Clinical Observation On The Effects Of Leflunomide In Treatment Of Refractory IgA Nephropathy

BackgroundIgA nephropathy (IgAN) is a class of chronic glomerular diseases with commonimmunopathologic features, which can be caused by various pathogenies. It refers tothe clinical-pathological syndrome of different clinical symptoms and pathologicalchanges that result from the dispersed deposition of IgA or IgA-dominantimmunoglobulins on the glomerular mesangium and the capillary loop. Currently it isviewed as the most common chronic glomerular disease in those countries whererenal biopsy is widely used. IgAN is not a benign lesion; instead it is one of the mostcommon reasons resulting in chronic renal failure (CRF)-about 30% of the patientsend with end-stage renal disease (ESRD) after 20 years. Thus, therapies to delay thedevelopment of IgAN so as to reduce the occurrence of uremia are urgently demandedfor clinic treatment.However, there is still a dispute over the therapy of IgAN. One is that the clinicand pathologic manifestation and prognosis of IgAN are quite different. There is nogeneral consensus on what kind of patients need treatments or when and how theyshould be treated. Another problem is the lack of sufficient large sample, long-term,randomized controlled trails as the evidences for the evidence-based medicine. InChina, currently there is no common opinion on the treatment of IgAN, and most doctors still rely on their own experiences. Internationally the treatment methods ofIgAN include: (1) reducing the synthesis of IgA immune complexes; (2) inhibiting theaccumulation of IgA immune complexes on the glomerular mesangium; (3)antagonizing the function of platelet-derived growth factors and transforming growthfactors, and slowing the proliferation of glomerular mesangium and glomerularsclerosis (4) abating the damage of infiltrative neutrophil to glomerulus. Currently theordinary medicines used to treat IgAN throughout the world are angiotensinconverting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB),glucocorticoid, immunodepressant, fish oil, anticoagulation, platelet aggregationinhibitor, HMG-CoA reducase inhibitor (statins) and lipid-lowering therapy, Chineseherbs (in China), tonsil removal, etc. Because the prognosis of IgAN is mainly relatedto persistent proteinuria, hypertension, renal dysfunction, glomerular and interstitialfibrosis, and arteriolonephrosclerosis, the selection of IgAN treatment method usuallydepends on the extent of damage of the above indicators. The treatments focus onreducing proteinuria concentration, controlling blood pressure and postponingglomerular and interstitial fibrosis to slow down the renal hypofunction and delay theoccurrence of end-stage renal failure.The mechanism for the occurrence of IgAN is still unknown. Currently it isconsidered to be related to infection, immune reaction, mediators of inflammation andinheritance. No matter what the initiating agent is, one thing is quite clear-it is aclass of immune diseases, and immune, inflammation factor and extracellular matrixaccumulation play an important role in its development. Leflunomide is a newimmunodepressant that can work on the various stages of immune reaction. First,leflunomide can reduce the activity of protein tyrosine kinase (PTK) and NF—κB toblock the transmission and magnification of signals in T lymphocytes and suppressthe occurrence of immune reactions. More importantly, leflunomide can reduce the activity of dihydroorotate dehydrogenase (DHODH) and cyclin dependent kinase(CDK) so as to suppress the proliferation of T or B lymphocytes and theirparticipation in immune reactions. Furthermore, leflunomide can restrain the adhesionof inflammatory cells to the wall as well as their travel to the focuses of infection bysuppressing the cellular adhesion molecules so that the inflammatory reactions can berestrained. In summary, leflunomide confines the occurrence and progressing ofimmune reactions via various paths, showing in theory its possible applications in thetreatment of IgAN primarily caused by abnormal immune regulations. Till now theeffectiveness of leflunomide has already been demonstrated adequately inexperimental study of the treatment of immune-related diseases, for example,rheumatoid arthritis, systemic lupus erythematosus and graft rejection, and the sideeffects are mild. For renal diseases, several animal experiments were also reported toconfirm its effectiveness, such as in the treatment of interstitial nephritis andglomerular nephritis induced by antibasement membrane antibody. In clinical trials,Yu Rongjie et al. and Wang Chen et al. reported the treatment of refractory hydremicnephritis using leflunomide, which showed good therapeutic effects and little adversedrug reactions. The above results show that leflunomide may be effective in theclinical treatment of primary kidney diseases.As revealed in current clinical practices, quite a few IgAN patients are notresponsive to corticosteroid therapy, and clinically their proteinuria quantitationpersists to be higher than 1 g/24h after treating with sufficient hormone for at least 12weeks or the decrease is less than 25% compared to pre-treatment (with a controlledblood pressure≤140/90 mmHg). These patients usually show significant pathologicallesion (most are GradeⅢor above according to the Lee's histopathologicalclassification). Both the extent of pathological damage and persistent proteinuria areproven to be independent risk factors in the prognosis of IgAN, thus