmia. DCPs with Time Division Multiple Access (TDMA) pulsed amplitude modulation caused the most pronounced effect--high voltage firing or inhibition of pacing output of the ICDs. This electromagnetic interference (EMI) occurred only when the phones were within 2.3-5.8 cm of the ICD pulse generator that was submerged 0.5 cm in 0.18% saline. ICD performance always reverted to baseline when the cellular phones were removed from the immediate proximity of the ICD. Three models of ICDs were subjected to EMI susceptibility testing using two types of digital phones and one analog cellular phone, each operating at their respective maximum output power. EMI was observed in varying degrees from all DCPs. Inhibition of pacer output occurred in one ICD, and high voltage firing occurred in the two other ICDs, when a TDMA-11 Hz DCP was placed within 2.3 cm of the ICD. For the ICD that was most sensitive to delivering unintended therapy, inhibition followed by firing occurred at distances up to 5.8 cm. When a TDMA-50 Hz phone was placed at the minimum test distance of 2.3 cm, inhibition followed by firing was observed in one of the ICDs. EMI occurred most frequently when the lower portion of the monopole antenna of the cellular phone was placed over the ICD header.     

The treatment with levamisole of frequently recurring steroid-sensitive idiopathic nephrotic syndrome in children

BACKGROUND AND OBJECTIVE: The treatment of frequently relapsing steroid-sensitive nephrotic syndrome in children with established immunosuppressive drugs (steroids, cyclophosphamide, cyclosporin A) sometimes presents problems because of the expected incidence of side effects. Stimulation of the immune system with the anthelminthic drug levamisole in this disease has been documented. Aim of this study was to assess in a prospective but uncontrolled series of observations its value and side effects. PATIENTS AND METHODS: 25 patients (15 boys, ten girls; median age 10 [3.5-22] years) were given levamisole, 2 mg/kg/48 h. Before this treatment was started eight of the children/adolescents (32%) had frequent relapses and 17 (68%) had become steroid-dependent. Treatment was started during steroid-induced remission and continued for 3-24 (median 6) month, while steroids were discontinued after four weeks. RESULTS: Relapse frequency per patient month was reduced from a mean of 0.5 (0.33-0.83) before to 0.31 (0-0.67) during levamisole administration (P < 0.001). In 12 patients (48%) no or considerably fewer relapses were observed. Patients with exclusively frequent relapses responded to levamisole better than those with steroid dependence (7/8 [87.5%] vs. 5/18 [27.7%], P = 0.01). Side effects were reversible leukopenia in two patients and nonspecific skin rash as well as epigastric pain in one patient. CONCLUSION: Levamisole is an efficacious addition or alternative, with a low incidence of side effects, in the treatment of frequently relapsing nephrotic syndrome, particularly so in yet steroid-dependent patients.     

The polymorphism of the immunoglobulin heavy chain switch region gene in IgA nephropathy, Henoch-Sch?nlein nephritis and idiopathic nephrotic syndrome

It is well known genetic predisposition may play an important role in the pathogenesis of renal diseases. Recently, there has been some controversy about the possible role of the polymorphism of the immunoglobulin heavy chain switch region gene. We have studied this gene by SstI restriction fragment length polymorphisms using DNA from 41 children with IgA nephropathy, 44 with Henoch-Sch?nlein nephritis and 60 with idiopathic nephrotic syndrome. There was no association of specific genotype with these diseases, in contrast to previous reports. These results are probably due to the differing genetic background of Japanese and Caucasoid patients as far as the switch region is concerned; no switch region genotype constitutes a genetic risk factor for the Japanese in these diseases.     

Fish oil therapy for IgA nephropathy: efficacy and interstudy variability

Published reports examining the efficacy of fish oil for preserving renal function in immunoglobulin A (IgA) nephropathy have yielded conflicting results. This investigation was a meta-analysis conducted to determine whether the medical literature supports this therapy. In addition, the sources of variability among published findings were examined. Studies were combined using a random effects model. Five controlled studies were identified, two with positive results and three with negative results. Forty-four percent of the between-study variance could be attributed to differences in follow-up times and, less significantly, the number of renal function measurements; a weighting procedure was developed, eliminating this variance from the combined result. When all studies were combined, the mean effect, +0.25 +/- 0.23 SD (positive effects indicate that treatment was superior to control), was not statistically significant; however, the probability of at least a minor beneficial effect was 75%. Mixed-effects regression suggested that this therapy may be more effective among individuals with more proteinuria. The medical literature, therefore, does not prove the efficacy of fish oil therapy in IgA nephropathy, but suggests that an additional placebo-controlled trial is warranted. A sample-size calculation indicated that such a trial should be larger than those to date or should attempt to increase the treatment effect, perhaps by treating for more than 2 yr or enrolling more severely proteinuric individuals.     

