Table of Contents

Original Investigation

JNEPHROL 2000; 13: 271-274

Pefloxacin in steroid dependent and resistant idiopathic nephrotic syndrome

Raj Kumar Sharma, Krishna Mohan Sahu, Sanjeev Gulati, Amit Gupta - Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow - India

ABSTRACT: Children with nephrotic syndrome who are either steroid dependent or resistant are difficult to manage. Ten children (age 8-14 years, mean 13.2 years) with idiopathic nephrotic syndrome (5 steroid dependent, 5 steroid resistant) formed the study group. All of them had received a course of cyclophosphamide at least six months previously and were now given pefloxacin in the dose of 200mg to 400mg twice daily (mean dose 2-4.6mg/kg/daily) for 4 to 8 weeks. They did not get steroid along with pefloxacin. After a mean follow up period of 18 weeks (12-20 weeks), 7 patients were in remission (2 complete, 5 partial), while 2 patients did not show any response; one patient discontinued pefloxacin within 2 weeks of start of therapy due to nausea and vomiting. One patient developed arthralgia and another discoloration of nails. There was a significant reduction in proteinuria after pefloxacin therapy (pre- 3.6±2.02gm/24h; post 1.9±1.8gm/24h, p<0.006), and side effects were minimal and reversible. Thus for the subgroup of idiopathic nephrotic children who are steroid dependent or resistant and do not respond to a course of cyclophosphamide, pefloxacin could be helpful in inducing remission.

Key words: Pefloxacin, Idiopathic nephrotic syndrome, Steroid dependence, Steroid resistance

Introduction

The treatment of nephrotic syndrome continues to pose a therapeutic challenge especially in the subgroup of patients who are steroid dependent or steroid resistant (1). A number of therapeutic agents have been tried in these patients. Pefloxacin is an antibiotic belonging to the quinolones which also has an immunomodulatory effect (2-4). There have been few reports regarding the use of pefloxacin in patients with idiopathic nephrotic syndrome but the data are scant and conflicting (5-7). We conducted a prospective study to evaluate the role of pefloxacin in steroid dependent and steroid resistant patients with idiopathic nephrotic syndrome who had not shown
response to cyclophosphamide.

Material and Methods

The study group was comprised of ten patients (eight boys and two girls). Their mean age was 13.2±4.8 years (range 8-14 years). All of them had normal renal function (serum creatinine between 0.8-1.1mg/dl). Histopathology revealed that seven of these patients had focal segmental glomerulosclerosis (FSGS), two had minimal change nephrotic syndrome (MCNS) while one patient had mesangial proliferative glomerulonephritis (MesPGN). Five of these patients were steroid dependent with evidence of steroid toxicity and another five were steroid resistant. Steroid dependent nephrotic syndrome was defined as that occurring in a patient who was initially responsive to prednisolone and had two consecutive relapses either during the period of steroid taper or within two weeks of ending a course of steroid therapy. Steroid resistant nephrotic syndrome was defined as occuring in a patient who failed to respond (proteinuria free) to 8 weeks of standard therapy (60mg/m²/day of prednisolone for 4 weeks followed by 40mg/m²/alternate day for 4 weeks). Oral cyclophosphamide was administered at a dose of 2mg/kg/day for 12 weeks along with the usual doses of prednisolone.
In this study we included cases who had completed their steroid or cyclophosphamide therapy at least 6 months back and did not have any evidence of active infection. Informed consent was obtained for all of these patients, who then had baseline tests on hemoglobin, total and differential leukocyte count, ESR, serum total protein, serum albumin, serum cholesterol, serum creatinine, blood urea nitrogen, urine analysis and 24 hour urine protein excretion. Serum levels of C3, anti-nuclear antibody and anti-dsDNA antibody were assayed in all of them as well as kidney biopsy in view of steroid dependence or steroid resistance. These patients were treated with pefloxacin (400-800mg/day for a duration of 8 weeks) and were followed up every 2 weeks for clinical and biochemical parameters of the nephrotic state and evidence of any drug toxicity. The response to therapy was defined as follows: (i) complete response - patient being proteinuria free (less than 5mg/kg/day), (ii) partial response - more than 50% decrease in the 24 hour urine protein excretion, and (iii) no response - persistence of proteinuria without any significant decrease. The results were analysed for statistical significance using the paired t test.

Results

Nine out of the ten patients, included in this study, completed the entire course of therapy. One patient developed nausea and vomiting after 2 weeks of treatment and the drug had to be discontinued and he was excluded from the final analysis. One patient developed arthralgia and another patient developed discoloration of the nails. Both of these patients continued pefloxacin for a total period of 8 weeks, with these manifestations disappearing after therapy stopped. The mean dose was 24.6mg/kg/day (range 15.0-33.3mg/kg/day) and the mean duration of follow up after discontinuation of pefloxacin was 18 weeks (range 12-26 weeks). Of the 9 patients who took pefloxacin for 8 weeks, 7 patients showed a response (5 partial, 2 complete), while 2 others did not show any response. Of the 7 patients with FSGS, 5 responded (2 complete response, 3 partial response). One patient with MCNS and the only patient with MesPGN had a partial remission of proteinuria. The response to pefloxacin was correlated to the steroid response.
We observed that of the 5 steroid dependent patients, 2 had complete and 2 had partial response while one patient dropped out. Of the 5 patients who were steroid resistant, 3 had partial response while the remaining 2 had no response. There was a significant decrease in mean proteinuria following pefloxacin therapy (post treatment 1.9±1.8gm/24h; 73.07 ± 69.23 mg/kg/24h) as compared to proteinuria prior to pefloxacin therapy (3.67 ± 2.02 gm/24h; 141.15 ± 77.69 mg/kg/24h) (P<0.006). The proteinuria in the subgroup of steroid dependent and steroid resistant patients before and after pefloxacin therapy is depicted in Table I. Of the two steroid dependent patients who showed complete response, one continued to be in complete remission, 26 weeks after stopping pefloxacin, while the other relapsed after being in remission for 22 weeks. This patient was treated with a second 8 weeks course of pefloxacin and achieved complete remission of proteinuria. On subsequent follow up for an additional 24 weeks, there was one relapse in the steroid resistant group after 38 weeks. This patient did not respond to a second course of pefloxacin. None of the patients in the steroid dependent group had any subsequent relapse up to the last follow up.

