Skip to main content

Main menu

  • Home
  • Content
    • Early Access
    • Current Issue
    • Kidney360 Podcasts
    • Subject Collections
    • Archives
    • ASN Meeting Abstracts
  • Clinical Images
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • More
    • About Kidney360
    • Advertising
    • Disqus Commenting
    • Reprint Information
    • Feedback
    • Email Alerts
  • ASN Kidney News
  • Other
    • JASN
    • CJASN
    • Kidney News Online
    • American Society of Nephrology

User menu

Search

  • Advanced search
American Society of Nephrology
  • Other
    • JASN
    • CJASN
    • Kidney News Online
    • American Society of Nephrology
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Early Access
    • Current Issue
    • Kidney360 Podcasts
    • Subject Collections
    • Archives
    • ASN Meeting Abstracts
  • Clinical Images
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • More
    • About Kidney360
    • Advertising
    • Disqus Commenting
    • Reprint Information
    • Feedback
    • Email Alerts
  • ASN Kidney News
  • Visit ASN on Facebook
  • Follow Kidney360 on Twitter
  • Community Forum
  • Kidney360 RSS
Original InvestigationsGlomerular and Tubulointerstitial Diseases

Substitution of Oral for Intravenous Cyclophosphamide in Membranous Nephropathy

Leonella Luzardo, Gabriela Ottati, Jimena Cabrera, Hernando Trujillo, Mariela Garau, Carlota González Bedat, Ruben Coitiño, María H. Aunchayna, José Santiago, Graciela Baldovinos, Ricardo Silvariño, Alejandro Ferreiro, Francisco González-Martínez, Liliana Gadola, Oscar Noboa and Hena Caorsi
Kidney360 September 2020, 1 (9) 943-949; DOI: https://doi.org/10.34067/KID.0002802020
Leonella Luzardo
1Department of Nephrology, Clinic Hospital, University of the Republic, Montevideo, Uruguay
2Uruguayan Registry of Glomerulopathies, Montevideo, Uruguay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gabriela Ottati
1Department of Nephrology, Clinic Hospital, University of the Republic, Montevideo, Uruguay
2Uruguayan Registry of Glomerulopathies, Montevideo, Uruguay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jimena Cabrera
2Uruguayan Registry of Glomerulopathies, Montevideo, Uruguay
3Department of Nephrology, Military Hospital, Montevideo, Uruguay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hernando Trujillo
4Department of Nephrology, University Hospital 12 October, Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mariela Garau
2Uruguayan Registry of Glomerulopathies, Montevideo, Uruguay
5Department of Quantitative Methods, School of Medicine, University of the Republic, Montevideo, Uruguay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carlota González Bedat
6Department of Nephrology, CASMU, Montevideo, Uruguay
7Uruguayan Dialysis Registry, Montevideo, Uruguay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ruben Coitiño
1Department of Nephrology, Clinic Hospital, University of the Republic, Montevideo, Uruguay
2Uruguayan Registry of Glomerulopathies, Montevideo, Uruguay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
María H. Aunchayna
2Uruguayan Registry of Glomerulopathies, Montevideo, Uruguay
8Department of Pathology, Clinic Hospital, School of Medicine, University of the Republic, Montevideo, Uruguay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
José Santiago
1Department of Nephrology, Clinic Hospital, University of the Republic, Montevideo, Uruguay
9Department of Nephrology, Médica Uruguaya, Montevideo, Uruguay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Graciela Baldovinos
2Uruguayan Registry of Glomerulopathies, Montevideo, Uruguay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ricardo Silvariño
1Department of Nephrology, Clinic Hospital, University of the Republic, Montevideo, Uruguay
2Uruguayan Registry of Glomerulopathies, Montevideo, Uruguay
10Department of Nephrology, COSEM, Montevideo, Uruguay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alejandro Ferreiro
1Department of Nephrology, Clinic Hospital, University of the Republic, Montevideo, Uruguay
6Department of Nephrology, CASMU, Montevideo, Uruguay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Francisco González-Martínez
1Department of Nephrology, Clinic Hospital, University of the Republic, Montevideo, Uruguay
2Uruguayan Registry of Glomerulopathies, Montevideo, Uruguay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Liliana Gadola
1Department of Nephrology, Clinic Hospital, University of the Republic, Montevideo, Uruguay
2Uruguayan Registry of Glomerulopathies, Montevideo, Uruguay
6Department of Nephrology, CASMU, Montevideo, Uruguay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Oscar Noboa
1Department of Nephrology, Clinic Hospital, University of the Republic, Montevideo, Uruguay
2Uruguayan Registry of Glomerulopathies, Montevideo, Uruguay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hena Caorsi
1Department of Nephrology, Clinic Hospital, University of the Republic, Montevideo, Uruguay
2Uruguayan Registry of Glomerulopathies, Montevideo, Uruguay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

Visual Abstract

Figure1
  • Download figure
  • Open in new tab
  • Download powerpoint

Abstract

Background Optimal immunosuppressive treatment for membranous nephropathy is still a matter of controversy. Current recommendations include oral cyclophosphamide combined with steroids (modified Ponticelli regimen) as first-line treatment in patients who are high risk. However, concerns about the cumulative toxicity of oral cyclophosphamide persist. In the last 30 years, a protocol based on low-dose intravenous cyclophosphamide plus steroids has been used to treat membranous nephropathy in Uruguay. We aimed to assess the efficacy of this regimen to induce clinical remission in patients with membranous nephropathy.

