Monthly Pulses Of Cyclophosphamide Research Articles

Immunosuppressive therapy versus supportive care in IgA nephropathy patients with stage 3 and 4 chronic kidney disease.

The use of immunosuppressive therapy for immunoglobulin A nephropathy (IgAN) patients with stage 3 or 4 chronic kidney disease (CKD) is controversial. We performed a monocentric retrospective study on 83 consecutive IgAN patients with stage 3 or 4 CKD and proteinuria ≥0.75 g/d (age 41 [33-56] years, 72% male, estimated glomerular filtration rate 36.1 [25.4-47.5] mL/min/1.73 m2) who received uncontrolled supportive care (Supp) (n = 36), corticosteroids/corticotherapy (CS) (n = 14), or CS combined with monthly pulses of cyclophosphamide (CS + CFM) (n = 33) between 2010 and 2017. Patients were followed until composite endpoint (doubling of serum creatinine, end-stage kidney disease (dialysis or kidney transplant) or death, whichever came first) or end of study (January 2020). Patients were followed for a median of 29 (95% confidence interval = 25.2-32.7) months, and 12 (15%) patients experienced the composite endpoint. Within the limitation of a retrospective study, our results suggest no benefit from immunosuppressive therapy in patients with IgAN with stage 3 and 4 CKD as compared with supportive care. There were no differences between the 3 studied groups regarding age, estimated glomerular filtration rate, proteinuria, Oxford classification score, arterial hypertension, and therapy with renin-angiotensin system inhibitors. Mean kidney survival time for the entire cohort was 81.0 (95% confidence interval = 73.1-89.0) months, without significant differences between the 3 groups. In univariate and multivariate Cox regression analysis adjusted for IgAN progression factors, immunosuppressive therapy was not associated with better kidney survival when compared with supportive therapy.

Antineutrophil cytoplasmic antibody-associated vasculitis in presence of positive antiphospholipid antibody: a case report\xa0

BackgroundAntineutrophil cytoplasmic antibody-associated vasculitis is dominated by inflammatory occlusion of small vessels, causing tissue ischemia in various organs. This disorder has rarely been associated with vasculopathy, such as antiphospholipid syndrome.Case presentationWe report a case of a 48-year-old Persian male presenting with distal digital gangrene along with inflammatory arthralgia. High titers of anti-proteinase 3 and antiphospholipid antibodies (anticardiolipin antibody) were detected in laboratory evaluation. Therefore, a diagnosis of antineutrophil cytoplasmic antibody-associated vasculitis and antiphospholipid syndrome was made and treated with anticoagulant along with monthly pulses of cyclophosphamide and a daily dose of 1 mg/kg prednisolone.ConclusionOur case, along with other reports, illustrates that these two entities can coexist. Therefore, monitoring antiphospholipid antibodies in patients with antineutrophil cytoplasmic antibody-associated vasculitis with or without clinical evidence of any thrombosis and ruling out thrombosis in cases that do not respond to proper treatment of vasculitis may be relevant to prevent irreversible or fatal organ damage.

MO278IMMUNOSUPPRESSIVE THERAPY VERSUS SUPPORTIVE CARE IN IGA NEPHROPATHY PATIENTS WITH STAGE 3 AND 4 CHRONIC KIDNEY DISEASE