Current concepts and controversies in IgA nephropathy

A randomized, open trial involving 260 Tanzanian children, aged 1-5 years, with acute Plasmodium falciparum malaria was conducted to evaluate the efficacy of the combination antimalarial CGP 56697 (artemether and benflumetol), and to compare it with chloroquine, the standard drug used for malaria treatment in the Kilombero area. Children who had received rescue medication within the first 48 h or had a negative slide at the same time were excluded. Seven-day parasitological cure rates were 94% (95% CI 88-97.5) for CGP 56697 and 35.4% (95% CI 25.9-45.8) for chloroquine. Using the same definition, the 14-day parasitological cure rates were 86.4% (95% CI 78.5-92.2) for CGP 56697 and 10.3% (95% CI 5.1-18.1) for chloroquine. Gametocytes were more effectively suppressed by CGP 56697 than by chloroquine. There were no major adverse events with either drug. CGP 56697 is highly efficacious against P. falciparum in this area of Tanzania. The study contributes to the discussion on treatment strategies, particularly whether chloroquine may still fulfil its role as first-line drug in an area of high malaria transmission and very high levels of chloroquine resistance.     

Cyclosporin A therapy for severe solar urticaria

Solar urticaria is characterized by itching weals that occur a few minutes after exposure to visible or ultraviolet light. The symptoms may sometimes restrict normal daily life. Treatment is difficult in more severe cases. We describe one patient with solar urticaria who was successfully treated with cyclosporin A. The patient had first been treated with antihistamine, PUVA and chloroquine phosphate without effect. Cyclosporin was given in a dose of 4.5 mg/kg body weight/day. Phototesting before, during and after treatment showed a decreased light sensitivity to UVA, UVB and visible light during cyclosporin treatment compared with phototesting before therapy. The patient could be out in the sun for at least 1 h with minimal urticaria during cyclosporin therapy compared with only a few minutes previously. However, 1-2 weeks after cyclosporin therapy was discontinued, skin symptoms returned. Cyclosporin therapy is a possible treatment in severe cases of solar urticaria where other treatments have failed, especially in countries where treatment is necessary only for a few months during summer.     

Acute renal failure and nephrotic syndrome with alpha interferon therapy

Analysis of dimethylsulfoxide reductase from Rhodobacter capsulatus showed that it contained 1 mol Mo and 2 mol GMP. This indicates that the molybdenum cofactor in dimethylsulfoxide reductase is bis(molybdopterin guanine dinucleotide) molybdenum. The absorption spectrum of the molybdopterin guanine dinucleotide released from dimethylsulfoxide reductase after denaturation of the holoenzyme was compared with those of pterin standards of known redox state. The spectra were most similar to pterin standards in the dihydro state and oxidised state. The reduction of 2,6-dichloroindophenol by molybdopterin guanine dinucleotide released from dimethylsulfoxide reductase and by pterin standards was also measured and approximately 2 mol electrons/2 mol molybdopterin guanine dinucleotide were found to reduce 2,6-dichloroindophenol. These results are consistent with the presence of one molybdopterin guanine dinucleotide moiety with a pyrazine ring at the oxidation level of a dihydropteridine and one molybdopterin guanine dinucleotide moiety with a pyrazine ring at the oxidation level of a fully aromatic pteridine. It is suggested that the pyrazine ring of Q-molybdopterin guanine dinucleotide is fully aromatic and contains a 5,6 double bond.     

A post-thymomectomy case of myasthenia gravis which developed nephrotic syndrome with membranous nephropathy during azathioprine administration

We report a 46-year-old woman who has been suffered from myasthenia gravis and underwent thymomectomy in December 1988. Her myasthenic symptoms improved by treatment with corticosteroid and azathioprine; the latter drug was administrated for more than one year. She noticed weight gain of 10 kg and edema in both legs and feet, which developed acutely in August 1994. Laboratory data showed that she suffered from nephrotic syndrome with a large amount of proteinuria (15 g/day). Renal biopsy revealed that biopsied glomeruli showed early stage of membranous nephropathy associated with acute tubular necrosis. Although therapeutic trials of steroid pulses could not eliminate proteinuria, substitution of cyclophosphamide for azathioprine brought marked improvement of the nephrotic syndrome with disappearance of the urinary protein excretion within 10 days. From reports of similar cases with myasthenia gravis in Japan and in Europe, therapeutic usage of azathioprine in patients with myasthenia gravis associated with thymoma should be cautious for appearance of nephrotic syndrome when azathioprine is continued for more than one year.     