Methods In this retrospective, observational cohort study, we analyzed the outcome of 55 patients with membranous nephropathy treated between 1990 and 2017 with a 6-month course of alternating steroids (months 1, 3, and 5) plus intravenous cyclophosphamide (single dose of 15 mg/kg on the first day of months 2, 4, and 6).

Results At 24 months, 39 (71%) patients achieved clinical response with complete remission observed in 23 patients (42%) and partial remission in 16 (29%). Median time to achieve partial and complete remission was 5.9 and 11.5 months, respectively. Absence of response was observed in 16 patients (29%), five of whom started chronic RRT after a median follow-up of 3.5 years. Clinical relapse occurred in nine of 33 (27%) patients at a median of 34 months after treatment discontinuation.

Conclusions Replacement of oral cyclophosphamide with a single intravenous pulse on months 2, 4, and 6 of the modified Ponticelli regimen can be an effective and safe alternative for treatment of membranous nephropathy.

Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/K360/2020_09_24_KID0002802020.mp3

  • glomerular and tubulointerstitial diseases
  • glomerulopathies
  • intravenous cyclophosphamide
  • membranous glomerulonephritis
  • membranous nephropathy
  • nephrotic syndrome
  • relapse
  • remission

Introduction

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. The usual clinical presentation is a full nephrotic syndrome with preserved kidney function (1). Considering that about a third of patients undergo spontaneous remission and a third progress to ESKD, the optimal management of MN is still a matter of debate (2⇓⇓⇓⇓⇓–8). The identification of the M-type phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain–containing 7A as glomerular antigens involved in the pathogenesis of primary MN have improved our understanding of the mechanisms of disease (9,10). Furthermore, the elucidation of an autoimmune etiology has led to a renewed enthusiasm in the role of immunosuppressive therapy (11). Current international guidelines recommend a 6-month course of alternating monthly cycles of intravenous (IV) and oral steroids (ST) plus oral cyclophosphamide (CYC), the modified Ponticelli regimen, as first-line therapy in patients at high risk of progression to ESKD (12⇓–14). Nevertheless, there is great concern about the toxicity induced by high doses of CYC as a consequence of regimens based on oral administration. A relatively recent analysis showed a three-fold increase in cancer risk in patients with MN who received oral CYC compared with controls (15). Additionally, another contemporary study reported significantly fewer adverse events in patients treated with rituximab compared with patients who received oral CYC-based regimens (16). However, it is important to emphasize that the mean cumulative dose of CYC in the latter studies was considerably high (between 18 and 37 g). This might explain, at least in part, the large number of adverse events observed in patients treated with CYC.

During the 1990s, Uruguay had poor availability of oral CYC and, consequently, the implementation of the modified Ponticelli regimen required substitution with IV CYC. The aim of this study was to analyze the efficacy and long-term outcomes of treatment with low-dose IV CYC plus steroids in a cohort of patients with biopsy sample–proven MN (17,18).

Materials and Methods

Patient Population

A total of 55 patients with a biopsy sample–proven diagnosis of MN who were treated with alternating steroids plus low-dose IV CYC between 1990 and 2017 were included. Patients with clinical, histologic, or serologic evidence of secondary MN were excluded. Secondary causes were excluded as per standard policy, including a complete medical history and physical exam; history of drugs used; chest x-ray; kidney ultrasound; hepatitis B, hepatitis C, and HIV status; treponemal test; antinuclear antibodies; and screening for occult malignancy (according to age and sex). All patients had new-onset MN; hence, none of them had previously received immunosuppressive treatment. The study was approved by the Ethics Committee at the School of Medicine, Clinical Hospital Dr. Manuel Quintela.

Treatment Regimen

All patients received a 6-month course of alternating monthly steroids plus CYC, as described in the modified Ponticelli regimen, but CYC was administered intravenously instead of orally (15 mg/kg IV single dose on day 1 of months 2, 4, and 6). CYC initial dose was decreased by 2.5 mg/kg in patients >60 years and 5 mg/kg in patients >70 years; and it was decreased by 2.5 mg/kg if serum creatinine was >2.7 mg/dl. Subsequent doses were adjusted to achieve a 2-week nadir leukocyte count of >3000/mm3. None of the patients received a total cumulative dose of >3 g of CYC. The steroid protocol was administered during months 1, 3, and 5 and included 20 mg/kg IV methylprednisolone (maximum 1 g) daily for three doses (days 1, 2, and 3), and then oral prednisone (0.5 mg/kg per day) for 27 days, followed by a quick tapering (10 mg/wk). Treatment with angiotensin-converting enzyme inhibitors. has been formally indicated in national protocols since the 1990s. IV 2-mercaptethanesulfonate was used as prophylaxis of CYC-induced hemorrhagic cystitis.

Definitions and Follow-up

Complete remission (CR) was defined as proteinuria of <300 mg per 24 hours. Partial remission (PR) was defined as a reduction in proteinuria of at least 50% from baseline plus final proteinuria between 300 and 3500 mg per 24 hours. No remission (NR) was defined as proteinuria >3500 mg per 24 hours. Relapse was defined as the development of proteinuria of >3500 mg per 24 hours after achieving CR or PR. eGFR was calculated with the CKD–Epidemiology Collaboration equation. Severe adverse events during treatment were assessed, including hospital admissions due to infections and myelosuppression that required granulocyte–colony stimulating factor or blood transfusions. Cancer incidence was evaluated as a long-term adverse effect of CYC.