Abstract Background and Aims The use of immunosuppressive therapy for IgA nephropathy (IgAN) patients with stage 3 or 4 chronic kidney disease (CKD) is controversial. Method We performed a monocentric retrospective study on 83 consecutive IgAN patients (age 41 [33-56] years, 72% male, eGFR 36.1 [25.4-47.5] mL/min) with stage 3 or 4 CKD and proteinuria ≥ 0.75g/day who received uncontrolled supportive care (Supp) (n=36), corticosteroids (CS) (n=14) or CS combined with monthly pulses of cyclophosphamide (CS+CFM) (n=33) between 2010-2017. Patients were followed until composite endpoint (doubling of serum creatinine, ESKD (dialysis or renal transplant) or death, whichever came first) or end of study (May 2018). Results Patients were followed for a median of 29 (95%CI 25.2, 32.7) months, and 12 (15%) patients experienced the composite endpoint. There were no differences between the three studied groups regarding age (Supp 46 [33.5-61.0] vs CS 40 [33-47] vs CS+CFM 41 [34-48] years), eGFR (Supp 37.7 [27.5-49.2] vs CS 40.3 [32.5-54.6] vs CS+CFM 31.5 [22.7-44.3] mL/min), proteinuria (Supp 1.9 [1.4-3.5] vs CS 1.3 [1.0-1.7] vs CS+CFM 1.7 [1.1-2.9] g/g creatinine), MESTC score (Supp 2.5 [1.5-4.0] vs CS 2 [0-2] vs CS+CFM 3 [2-3]), hypertension (Supp 94% vs CS 86% vs CS+CFM 94%) and therapy with renal angiotensin system inhibitors (Supp 83% vs CS 64% vs CS+CFM 67%). Mean renal survival time for the entire cohort was 81.0 (95%CI 73.1, 89.0) months; we found similar renal survival time between the three groups (Supp 79.0 (95%CI 66.5, 91.6) vs CS 69.3 (95%CI 47.7, 91.0) vs CS+CFM 73.7 (95%CI 66.0, 81.4) months, p=0.4). In univariate and multivariate Cox regression analysis adjusted for IgAN progression factors, immunosuppressive therapy was not associated with better renal survival when compared to supportive therapy (Table 1). Conclusion Within the limitation of a retrospective study, we found no benefit from immunosuppressive therapy in patients with IgAN with stage 3 and 4 CKD as compared to supportive care.

P0335PULMONARY HEMORRAHGE IN IG A NEPHROPATHY: A RARE MANIFESTATION

Abstract Background and Aims Ig A nephropathy is the most frequent cause of glomerulonephritis worldwide. Renal-limited disease is the habitual clinical form of the disease. Pulmonary involvement may also be seen in rare cases. Capillaritis with pulmonary hemorrhage is the most frequent pulmonary involvement and is lifethreatening. We reported the case of patient presenting a rapidly progressive glomerulonephritis with pulmonary hemorrhage revealing Ig A nephropathy. Method A case report Results A 23 year-old man admitted for a rapidly progressesive glomerulonephritis with sever hypertension. He presented a respiratory distress with hemoptysis. At biology serum creatinine was at 2200µmol/l (eGFR = 2.4 ml/min) and Hemoglobin was at 5g/dl. Immunoassays of anti-glomerular basement antibodies and antineutrophil cytoplasmic autoantibodies were negatives. Computed tomography scan showed diffuse intra alveolar hemorrhage associated with pleural effusion. Bronchoalveolar lavage confirms this diagnosis. Renal histology showed Ig A nephropathy. Treatment consisted of daily depleted haemodialysis with blood transfusion and corticosteroids associated with monthly pulses of cyclophosphamide. His hemoptysis gradually resolved with a stable hemoglobin at 11 g/dL. However, renal failure persisted requiring maintenance hemodialysis regularly. Conclusion Pulmonary hemorrhage is a rare but serious complication of Ig A Nephropathy which is associated with significant morbidity and mortality. The exact cause for this “extra renal bleed” in Ig A Nephropathy is not known but it possibly represents IgA capillaritis. Though no evidence-based treatment protocol exists, therapeutic options includes steroids, plasmapheresis, cyclophosphamide and rituximab.

Mycophenolate mofetil following cyclophosphamide in worsening systemic sclerosis-associated interstitial lung disease