Morphologic high-risk factors in IgA nephropathy

The 2-benzoylthiophene chromophore of the photosensitizing drug tiaprofenic acid and of its decarboxylated derivative is characterized by a unusually high energy gap between the T1 (pi, pi*) and T2 (n, pi*) excited states, which makes this a unique system to study the intrinsic photoreactivity of the two states. Weak fluorescence and phosporescence emission were detected at room temperature. Tiaprofenic acid undergoes photodecarboxylation from the triplet manifold as the main reaction. The photoprocess is temperature dependent with activation energy of 7-10 kcal/mol, close to the energy gap between T1 and T2. The decarboxylated product abstracts hydrogen in type I reactions. The involvement of T2 in the above processes is proposed. Moreover the decarboxylated derivative exhibits reactivity toward phenols, consistent with a participation of the T1 state as electron acceptor. The observed photoprocesses can account for biological photosensitization reactions, like membrane damage and protein modification.     

Systemic and mucosal IgA responses to systemic antigen challenge in IgA nephropathy

IgA nephropathy (IgAN) is characterized by the deposition of glomerular IgA. The source of the deposited IgA is not known, but both the mucosal and systemic IgA systems have been implicated. In order to investigate mucosal and systemic antibody production to systemic antigen challenge in IgAN, 20 patients and 20 controls where immunized with tetanus toxoid (TT). While patients with IgAN responded with a similar serum IgG, IgA, IgA1, and IgA2 antibody response to controls, they did, however, produce more IgA1 antibodies relative to IgA2 (P < 0.05). No salivary IgA antibody response was observed to systemic immunization in controls; however, there was a significant IgA response to TT in the saliva of patients with IgAN. IgA antibodies were produced in vitro by Epstein Barr virus (EBV)-transformed peripheral blood lymphocytes (PBLs) obtained from control blood only when taken shortly (1 or 2 weeks) after immunization. Patients with IgAN produced significantly more IgA anti-TT positive cultures than controls and for a longer period (P < 0.01) after immunization. In contrast, IgG anti-TT was produced in EBV-transformed cultures at all time points, but with no difference between IgAN and controls in the proportion of IgG producing cultures. These results demonstrate increased IgA antibody production in both the systemic and mucosal IgA systems following systemic immunization in IgAN and suggest an abnormal overlap between the two systems in IgAN.     

Steroid therapy during the early stage of progressive IgA nephropathy. A 10-year follow-up study

This study was undertaken to clarify the effect of corticosteroids on the long-term clinical course of the early stage of progressive IgA nephropathy. The early stage of progressive IgA nephropathy was defined as having moderate proteinuria between 1 and 2 g/day, creatinine clearance values of 70 ml/min or more, and a histological severity score of 7 or more. The number of patients who fulfilled these three conditions during 12 years from 1972 and then were continuously followed up for 10 years or more in our renal unit was 46. Twenty of them received steroid treatment for an average period of 18 months, and the remaining 26 patients had no steroid treatment. The initial data of proteinuria, creatinine clearance values, frequency of hypertensive cases, and histological scores of 7 or more were not different between the two groups: 1.4 +/- 0.4 vs. 1.3 +/- 0.3 g/day, 85 +/- 14 vs. 88 +/- 13 ml/min, 25 vs. 38%, and 10.7 +/- 2.5 vs. 11.0 +/- 3.0, respectively. During the follow-up period of 10 years, the renal survival rate was significantly different between the two groups (100 vs. 84% 5 years after starting therapy and 80 vs. 34% 10 years later; p < 0.001). The final creatinine clearance values were significantly different between the two groups (54 +/- 35 vs. 20 +/- 29 ml/min; p < 0.005). On the other hand, the patient groups with mild histological changes or decreased renal function due to moderate proteinuria showed no significant differences in the final outcome. These results indicate that corticosteroids are beneficial in stabilizing the renal function for a long time during the early stage of progressive IgA nephropathy, although this study was not a randomized one.