Outcomes

The primary outcome was clinical remission (partial or complete) at 24 months. Secondary outcomes included incidence of relapse, progression to ESKD, and severe treatment-related adverse events.

Statistical Analyses

Quantitative variables were described as medians and interquartile ranges. The Kolmogorov–Smirnov test was used to test the normality of distributions. Because variables were not normally distributed, groups were compared using the Mann–Whitney or Kruskal–Wallis test as required. Categoric variables were described as frequencies and percentages and were analyzed using the chi-squared test. Kidney survival was estimated using the Kaplan–Meier method, and log-rank tests were used to compare survival distribution. All statistical tests were two sided, and differences were considered significant with a P value <0.05. Statistical analyses were performed using IBM SPSS Statistics version 22.0 (IBM Co., Armonk, NY).

Results

Demographics and baseline clinical characteristics of patients according to treatment response are detailed in Table 1. A total of 38 (69%) patients were men, with a median age at the time of kidney biopsy of 53 years. Median serum creatinine at clinical presentation was 1.0 mg/dl (interquartile range [IQR], 0.79–1.28) and median proteinuria was 7.6 g/24 h (IQR, 4.5–11.2). Median baseline systolic and diastolic BP were 130 mm Hg (IQR, 111–140) and 80 mm Hg (IQR, 70–90), respectively. Although no significant differences were observed, baseline eGFR was lower and proteinuria was higher in the group that did not respond to treatment.

View this table:
  • View inline
  • View popup
Table 1.

Baseline clinical characteristics of the study cohort according to remission

Primary Outcome

At 24 months, 39 (71%) patients achieved clinical response; there was CR in 23 (42%) of patients and PR in 16 (29%). NR was observed in 16 (29%) patients. Detailed outcome of clinical response at 6–24 months is presented in Table 2. In the group that achieved CR, proteinuria decreased from 6.3 g/24 h (IQR, 3.7–8.6) to 0 g/24 h (IQR, 0–0.17) (P<0.001); in the PR group, proteinuria decreased from 8.0 g/24 h (IQR, 4.5–13.3) to 1.1 g/24 h (IQR, 0.7–1.7) (P<0.001). Proteinuria levels in patients without treatment response were 6.8 g/24 h (IQR, 5.1–10.0). The median time from kidney biopsy to treatment onset was 2.7 months (IQR, 1.8–5.4). The median time between treatment and clinical response was 5.9 (IQR, 4.6–16.0) and 11.5 (IQR, 5.9–15.0) months to achieve PR and CR, respectively. Response rate (CR plus PR) reached 76% at month 12 after treatment, however, two patients relapsed before month 24; thus, the response rate decreased to 71% (Table 2).

View this table:
  • View inline
  • View popup
Table 2.

Outcome of complete and partial remission at 6–24 months

Secondary Outcomes

Median follow-up of the entire cohort was 7.1 years (IQR, 3.2–13.9). During the study period, nine (16%) patients were lost to follow-up; therefore, analysis of relapse rate included a total of 33 patients. After treatment discontinuation, relapse occurred in five of 19 (26%) patients with CR, and in four of 14 (29%) patients with PR (Figure 1). This relapse rate (27%; nine of 33) should be interpreted in the context of the long follow-up period of those 33 patients (85.2 months; IQR, 42.6–159.3). Considering only the first 24 months after treatment, only two of 33 (6%) patients relapsed. Both patients relapsed on month 12 after treatment. The median time between treatment and relapse was 34 months (IQR, 18–67) (Figure 2).

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Flowchart of the study. CR, complete remission; PR, partial remission.

Figure 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2.

Incidence (number of patients) of relapse during follow-up. Relapse occured in nine patients, two of them within the first 24 months after treatment. The median time between treatment and relapse was 34 months (IQR, 18–67).

Over the course of the entire follow-up period, five of 46 (11%) patients progressed to ESKD in a median time of 3.5 years (IQR, 2.3–10.1) since kidney biopsy. All of these patients were included in the NR group (Figure 3). Baseline serum creatinine was higher in the group of patients that developed ESKD (2.32 mg/dl [IQR, 1.75–3.55] versus 0.95 mg/dl [IQR, 0.79–1.20]), although the difference was NS (P=0.15). Baseline proteinuria was similar in the ESKD group (6.9 g/24 h; IQR, 3.5–14.2) and in subjects that did not require chronic RRT (7.8 g/24 h; IQR, 4.7–11.5) (P=0.67). On the other hand, patients that achieved CR or PR had significantly better kidney survival than those with NR (P=0.002) (Figure 2). Median follow-up of patients with clinical response that did not progress to ESKD was 7.2 years (IQR, 3.5–14.9).

Figure 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 3.

Long-term kidney survival of patients with complete, partial and no remission. Five patients (10.8%) progressed to ESKD in a median time of 3.5 years since kidney biopsy. Of note, all of them were included in the NR group. NR, no remission.

Adverse Events

None of the patients required blood transfusions or granulocyte–colony stimulating factor for the management of myelosuppression. One patient developed community-acquired pneumonia 2 weeks after the first CYC dose and required hospital admission. When the infection improved, immunosuppressive treatment was successfully completed. Three patients (7%) were diagnosed with cancer: two cases of basal cell carcinoma of the skin and one case of multiple myeloma (de novo). Time between the first CYC bolus and the oncologic diagnosis was 3 and 11 years, respectively, for the patients with skin cancer, and 7 years for the patient with multiple myeloma. Five patients died during follow-up at 1, 7, 13, 15, and 18 years after MN diagnosis. The median age at death was 71 years (IQR, 42–82).