these patients are liable to develop into chronic renal failure and the corresponding treatment is ratherdifficult, which can be defined as "refractory IgAN". For these patients, a usualconsideration is to add an immunodepressant (for example, cyclophosphamide,azathioprine and mycophenolate) to the corticosteroid therapy. However, there remainother problems like significant side effects, high cost and uncertain therapeutic effects.Leflunomide is a new immunodepressant, and there are few reports on the treatmentof refractory IgAN using both leflunomide and corticosteroid. The present project isto investigate the effects and safety of leflunomide in the treatment of refractory IgAnephropathy by adopting a single center, prospective, open-label, self-control clinicaltrial, with the purpose of providing a new, safe and effective method to treatrefractory IgA nephropathy.Methodology1 Experimental design: Adopting a single-center, prospective, open-label self-controlclinical trial protocol.2 Clinical resources: Totally 14 of the patients treated in the Southern Hospital fromApril 2005 to May 2006 met the requirements for this study, among which one waslost contact while the complete data of the others were collected. All patients wereconfirmed to have IgAN by renal biopsy and were graded according to the Lee'shistopathological classification.3 Treatment methods: Leflunomide was applied at a dose of 50 mg/d in the first threedays during the treatment and reduced to 30 mg/d later. After complete remissionthe amount of leflunomide was gradually reduced to 10 mg/d and maintained at thatlevel for at least 24 weeks. The initial dose of hormone was set at 1 mg/(kg.d) andgradually reduced at a rate of 5 mg per two weeks according to the therapy effects.If the dose of hormone decreased to 0.5 mg/kg, the drug was then taken at a draughtevery other day. Other treatments: the blood pressure was controlled at =140/90 mmHg before the treatment started. If the patients had already taken angiotensinconverting enzyme inhibitors (ACEI) or angiotensin receptor blocker (ARB) priorto the treatment, the dose should be maintained during the treatment period; Or ifblood pressure continued to rise after the treatment started, calcium channel blocker(CCB),βreceptor-blockers and/or diuretic, rather than the above two medicines,should be used.4 Examination contents: The urea routine, blood routine, blood pressure, body weight,24 h proteinuria quantitation, AST, ALT, serum albumin, serum creatinine, bloodurea nitrogen and creatinine clearance rate of all patients were monitored before thetreatment and at the 2nd, 4th, 8th, 12th, 16th, 20th and 24th week after the treatmentstarted, and the adverse effects were recorded.5 Evaluation criteria of therapy effects:Complete remission: Proteinuria darkens, 24 h proteinuria quantitation＜0.2 g,serum albumin =35 g/L, serum creatinine is at normal level;Markedly effective: Decrease in 24 h proteinuria quantitation is higher than 50%compared to pre-treatment, and serum creatinine level is constant;Effective: Decrease in 24 h proteinuria quantitation is between 25% and 50%, andserum creatinine level is constant;No effect: No significant improvement and worsening are observed in the abovelaboratory indicators.6 Statistic analysis: Measurement data were shown in the format of (?)±s, significancetesting was performed by variance analysis on repeated measurement data, andmultiple comparisons were conducted by LSD test. If the data did not satisfy thesphericity assumption, Greenhouse-Geisser correction factor was then applied toadjust the degree of freedom. All data were processed statistically using softwareSPSS13.0 and a difference was considered to be significant in statistics if P≤0.05. Results1 Change of main clinical indicators before and after treatment with the leflunomideand hormone therapy: Compared to pre-treatment, the 24 h proteinuria quantitationdecreased after treating with the leflunomide and hormone therapy for 4, 8, 12 and24 weeks, and the results were of statistical significance (P＜0.05). The multiplecomparison showed that differences in 24 h proteinuria quantitation betweensuccessive periods were also of statistical significance (P＜0.05). On the other hand,serum albumin increased compared to pre-treatment, and the difference was ofstatistical significance (P＜0.05). The multiple comparison showed that differencesin serum albumin between successive periods were of statistical significance(P＜0.05) except that between the 12th and 8th week (P=0.104). Furthermore, thedifferences in blood urea nitrogen, serum creatinine, creatinine clearance rate andmean arterial pressure were of no statistical significance before and after treatment(P＞0.05).2 Therapy effects: Complete remission: 3 cases; markedly effective: 6 cases; effective:3 cases; no effect: 1 case.3 Adverse effects: No significant abnormity was observed in platelets and white bloodcells after treatment started, and the difference was not of statistical significance(P＞0.05); One patient showed a slight increase in transaminase concentration,which returned to normal after liver-protecting treatment; One patient showed thesymptoms of alopecie, which was alleviated by decreasing the dose of leflunomide.ConclusionsLeflunomide and hormone therapy can decrease the 24 h proterinuriaquantitation and increase the serum albumin level of refractory IgA patients, and theadverse effects are mild. Thus, it can be used as a safe and effective method intreating refractory IgA nephropathy.