Balancing Cancer Risk and Efficacy of Using Cyclophosphamide to Treat Idiopathic Membranous Nephropathy

Khan, Sana; Bolton, W. Kline

doi:10.2215/cjn.04130414

Cited by 4 publications

(4 citation statements)

References 35 publications

(34 reference statements)

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“…Proteinuric relapses, seen in about 25% of patients, are not predicted by any clinical parameter, but usually follow the return of anti-PLA2R/THSD7A antibody and are treated by repeating the same therapy that induced the initial remission (1,2,(56)(57)(58)(59)(60). A course of cyclophosphamide should be repeated only once because cumulative doses .36 g are associated with an increased incidence of malignancy (55), although increased incidence ratios for malignancy have been reported in PMN at all levels of cumulative cyclophosphamide dose (66). Advantages of the Ponticelli regimen include the well established efficacy, including reduction in ESRD, lower relapse rate (25%), and considerable experience with its use (4,59,60,62).…”

Section: Ist Regimens In Pmnmentioning

confidence: 99%

“…Advantages of the Ponticelli regimen include the well established efficacy, including reduction in ESRD, lower relapse rate (25%), and considerable experience with its use (4,59,60,62). Disadvantages include a relatively high adverse event rate (25%) that includes infection, need for close monitoring of hematologic parameters, infertility, and later malignancy (56,57,62,66). CNIs (cyclosporin [CSA] or tacrolimus [TAC]), used either as monotherapy or combined with low-dose steroids, which is thought to improve response and reduce nephrotoxicity, have also been shown to decrease proteinuria, reduce the rate of loss of renal function, and decrease anti-PLA2R levels in PMN (1,2,4,(56)(57)(58)(59)(60).…”

Section: Ist Regimens In Pmnmentioning

confidence: 99%

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Primary Membranous Nephropathy

Couser

2017

CJASN

489

450

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Membranous nephropathy (MN) is a unique glomerular lesion that is the most common cause of idiopathic nephrotic syndrome in nondiabetic white adults. About 80% of cases are renal limited (primary MN, PMN) and 20% are associated with other systemic diseases or exposures (secondary MN). This review focuses only on PMN. Most cases of PMN have circulating IgG4 autoantibody to the podocyte membrane antigen PLA2R (70%), biopsy evidence PLA2R staining indicating recent immunologic disease activity despite negative serum antibody levels (15%), or serum anti-THSD7A (3%-5%). The remaining 10% without demonstrable anti-PLA2R/THSd7A antibody or antigen likely have PMN probably secondary to a different, still unidentified, anti-podocyte antibody. Considerable clinical and experimental data now suggests these antibodies are pathogenic. Clinically, 80% of patients with PMN present with nephrotic syndrome and 20% with non-nephrotic proteinuria. Untreated, about one third undergo spontaneous remission, especially those with absent or low anti-PLA2R levels, one-third progress to ESRD over 10 years, and the remainder develop nonprogressive CKD. Proteinuria can persist for months after circulating anti-PLA2R/THSD7A antibody is no longer detectable (immunologic remission). All patients with PMN should be treated with supportive care from the time of diagnosis to minimize protein excretion. Patients with elevated anti-PLA2R/THSD7A levels and proteinuria >3.5 g/d at diagnosis, and those who fail to reduce proteinuria to <3.5 g after 6 months of supportive care or have complications of nephrotic syndrome, should be considered for immunosuppressive therapy. Accepted regimens include steroids/cyclophosphamide, calcineurin inhibitors, and B cell depletion. With proper management, only 10% or less will develop ESRD over the subsequent 10 years.

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Section: Ist Regimens In Pmnmentioning

confidence: 99%

Section: Ist Regimens In Pmnmentioning

confidence: 99%

Primary Membranous Nephropathy

Couser

2017

CJASN

489

450

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“…For a long time, CTX based regimens have been the standard of treatment because they have been proven to be able to prevent the occurrence of ESRD and more effective in high-risk patients [ 22 , 23 ]. However, there are many disadvantages of CTX including relatively high incidence of adverse events, such as bone marrow suppression, liver function injury, infertility and malignant tumors, and so on [ 24 , 25 ]. CNIs have immunosuppressive effects, which can directly act on kidney podocytes, thereby reducing proteinuria and inducing a higher remission rate [ 26 ], but high recurrence rate and nephrotoxicity are concerns for long-term treatment [ 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

A preliminary nomogram model for predicting relapse of patients with primary membranous nephropathy