Discussion

In this retrospective, observational study, we found that the substitution of oral with low-dose IV CYC in the modified Ponticelli regimen can be an effective and safe option for treating patients with MN. It should be noted that we analyzed a proven therapy for MN by a different dose and route. The efficacy of cytotoxic drugs in the management of MN has already been demonstrated (19,20); nonetheless, the risk of malignancy is still a matter of concern. One of the main drawbacks of using oral CYC is a high cumulative dose with potential serious adverse effects. Our study shows that the use of IV CYC has the advantage of a significantly lower cumulative dose without losing efficacy. Of the 55 patients included in our cohort, >75% achieved a clinical response (CR plus PR) after 1 year. Additionally, it is reasonable to assume that the substantial reduction in proteinuria (far below the nephrotic range) in patients who attained PR had a positive effect on kidney prognosis. Although relapse occurred in 27% (nine of 33) of the patients, it is important to emphasize that even patients who experienced a relapse remained on remission for almost 3 years. The importance of remission duration on outcome has been previously stated by other authors (21). Kidney survival after a median follow-up of 7.1 years was excellent (90%). In fact, none of the patients that achieved CR developed ESKD throughout the follow-up period. Baseline serum creatinine has been described as a significant, independent predictor factor for spontaneous remission and a predictor factor for response to treatment (5). In line with this, we observed higher baseline creatinine values in those patients who did not exhibit a treatment response. On the other hand, the incidence of cancer was lower than that reported for oral CYC (15,16,22,23).

Current Kidney Disease Improving Global Outcomes guidelines recommend steroids plus cyclical oral CYC as first-line therapy in patients with MN who are high risk (12). In the landmark study by Ponticelli et al. (19), where a 6-month course of alternating ST plus chlorambucil was compared with ST plus oral CYC, CR or PR was achieved in 93% of the patients in the CYC arm (versus 82%) after a median follow-up of 42 months. Relapse occurred in 25% of the patients (versus 30% in the chlorambucil group) between 6 and 30 months after initial therapy. Subsequently, in a prospective, randomized trial by Jha et al. (20), a similar scheme of ST plus oral CYC was compared with a control group that received supportive treatment only. Clinical response was attained in 72% of the patients (CR, 15; PR, 19) in the ST plus CYC arm versus 35% in the control group. Median follow-up duration was 11 years and relapses were noted in eight of 34 (24%) patients in the ST plus CYC group. Remarkably, kidney survival at 10 years was considerably superior in the experimental group (89% versus 65%) (20).

Adverse effects associated with alkylating agents, particularly the increased risk of cancer, represent a great concern and may restrict the use of this highly effective therapeutic option. CYC has been related to infections, bladder toxicity, myeloid dysplasia, and nonmelanoma skin cancer. As recently stated by Ponticelli et al. (7), the oncogenic risk is related to the intensity and length of the treatment and to the use of other immunosuppressive agents. In patients with MN, van den Brand et al. (15) reported that the risk of malignancy in CYC-treated subjects was approximately three times higher compared with those not exposed to CYC. Over a median follow-up period of 6 years, the observed cancer incidence was 21.2 per 1000 person-years in patients treated with CYC versus 4.6 per 1000 person-years in the control group, resulting in crude and adjusted incidence ratios of 4.6 and 3.2, respectively. However, it is important to mention that the median cumulative dose of CYC received by patients in the aforementioned study was 37 g (15). This remarkably high cumulative dose must be considered when analyzing potential CYC toxicity because the usual cumulative dose in the modified Ponticelli regimen is approximately 9–13 g. Of note, the protocol described in our study enables a substantial reduction of the total cumulative CYC dose compared with the oral or even the monthly IV protocols recently described by other authors (24⇓–26).

Outside the setting of MN, follow-up data from the European Vasculitis Study Group clinical trials suggested that the less-extensive use of immunosuppressive drugs might result in a lower cancer risk compared with historical studies (23). Interestingly, in a study that compared pulse versus daily oral CYC for induction of remission in ANCA-associated vasculitis (the CYCLOPS trial), no differences were found between the two groups with regard to the incidence of malignancy. After a median follow-up of 4.3 years, 10% of patients in the oral CYC group versus 12% in the IV CYC group developed cancer (27).

It is reasonable to assume that a decrease in the total cumulative dose of CYC may reduce its adverse effects. In this study, we have addressed the oncologic risk of CYC over a period of 8.9±6.3 years and found only three cases of cancer, none of which affected the urinary tract. The long observation period between kidney biopsy and the occurrence of malignancy virtually excludes the possibility that a diagnosis of cancer may have been missed at the time of MN presentation.

To date, there are few reports that have explored the effectiveness of IV CYC in the setting of MN. A study from 1992 concluded that treatment with steroids plus IV CYC (n=13) compared with steroids alone (n=13) did not improve kidney function in patients with deteriorating kidney function or persistent proteinuria. In both groups, the same number of patients progressed to ESKD and required chronic dialysis during follow-up (28). Notably, all patients had an elevated serum creatinine level before starting immunosuppressive therapy (2.7±1.6 mg/dl steroids versus 2.3±1.0 mg/dl CYC plus steroids). A similar analysis reported by Reichert et al. (29) compared the efficacy of chlorambucil plus steroids (n=9) versus IV CYC plus steroids (n=9), and found that kidney survival was significantly better in the chlorambucil arm. Similar to the former study, the number of patients was small and had impaired kidney function at treatment onset.