Objectives Randomized controlled trials have shown that cyclophosphamide (CYC) was an option in systemic sclerosis-associated interstitial lung disease (SSc-ILD). The observed improvement disappeared after CYC was stopped suggesting that a maintenance regimen was mandatory. Immunosuppressants were suggested to be more effective in patients with worsening (i.e., with worsening of dyspnea and/or pulmonary functional tests) SSc-ILD. We aimed to assess the efficacy of mycophenolate mofetil (MMF) as a maintenance regimen after CYC in worsening SSc-ILD. Methods All patients (n = 20) with worsening SSc-ILD were retrospectively included. Treatment consisted of 6 to 12 monthly pulses of CYC followed by MMF and response was assessed by the evolution of the forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLCO) during follow-up. Results At the end of CYC pulses, SSc-ILD had improved in 7 (35%) patients, stabilized in 10 (50%) (i.e., 85% of responders) and worsened in 3 (15%) when compared to baseline. After 6 months of MMF, 70% were still responders while 30% had worsened when compared to baseline (i.e., before CYC). After 12 months on MMF, 55% were responders and 45% had worsened when compared to baseline. Evolution of the FVC slope significantly improved on CYC as well as on MMF. Conclusions A strategy combining IV CYC followed by maintenance MMF for worsening SSc-ILD was associated with stabilization or improvement of pulmonary function tests in only 55% of patients after 12 months of MMF. This suggests that careful monitoring for worsening is mandatory during MMF maintenance and that improvement in managing worsening SSc-ILD is still needed.

Partial Remission of Resistant Nephrotic Syndrome After Oral Galactose Therapy

Focal segmental glomerulosclerosis is sometimes associated with a circulating permeability factor. It was proposed that this factor interacts with the sugars of the glycocalyx, and its high affinity for galactose was shown on the basis of chromatographic studies. Galactose inactivates it and seems to lead to its clearance from plasma. A toddler with a nephrotic syndrome resistant to corticosteroids was admitted. A renal biopsy revealed minimal change disease with deposition of immunoglobulin M. Immunosuppressive therapy with pulses of cyclophosphamide, low-dose combination immunosuppressive therapy, and later with mycophenolate mofetil failed to induce remission. A renal biopsy six years later showed transformation to FSGS. After unsuccessful treatment with monthly pulses of cyclophosphamide, we began therapy with tacrolimus, which showed no effect. After two months, we added oral galactose to tacrolimus for one month, after which proteinuria decreased by 50%. Seven months later, galactose was again added for six months, after which proteinuria remained below 2 g/24 h and the plasma albumin and cholesterol concentrations normalized. An adolescent girl with a nephrotic syndrome resistant to corticosteroids was admitted. A renal biopsy revealed mesangioproliferative glomerulonephritis with C1q nephropathy. Therapy with tacrolimus failed to induce remission. After six months, we added galactose for three months, which reduced proteinuria to 0.76 g/24 h. After the discontinuation of galactose therapy, proteinuria increased to 2.48 g/24 h, despite further treatment with tacrolimus. It seems that oral galactose at a dose of 0.2 g/kg twice a day could be a promising new and nontoxic therapy for the treatment of resistant nephrotic syndrome.

Cyclophosphamide and Lupus Nephritis: When, How, For How Long?

Ever since the introduction of cyclophosphamide (CY), the management of lupus nephritis has dramatically changed, and its prognosis has greatly improved. Based on randomized controlled trials and long-term observational studies, pulse therapy with CY in combination with methyl-prednisolone (MP) is the "gold standard" of therapy for severe lupus. The realization of the significant gonadal toxicity intensified the efforts for the development of alternative immunosuppressive agents. In a large, randomized controlled trial, newer agents such as mycophenolate mofetil (MMF) have demonstrated comparable efficacy and less toxicity for moderately severe disease. To date, combinations of monthly pulses of CY with MP remain the gold standard for the induction of remission in severe lupus. For maintenance, less toxic agents such as azathioprine or MMF are equally effective and are routinely used in the current therapy of lupus.

Treatment of lupus nephritis in children.