TABLE I - EFFECT OF PEFLOXACIN ON PROTEINURIA

Discussion

Despite the availability of new therapeutic agents, the treatment of steroid dependent and steroid resistant idiopathic nephrotic patients poses a difficult problem. Steroid toxicity and problems due to hypoproteinemia and proteinuria makes their management an enigma to pediatricians and nephrologists. Frequent infections, malnutrition, hyperlipidemia and anasarca add to the various other problems of clinical management of these patients. There have been four studies regarding the role of pefloxacin in idiopathic nephrotic syndrome with contradictory results (3-6). These studies have involved a small number of patients belonging to different age groups (children or adult) with variable steroid response status, and they used different doses of pefloxacin. Pruna et al found pefloxacin to be extremely effective with minimal side-effects and even recommended it as a first line drug (4). This is in contrast to another study in which it was found to be of no use (5). However, all the patients in the second study group were adults with FSGS of long duration. Two other preliminary reports have found it to be beneficial in steroid sensitive patients (6, 7).
In our study pefloxacin was found to be effective in the management of difficult to manage steroid dependent and steroid resistant cases. Of the ten patients, 7 had a partial or complete response, while in one, the therapy had to be discontinued. The mean dose administered in our study was higher than the previous studies and this may account for the better results. Although there was a decline in proteinuria in both the steroid dependent and resistant patients, the steroid dependent group had a significantly better response (p <0.02). Out of five steroid dependent patients, 4 responded (2 complete, 2 partial), while one patient dropped out due to nausea and vomiting. In three steroid resistant patients, an 8 week course of pefloxacin significantly reduced proteinuria and produced partial remission.
The rationale for the use of pefloxacin in idiopathic nephrotic syndrome is based on its immunomodulatoryrole (2, 3). Though not well understood, immunomod-
ulatory effects of pefloxacin include an antiproliferative effect on lymphocytes and monocytes in vitro (8). It also increases interleukin-2 production at the transcriptional level, but at the same time decreases the interleukin-2 receptor concentration by about 50%, possibly through inhibition of RNAase (9). As it is now gradually being established that idiopathic nephrotic syndrome is a T cell disorder and interleukins are involved in its pathogenesis, the interference with proliferation of lymphocytes and decreased production of interleukin-2 receptors by pefloxacin could explain, in part, its beneficial effects in patients with idiopathic nephrotic syndrome. Quinolones have been reported to produce irreversible cartilage toxicity in animals. The rheumatological side effects of quinolones are related to their direct effect on chondrocytes. However, there is little evidence for such a corresponding effect in clinical practice. Moreover, interspecies differences have been found to be important factors in quinolone- induced effects on articular cartilage.
In our study, pefloxacin was used in the subgroup of patients who had previously not responded to a full 12 week course of cyclophosphamide. An additional dose of cyclophosphamide was not only unlikely to be of significant benefit but would have also increased risk of gonadotoxicity and neoplasia (1). Neither has cyclosporine been found to be of significant benefit in this subgroup of patients as most of them relapse after its discontinuation. Besides the increased cost, an important constraint in developing countries, there is the risk of nephrotoxicity associated with its long term use.
Thus, our study suggests that pefloxacin may be a useful therapeutic alternative in steroid dependent and steroid resistant children with idiopathic nephrotic syndrome who have already received cytotoxic therapy. The response is definitely encouraging in the steroid dependent group where 4 out of 5 patients achieved remission. However, in the steroid resistant group only 3 out of 5 patients achieved remission, and only partial in one of them. In our study we used a second course of pefloxacin in one patient who was steroid dependent and had been in remission for 22 weeks following the first course of pefloxacin. Importantly, he again achieved complete remission. This may suggest that steroid dependent patients who are pefloxacin responsive, may respond to a second course in case of relapse and thus it is worthwhile to do so in these cases. However, the second course of pefloxacin is probably not effective after relapse in steroid resistant cases. Prospective large controlled trials are required to provide sure information on the role of pefloxacin therapy in steroid dependent and steroid resistant children with idiopathic nephrotic syndrome and to see whether long term pefloxacin can be used for the prevention of relapse.

Reprint requests to: Raj K. Sharma, M.D. - Department of Nephrology Sanjay Gandhi Post Graduate Institute of Medical Sciences Raebareli Road Lucknow 226014, India rksharma@sgpgi.ac.in

References (when available, each reference has been linked to PubMed)

Received: June 08, 1998 Revised: April 24, 2000 Accepted: June 03, 2000

Copyright (c) 2000 Italian Society of Nephrology

Back to Home Page