A more recent analysis of 32 cases with MN treated with IV CYC (500–750 mg/m2 every month for 6 months) plus steroids reported that 81% of the patients achieved CR (13/32) or PR (13/32). Kidney survival was 100% and relapse occurred in five (16%) patients after a median of 16 months after cessation of treatment. The main limitation of this retrospective study was the relatively short follow-up period (30 months) (24). Another current study that compared prospective data of 41 patients treated with IV CYC plus prednisone with a historical cohort of patients who did not receive immunosuppression found that, in the former group, a significantly higher number of patients achieved remission and a more rapid normalization of serum albumin. The median cumulative dose of CYC was 7.2 g and the follow-up period was 2 years. Treatment was well tolerated and few serious adverse events were observed (25).

IV CYC plus steroids has also proved efficacy in attaining immunologic response in a small study from the United Kingdom that included new-incident and relapse patients. Anti-PLA2R levels decreased from 244 U/L to <14 U/L at 6 months. Furthermore, all patients achieved PR at 6 months, despite receiving approximately half the cumulative dose of CYC (4.2–5.4 g) than that of the standard regimen. After a median follow-up of 32 months, 44% of the new-incident patients achieved CR and only two of nine (22%) developed a subsequent relapse (9 and 24 months after initial therapy) (26).

Severe MN with persistent nephrotic syndrome progresses to ESKD in approximately 40%–50% of patients over a period of 10 years (30). In this setting, achieving not only CR but also PR can slow the rate of kidney function decline and has been associated with prolonged kidney survival (30,31). There is general consensus that an effective therapy with a favorable risk-benefit profile is required and there has long been a desire to find a less toxic, but equally effective, therapy than oral CYC (11).

This study must be interpreted within the context of its limitations and strengths. First, it is a retrospective study with an uncontrolled and nonrandomized design. An interesting idea for future prospective randomized trials in MN would be to compare oral versus IV CYC, carefully addressing the efficacy and safety of using lower cumulative doses as in this therapeutic scheme. Secondly, nine patients were lost to follow-up; therefore, information about relapses was not available for the entire cohort. Lastly, we have not been able to describe information related to immunologic remission because serum anti-PLA2R antibody levels were not available in the majority of patients. This must be understood in the context of a historical retrospective analysis in which most patients were diagnosed before the description of PLA2R in 2009.

The main strength of our study is the long follow-up period that allowed us to assess the influence of the therapeutic intervention on kidney survival. The slow-to-form, slower-to-resolve immune deposits (32) suggest that remissions in MN may take years; hence, clinical trials limited to 24 months may not fully describe the true effect on kidney outcomes. We consider that studies based on “real-world experience,” as is the case of this work, provide relevant and useful information about uncommon diseases such as MN because they can serve to generate hypotheses. Moreover, we believe the veracity of our data is robust because detailed review of the clinical record of each patient was done and follow-up information was supported by concordance with national coverage databases. To the best of our knowledge, this is the largest cohort of patients with MN treated with IV CYC and, more importantly, with the lowest total cumulative dose.

In conclusion, substitution of oral with low-dose IV CYC in the modified Ponticelli regimen seems to be an effective, safe, and affordable treatment for patients with MN. Prospective controlled trials comparing different doses and routes of CYC in MN are needed to address the better safety and efficacy profile. CYC-based regimens remain a viable option, especially in countries where access to new treatment strategies is not yet universally guaranteed.

Disclosures

All authors have nothing to disclose.

Funding

The Fondo Nacional de Recursos financially supports the Uruguayan Registry of Glomerular Diseases. The Fondo de Investigación en Nefrología of Hospital de Clínicas supports research in glomerulopathies. This work has been made possible through an International Society of Nephrology fellowship for L. Luzardo.

Acknowledgments

We thank the medical and supporting staff of the Uruguayan Registry of Glomerular Diseases: Dr. Rossana Cordero, Dr. Pablo Ríos, Dr. Lucía Orihuela, Dr. Vanessa Gutiérrez, Dr. Sebastián Rath, Dr. Asunción Álvarez, Dr. Soledad Lecueder, Dr. Daiana Geido, Dr. Víctor Scaffo, Dr. Soledad Giró, Dr. María García, Dr. Silvana Giménez, Dr. Carina Subiza, Dr. Lidia Pereira, Dr. Alejandra Chichet, Dr. Marianella Pastore, Dr. Mercedes Cha, Dr. Martha Lane, and Dr. Cecilia Burgos. We thank Dr. Manuel Praga for the critical review of the manuscript and helpful suggestions.

Author Contributions

M. Aunchayna, G. Baldovinos, R. Coitiño, C. González Bedat, J. Santiago, and R. Silvariño were responsible for resources; M. Aunchayna, J. Cabrera, A. Ferreiro, L. Gadola, L. Luzardo, G. Ottati, and O. Noboa were responsible for data curation; G. Baldovinos was responsible for validation; J. Cabrera, H. Caorsi, L. Gadola, F. González-Martínez, G. Ottati, and O. Noboa conceptualized the study; J. Cabrera, H. Caorsi, M. Garau, L. Gadola, F. González-Martínez, L. Luzardo, G. Ottati, O. Noboa, and H. Trujillo were responsible for formal analysis; J. Cabrera, L. Luzardo, and G. Ottati were responsible for investigation; H. Caorsi, L. Gadola, and F. González-Martínez provided supervision; R. Coitiño, C. González Bedat, J. Santiago, and R. Silvariño were responsible for visualization; M. Garau, L. Luzardo, and G. Ottati were responsible for methodology; L. Gadola, L. Luzardo, G. Ottati, O. Noboa, and H. Trujillo reviewed and edited the manuscript; L. Luzardo and G. Ottati were responsible for project administration; L. Luzardo, G. Ottati, O. Noboa, and H. Trujillo wrote the original draft; and all authors reviewed the final manuscript.