Wang

Lai

et al. 2023

Renal Failure

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Objective To explore the predictive factors and establish a nomogram model for predicting relapse risk in primary membranous nephropathy (PMN). Methods The clinical, laboratory, pathological and follow-up data of patients with biopsy-proven membranous nephropathy were collected in the Affiliated Hospital of Qingdao University. A total of 400 PMN patients who achieved remission were assigned to the development group ( n = 280) and validation group ( n = 120) randomly. Cox regression analysis was performed in the development cohort to determine the predictive factors of relapse in PMN patients, a nomogram model was established based on the multivariate Cox regression analysis and validated in the validation group. C-index and calibration plots were used to evaluate the discrimination and calibration performance of the model respectively. Result Hyperuricemia (HR = 2.938, 95% CI 1.875–4.605, p < 0.001), high C-reactive protein (CRP) (HR = 1.147, 95% CI 1.086–1.211, p < 0.001), and treatment with calcineurin inhibitors with or without glucocorticoids (HR = 2.845, 95%CI 1.361–5.946, p = 0.005) were independent risk factors, while complete remission (HR = 0.420, 95%CI 0.270–0.655, p < 0.001) was a protective factor for relapse of PMN according to multivariate Cox regression analysis, then a nomogram model for predicting relapse of PMN was established combining the above indicators. The C-indices of this model were 0.777 (95%CI 0.729–0.825) and 0.778 (95%CI 0.704–0.853) in the development group and validation group respectively. The calibration plots showed that the predicted relapse probabilities of the model were consistent with the actual probabilities at 1, 2 and 3 years, which indicated favorable performance of this model in predicting the relapse probability of PMN. Conclusions Hyperuricemia, remission status, CRP and therapeutic regimen were predictive factors for relapse of PMN. A novel nomogram model with good discrimination and calibration was constructed to predict relapse risk in patients with PMN early.

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“…3 However, adverse events are common in this protocol. 4,5 Calcineurin inhibitors (CNIs) are the only other level I treatment recommendation in the glomerular nephropathy (GN) guidelines for IMN patients who refused/failed cyclophosphamide/steroid therapy or had contraindications to this approach. Many important trials have been conducted, which have better defined the role of CNIs for the treatment of MN.…”

Section: Introductionmentioning

confidence: 99%

<p>Effects of CYP3A5 Polymorphisms on Efficacy and Safety of Tacrolimus Therapy in Patients with Idiopathic Membranous Nephropathy</p>

Zhang¹,

Duan²,

Guo³

et al. 2020

PGPM

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Background: Tacrolimus (TAC) is beneficial for patients with idiopathic membranous nephropathy (IMN). It has a narrow therapeutic concentration range and many factors influence TAC blood concentration. CYP3A5 is the most important enzyme in TAC metabolism. The aim of this study was to analyze the effects of CYP3A5 gene polymorphisms on the efficacy and safety of TAC in IMN patients. Patients and Methods: Patients with IMN who received oral TAC (0.05-0.075mg/kg/day) combined with prednisone (0.5mg/kg/day) from March 2016 to October 2018 were included. The data of clinical characteristics, therapeutic drugs and adverse reactions of patients were collected at baseline and during 24 weeks of treatment. Patients were divided into two groups according to different CYP3A5 genetic polymorphisms. The significant differences in the efficacy and side effects between the two groups were analyzed. Results: A total of 76 patients who completed follow-up were divided into CYP3A5 nonexpresser (CYP3A5*3/*3) group and CYP3A5 expresser (CYP3A5 *1/*3) group. The significant association between the CYP3A5 phenotype and TAC metabolism was observed. A total of 43 case-times patients exhibited adverse effects. The infection rate in CYP3A5 nonexpresser group (21.95%) was remarkably higher than the rate in CYP3A5 expresser group (5.71%). Blood concentration and C 0 /D levels were risk factors for adverse events through logistic regression analysis. There was no statistical difference between the study groups with respect to the efficacy. Conclusion: Our results demonstrated that CYP3A5 polymorphisms had important guiding roles in the treatment of IMN with tacrolimus. CYP3A5 expressers required higher daily doses of TAC to achieve the target drug concentration, but with fewer side effects. CYP3A5 genetic polymorphism might be used for TAC dosing adjustment to optimize the treatment for patients with IMN.

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Balancing Cancer Risk and Efficacy of Using Cyclophosphamide to Treat Idiopathic Membranous Nephropathy

Cited by 4 publications

References 35 publications

Primary Membranous Nephropathy

Primary Membranous Nephropathy

A preliminary nomogram model for predicting relapse of patients with primary membranous nephropathy

<p>Effects of CYP3A5 Polymorphisms on Efficacy and Safety of Tacrolimus Therapy in Patients with Idiopathic Membranous Nephropathy</p>

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