In children, systemic lupus erythematosus (SLE) is often more severe than in adults. Renal disease is very common in SLE, with clinical symptoms of renal involvement occurring in 30%-70% of patients. In the absence of appropriate treatment the child may die from the disease or progress rapidly to renal failure. However, aggressive treatment regimens, in particular corticosteroids, carry the risk of growth retardation, accelerated atherosclerosis, and severe infectious complications. Lupus nephritis is classified into six groups depending on the severity of the histological lesions. The most-appropriate treatment for optimal efficacy with minimal side-effects depends on the disease severity. Mild lesions (class I or II) require only careful follow-up to identify any disease progression. Patients with class III nephropathy (focal and segmental glomerulonephritis) may have mild clinical symptoms, in which case no specific therapy is indicated, or more-severe symptoms of the nephrotic syndrome, hypertension, and sometimes moderate renal insufficiency. These patients require the same aggressive therapy as those with class IV disease (diffuse proliferative glomerulonephritis). Our current protocol starts with three methylprednisolone pulses followed by 1.5 mg/kg per day oral prednisone and six monthly pulses of cyclophosphamide. After a second renal biopsy the patient may be maintained on azathioprine while the prednisone dosage is slowly tapered. In children with milder disease we use lower doses of oral prednisone (1-1.5 mg/kg per day). Patients with membranous glomerulonephritis (class V) require no specific therapy if they have pure membranous nephropathy, but require aggressive therapy if they have the nephrotic syndrome. In those patients who progress to end-stage renal disease, clinical and serological remission is common and renal transplantation can be performed, as recurrence in the transplant is very rare.

Preserving Renal Function in Patients with Membranous Nephropathy: Daily Oral Chlorambucil Compared with Intermittent Monthly Pulses of Cyclophosphamide

To compare oral chlorambucil and intravenous cyclophosphamide-based drug regimens in the treatment of patients with membranous nephropathy and deteriorating renal function. Randomized study. University hospital and teaching hospitals. 18 patients with membranous nephropathy, a nephrotic syndrome, and deteriorating renal function. Chlorambucil (0.15 mg/kg body weight per day orally in months 2, 4, and 6) and prednisone (three intravenous pulses of 1 g of methylprednisolone followed by oral prednisone at 0.5 mg/kg per day in months 1, 3, and 5) or intravenous cyclophosphamide (750 mg/m2 body surface area once every month for 6 months) and methylprednisolone (three intravenous 1-g pulses in months 1, 3, and 5). Serum creatinine, serum cholesterol, serum albumin, and urinary protein levels. Before treatment, no statistical differences were found between the treatment groups. Six months after treatment was started, serum creatinine levels had decreased in the group treated with chlorambucil, methylprednisolone, and prednisone from a mean of 260 +/- 112 mumol/L to 186 +/- 74 mumol/L (P = 0.003) and had increased in the group treated with intravenous cyclophosphamide and methylprednisolone from 218 +/- 85 mumol/L to 297 +/- 143 mumol/L (P = 0.02; difference between both groups, P < 0.001). Serum albumin levels increased in both groups by 9 and 6 g/L, respectively, and the urinary protein/creatinine ratio decreased by 2.6 and 3.1 g/10 mmol, respectively. At the end of follow-up (median, 15 months; range, 6 to 36 months), one patient in the chlorambucil group and four patients in the cyclophosphamide group had reached end-stage renal failure after 36, 12, 12, 18, and 18 months of therapy, respectively. One patient in the intravenous cyclophosphamide group died after 6 months of therapy. Thus far, both oral chlorambucil and oral cyclophosphamide have been shown to be effective in the treatment of patients with membranous nephropathy and deteriorating renal function. Our study shows that intermittent monthly pulses of low-dose cyclophosphamide are ineffective in preserving renal function in such patients.

Intravenous pulse cyclophosphamide therapy in myositis and Sjögren's syndrome

We describe a patient with primary Sjögren's syndrome who developed myositis. The results of muscle pathologic analysis before and after treatment with monthly pulses of cyclophosphamide (intravenously), are presented.

Administration of monthly pulses of cyclophosphamide in multiple sclerosis patients: Delayed recovery of several immune parameters following discontinuation of long-term cyclophosphamide treatment

Recovery of various components of the immune system was followed in eight patients with multiple sclerosis who had received monthly pulses of cyclophosphamide (CY) for approximately one year. CD8 cell numbers and NK and ADCC functions recovered in 1–2 months; B cells and FcR + cell numbers recovered in 2–4 months. The recovery of CD4 cells and total T cell numbers, CD4/CD8 ratio and proliferative responses to PHA took more than 4 months. The impaired proliferation was not attributable to low IL-2 receptor expression. Once immunosuppression has been achieved pulse administration of CY at 2- to 4-month intervals may be feasible for long-term maintenance treatment.