Footnotes

  • https://www.asn-online.org/media/podcast/K360/2020_09_24_KID0002802020.mp3.

  • Received May 14, 2020.
  • Accepted August 5, 2020.
  • Copyright © 2020 by the American Society of Nephrology

References

  1. ↵
    1. Glassock RJ
    : Diagnosis and natural course of membranous nephropathy. Semin Nephrol 23: 324–332, 2003
    OpenUrlCrossRefPubMed
  2. ↵
    1. Cattran D
    : Management of membranous nephropathy: When and what for treatment. J Am Soc Nephrol 16: 1188–1194, 2005
    OpenUrlFREE Full Text
  3. ↵
    1. Fervenza FC,
    2. Sethi S,
    3. Specks U
    : Idiopathic membranous nephropathy: Diagnosis and treatment. Clin J Am Soc Nephrol 3: 905–919, 2008
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Hofstra JM,
    2. Fervenza FC,
    3. Wetzels JF
    : Treatment of idiopathic membranous nephropathy. Nat Rev Nephrol 9: 443–458, 2013
    OpenUrlCrossRefPubMed
  5. ↵
    1. Polanco N,
    2. Gutiérrez E,
    3. Covarsí A,
    4. Ariza F,
    5. Carreño A,
    6. Vigil A,
    7. Baltar J,
    8. Fernández-Fresnedo G,
    9. Martín C,
    10. Pons S,
    11. Lorenzo D,
    12. Bernis C,
    13. Arrizabalaga P,
    14. Fernández-Juárez G,
    15. Barrio V,
    16. Sierra M,
    17. Castellanos I,
    18. Espinosa M,
    19. Rivera F,
    20. Oliet A,
    21. Fernández-Vega F,
    22. Praga M; Grupo de Estudio de las Enfermedades Glomerulares de la Sociedad Española de Nefrología
    : Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy. J Am Soc Nephrol 21: 697–704, 2010
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Cravedi P,
    2. Remuzzi G,
    3. Ruggenenti P
    : Rituximab in primary membranous nephropathy: First-line therapy, why not? Nephron Clin Pract 128: 261–269, 2014
    OpenUrlCrossRefPubMed
  7. ↵
    1. Ponticelli C,
    2. Escoli R,
    3. Moroni G
    : Does cyclophosphamide still play a role in glomerular diseases? Autoimmun Rev 17: 1022–1027, 2018
    OpenUrl
  8. ↵
    1. Fervenza FC,
    2. Appel GB,
    3. Barbour SJ,
    4. Rovin BH,
    5. Lafayette RA,
    6. Aslam N,
    7. Jefferson JA,
    8. Gipson PE,
    9. Rizk DV,
    10. Sedor JR,
    11. Simon JF,
    12. McCarthy ET,
    13. Brenchley P,
    14. Sethi S,
    15. Avila-Casado C,
    16. Beanlands H,
    17. Lieske JC,
    18. Philibert D,
    19. Li T,
    20. Thomas LF,
    21. Green DF,
    22. Juncos LA,
    23. Beara-Lasic L,
    24. Blumenthal SS,
    25. Sussman AN,
    26. Erickson SB,
    27. Hladunewich M,
    28. Canetta PA,
    29. Hebert LA,
    30. Leung N,
    31. Radhakrishnan J,
    32. Reich HN,
    33. Parikh SV,
    34. Gipson DS,
    35. Lee DK,
    36. da Costa BR,
    37. Jüni P,
    38. Cattran DC; MENTOR Investigators
    : Rituximab or cyclosporine in the treatment of membranous nephropathy. N Engl J Med 381: 36–46, 2019
    OpenUrlCrossRefPubMed
  9. ↵
    1. Beck LH Jr..,
    2. Bonegio RG,
    3. Lambeau G,
    4. Beck DM,
    5. Powell DW,
    6. Cummins TD,
    7. Klein JB,
    8. Salant DJ
    : M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 361: 11–21, 2009
    OpenUrlCrossRefPubMed
  10. ↵
    1. Tomas NM,
    2. Beck LH Jr..,
    3. Meyer-Schwesinger C,
    4. Seitz-Polski B,
    5. Ma H,
    6. Zahner G,
    7. Dolla G,
    8. Hoxha E,
    9. Helmchen U,
    10. Dabert-Gay AS,
    11. Debayle D,
    12. Merchant M,
    13. Klein J,
    14. Salant DJ,
    15. Stahl RAK,
    16. Lambeau G
    : Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med 371: 2277–2287, 2014
    OpenUrlCrossRefPubMed
  11. ↵
    1. Bomback AS,
    2. Fervenza FC
    : Membranous nephropathy: Approaches to treatment. Am J Nephrol 47[Suppl 1]: 30–42, 2018
    OpenUrl
  12. ↵
    Kidney Disease Improving Global Outcomes: KDIGO clinical practice guideline for glomerulonephritis. Available at: https://kdigo.org/wp-content/uploads/2017/02/KDIGO-2012-GN-Guideline-English.pdf . Accessed August 13, 2020
  13. ↵
    1. Hofstra JM,
    2. Wetzels JF
    : Management of patients with membranous nephropathy. Nephrol Dial Transpl 27: 6–9, 2012
    OpenUrlCrossRefPubMed
  14. ↵
    1. Cattran D,
    2. Brenchley P
    : Membranous nephropathy: Thinking through the therapeutic options. Nephrol Dial Transplant 32[Suppl 1]: i22–i29, 2017
    OpenUrlCrossRefPubMed
  15. ↵
    1. van den Brand JA,
    2. van Dijk PR,
    3. Hofstra JM,
    4. Wetzels JF
    : Cancer risk after cyclophosphamide treatment in idiopathic membranous nephropathy. Clin J Am Soc Nephrol 9: 1066–1073, 2014
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. van den Brand JAJG,
    2. Ruggenenti P,
    3. Chianca A,
    4. Hofstra JM,
    5. Perna A,
    6. Ruggiero B,
    7. Wetzels JFM,
    8. Remuzzi G
    : Safety of rituximab compared with steroids and cyclophosphamide for idiopathic membranous nephropathy. J Am Soc Nephrol 28: 2729–2737, 2017
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Garau M,
    2. Cabrera J,
    3. Ottati G,
    4. Caorsi H,
    5. Gonzalez Martinez F,
    6. Acosta N,
    7. Aunchayna MH,
    8. Gadola L,
    9. Noboa O
    : Temporal trends in biopsy proven glomerular disease in Uruguay, 1990–2014. PLoS One 13: e0206637, 2018
    OpenUrl
  18. ↵
    1. Mazzuchi N,
    2. Acosta N,
    3. Caorsi H,
    4. Schwedt E,
    5. Di Martino LA,
    6. Mautone M,
    7. Gadola L,
    8. Petraglia A,
    9. Noboa O; Programa de Prevención y Tratamiento de las Glomerulopatías
    : [Frequency of diagnosis and clinic presentation of glomerulopathies in Uruguay]. Nefrologia 25: 113–120, 2005
    OpenUrlPubMed
  19. ↵
    1. Ponticelli C,
    2. Altieri P,
    3. Scolari F,
    4. Passerini P,
    5. Roccatello D,
    6. Cesana B,
    7. Melis P,
    8. Valzorio B,
    9. Sasdelli M,
    10. Pasquali S,
    11. Pozzi C,
    12. Piccoli G,
    13. Lupo A,
    14. Segagni S,
    15. Antonucci F,
    16. Dugo M,
    17. Minari M,
    18. Scalia A,
    19. Pedrini L,
    20. Pisano G,
    21. Grassi C,
    22. Farina M,
    23. Bellazzi R
    : A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol 9: 444–450, 1998
    OpenUrlAbstract
  20. ↵
    1. Jha V,
    2. Ganguli A,
    3. Saha TK,
    4. Kohli HS,
    5. Sud K,
    6. Gupta KL,
    7. Joshi K,
    8. Sakhuja V
    : A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. J Am Soc Nephrol 18: 1899–1904, 2007
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Cattran DC,
    2. Kim ED,
    3. Reich H,
    4. Hladunewich M,
    5. Kim SJ; Toronto Glomerulonephritis Registry group
    : Membranous nephropathy: Quantifying remission duration on outcome. J Am Soc Nephrol 28: 995–1003, 2017
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Faurschou M,
    2. Sorensen IJ,
    3. Mellemkjaer L,
    4. Loft AG,
    5. Thomsen BS,
    6. Tvede N,
    7. Baslund B
    : Malignancies in Wegener’s granulomatosis: Incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J Rheumatol 35: 100–105, 2008
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. Heijl C,
    2. Harper L,
    3. Flossmann O,
    4. Stücker I,
    5. Scott DG,
    6. Watts RA,
    7. Höglund P,
    8. Westman K,
    9. Mahr A; European Vasculitis Study Group (EUVAS)
    : Incidence of malignancy in patients treated for antineutrophil cytoplasm antibody-associated vasculitis: Follow-up data from European vasculitis study group clinical trials. Ann Rheum Dis 70: 1415–1421, 2011
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Yuan J,
    2. Fang W,
    3. Zhang W,
    4. Ni Z,
    5. Qian J
    : Treatment of nephrotic idiopathic membranous nephropathy with monthly i.v. pulse cyclophosphamide and oral steroids: A single centre’s retrospective study. Nephrology (Carlton) 16: 440–445, 2011
    OpenUrlPubMed
  25. ↵
    1. Mathrani V,
    2. Alejmi A,
    3. Griffin S,
    4. Roberts G
    : Intravenous cyclophosphamide and oral prednisolone is a safe and effective treatment option for idiopathic membranous nephropathy. Clin Kidney J 10: 450–454, 2017
    OpenUrl
  26. ↵
    1. Kanigicherla DAK,
    2. Hamilton P,
    3. Czapla K,
    4. Brenchley PEC
    : Intravenous pulse cyclophosphamide and steroids induce immunological and clinical remission in New-incident and relapsing primary membranous nephropathy. Nephrology (Carlton) 23: 60–68, 2018
    OpenUrl
  27. ↵
    1. Harper L,
    2. Morgan MD,
    3. Walsh M,
    4. Hoglund P,
    5. Westman K,
    6. Flossmann O,
    7. Tesar V,
    8. Vanhille P,
    9. de Groot K,
    10. Luqmani R,
    11. Flores-Suarez LF,
    12. Watts R,
    13. Pusey C,
    14. Bruchfeld A,
    15. Rasmussen N,
    16. Blockmans D,
    17. Savage CO,
    18. Jayne D; EUVAS investigators
    : Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: Long-term follow-up. Ann Rheum Dis 71: 955–960, 2012
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Falk RJ,
    2. Hogan SL,
    3. Muller KE,
    4. Jennette JC; The Glomerular Disease Collaborative Network
    : Treatment of progressive membranous glomerulopathy. A randomized trial comparing cyclophosphamide and corticosteroids with corticosteroids alone. Ann Intern Med 116: 438–445, 1992
    OpenUrlCrossRefPubMed
  29. ↵
    1. Reichert LJM,
    2. Huysmans FTM,
    3. Assmann K,
    4. Koene RA,
    5. Wetzels JF
    : Preserving renal function in patients with membranous nephropathy: Daily oral chlorambucil compared with intermittent monthly pulses of cyclophosphamide. Ann Intern Med 121: 328–333, 1994
    OpenUrlPubMed
  30. ↵
    1. Troyanov S,
    2. Wall CA,
    3. Miller JA,
    4. Scholey JW,
    5. Cattran DC; Toronto Glomerulonephritis Registry Group
    : Idiopathic membranous nephropathy: Definition and relevance of a partial remission. Kidney Int 66: 1199–1205, 2004
    OpenUrlCrossRefPubMed
  31. ↵
    1. Laluck BJ Jr..,
    2. Cattran DC
    : Prognosis after a complete remission in adult patients with idiopathic membranous nephropathy. Am J Kidney Dis 33: 1026–1032, 1999
    OpenUrlCrossRefPubMed
  32. ↵
    1. Trivin-Avillach C,
    2. Beck LH Jr..
    : Management of membranous nephropathy after MENTOR. Clin J Am Soc Nephrol 15: 415–417, 2020
    OpenUrlFREE Full Text
View Abstract
PreviousNext
Back to top

Podcast

Subscribe to podcast
Download MP3

In this issue

Kidney360: 1 (9)
Kidney360
Vol. 1, Issue 9
24 Sep 2020
  • Table of Contents
  • Table of Contents (PDF)
  • Cover (PDF)
  • About the Cover
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article

Thank you for your interest in spreading the word on American Society of Nephrology.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Substitution of Oral for Intravenous Cyclophosphamide in Membranous Nephropathy
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Substitution of Oral for Intravenous Cyclophosphamide in Membranous Nephropathy
Leonella Luzardo, Gabriela Ottati, Jimena Cabrera, Hernando Trujillo, Mariela Garau, Carlota González Bedat, Ruben Coitiño, María H. Aunchayna, José Santiago, Graciela Baldovinos, Ricardo Silvariño, Alejandro Ferreiro, Francisco González-Martínez, Liliana Gadola, Oscar Noboa, Hena Caorsi
Kidney360 Sep 2020, 1 (9) 943-949; DOI: 10.34067/KID.0002802020

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Substitution of Oral for Intravenous Cyclophosphamide in Membranous Nephropathy
Leonella Luzardo, Gabriela Ottati, Jimena Cabrera, Hernando Trujillo, Mariela Garau, Carlota González Bedat, Ruben Coitiño, María H. Aunchayna, José Santiago, Graciela Baldovinos, Ricardo Silvariño, Alejandro Ferreiro, Francisco González-Martínez, Liliana Gadola, Oscar Noboa, Hena Caorsi
Kidney360 Sep 2020, 1 (9) 943-949; DOI: 10.34067/KID.0002802020
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Visual Abstract
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Disclosures
    • Funding
    • Acknowledgments
    • Author Contributions
    • Footnotes
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

Original Investigations

  • Impact of Social Media on Self-Referral Patterns for Living Kidney Donation
  • Characteristics, Outcomes and 60-Day Hospital Mortality of ICU Patients with COVID-19 and Acute Kidney Injury
  • A Model To Estimate Glucose Absorption in Peritoneal Dialysis: A Pilot Study
Show more Original Investigations

Glomerular and Tubulointerstitial Diseases

  • Long-Term Beneficial Effects of Tonsillectomy on Patients with Immunoglobulin A Nephropathy
  • Functionally Essential Tubular Proteins Are Lost to Urine-Excreted, Large Extracellular Vesicles during Chronic Renal Insufficiency
Show more Glomerular and Tubulointerstitial Diseases

Cited By...

  • No citing articles found.
  • Google Scholar

Similar Articles

Related Articles

  • No related articles found.
  • Google Scholar

Keywords

  • glomerular and tubulointerstitial diseases
  • glomerulopathies
  • intravenous cyclophosphamide
  • Membranous Glomerulonephritis
  • Membranous nephropathy
  • nephrotic syndrome
  • relapse
  • remission

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Author Resources
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • Kidney360
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About Kidney360
  • Kidney360 Email Alerts
  • Kidney360 Podcasts
  • Kidney360 RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Disqus Code of Conduct
  • Disqus Information
  • Feedback
  • Follow on Twitter
  • Subscribe to JASN and CJASN

© 2021 American Society of Nephrology

Online ISSN - 2641-7650

Powered by HighWire