Some Points for the KDIGO 2021 Guideline for Prophylactic Anticoagulation in Membranous Nephropathy: Is It Clear Enough for Us to Follow?

Context: Patients with membranous nephropathy (MN) are recognized as individuals with high risk of thrombosis. However, prophylactic anticoagulant therapy in this population is still a controversial topic for a lack of high-quality evidence. Subject of Review: The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases was published in Kidney International in October 2021, and it was updated on the topic of prophylactic anticoagulant therapy in patients with MN. Differing from the previous main concern about the risk of venous thromboembolism (VTE) in MN, it paid attention to the risk of arterial thromboembolism (ATE) as well. Additionally, the risk of ATE was considered to be associated with hypoalbuminemia. A tool for evaluating the risk of bleeding in patients with MN was proposed in the KDIGO 2021 guideline, and individuals with low risk of bleeding as well as high risk of VTE were suggested to use warfarin or low-molecular-weight heparin (LMWH) combined with aspirin, as an alternative regimen for warfarin. Second Opinion: Our analysis shows that no consensuses have been reached on whether the prevention of ATE is necessary for patients with MN or whether the risk of ATE is associated with hypoalbuminemia. The proposed tool is not the only choice of tools for bleeding assessment, and the HAS-BLED risk score might be a better choice from the perspective of general applicability and availability. Furthermore, in our opinion, the suggestion for prophylaxis regimen of LMWH combined with aspirin showed a lack of consideration and might be inappropriate to some degree. In summary, there are still many controversies in the field of prophylactic anticoagulation for MN; as a consequence, more high-quality studies are required to provide guidance.

© 2022 S. Karger AG, Basel

A comment on Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. The KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct;100(Suppl 4):S1–276.

Introduction

It is widely accepted that the risk of venous thromboembolism (VTE) is higher in patients with membranous nephropathy (MN) than in other pathologic classification of glomerulonephritis [1, 2]. The Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline for Glomerulonephritis [3] suggested that patients with idiopathic membranous nephropathy and nephrotic syndrome (NS), with marked reduction in serum albumin (<25 g/L) and additional risks for thrombosis should be considered to use warfarin for prophylactic anticoagulant therapy. The topic was updated in the KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases [4], in which it was suggested that prophylactic anticoagulant therapy in patients with MN should be based on an estimate of the risk of thrombotic events and the risk of bleeding complications. However, there is a lack of detailed explanations for several critical issues, leading to a confusion in understanding.

Why Patients with MN Are Suggested to Prevent Arterial Thromboembolism

A previous retrospective cohort study enrolled 298 patients with NS found that the individuals had an increased risk of both arterial thromboembolism (ATE) and VTE, and the risk was 8-fold higher than that of the general population over 10 years [5]. Another retrospective cohort study evaluated 404 patients with primary membranous nephropathy (PMN) and NS and showed that the incidence of cardiovascular events (CVEs) in these patients was markedly increased, especially in the first 2 years after diagnosis, which indicated a high risk of ATE as well [6].

However, on the aspect of the risk factor of ATE, the two studies [5, 6] hold converse opinions. The former [5] found that the risk of ATE was associated with traditional risk factors, such as sex, age, hypertension, diabetes, smoking, prior ATE, and estimated glomerular filtration rate (eGFR), but neither the degree of proteinuria nor the level of serum albumin was associated with ATE. The latter [6], in contrast, showed that early in the course of disease (within 2 years), the risk of CVEs was associated with severe proteinuria, hypoalbuminemia, or both, as well as age, previous CVE, and diabetes. Interestingly, beyond 2 years after diagnosis, it was not associated with nephrosis.

According to the results of the latter study [6], a commentary article published in Kidney International in 2016 [7] raised a new issue on preventing ATE in patients with PMN and NS with aspirin and developed an algorithm to guide the decision to start aspirin, taking into account serum albumin levels. The algorithm was entirely proposed by the KDIGO 2021 guideline, as depicted in Figure 1 [4]. Similarly, Figure 2 [4] was also adapted from the commentary, with the prophylaxis regimens partially modified, which will be discussed in the following text.

Fig. 1.

Prophylactic anticoagulation in adults with NS. Adapted from [4]. *Please go to https://www.med.unc.edu/gntools/bleedrisk.html.

/WebMaterial/ShowPic/1448318Fig. 2.

Prophylactic anticoagulant therapy in patients with MN. Adapted from [4]. ‡Albumin value of 25 g/L or 32 g/L (2.5 g/dL or 3.2 g/dL) is measured using bromocresol green (BCG). *Please go to https://www.med.unc.edu/gntools/bleedrisk.html.

/WebMaterial/ShowPic/1448316

However, no consensuses have been reached on whether the prevention of ATE is necessary for patients with PMN or whether the risk of ATE is associated with serum albumin levels. Previous studies mainly focus on the risk of VTE relevant to PMN or NS, and there are few research reports about the risk of ATE. What’s more, current studies have yielded opposite results on the issue of whether hypoalbuminemia is a predictor of ATE. A systematic review of anticoagulation in NS published in 2020 [8] suggested to use either warfarin or enoxaparin to prevent VTE, but prophylactic antiplatelet therapy for ATE was not suggested. However, this article was not cited by the KDIGO 2021 guideline.

How to Evaluate the Risk of ATE

The commentary [7] as well as the KDIGO 2021 guideline [4] have proposed some items and set a cutoff value for assessment, as detailed in Figure 1 [4, 7]. The “20/1,000 patient-years” means that there are 20 patients who develop ATE out of 1,000 patients per year. According to the data from the randomized controlled trial (RCT) of aspirin in primary and secondary prevention of vascular diseases, the annual incidence of major bleeds due to aspirin was 0.1%, meanwhile, the annual incidence of ATE was reduced by 20% [9] (by the way, it is necessary to remind that the commentary [7] mistook “20%” for “25%” to avoid confusion). If we set 4:1 as an acceptable benefit-risk ratio, prophylactic anticoagulant therapy seems beneficial in a population with the ATE risk of ≥20/1,000 patient-years [7].

The estimation items for ATE risk include Framingham risk score (FRS), eGFR, diabetes, history of previous ATE, and additional risk due to NS, including proteinuria [4, 7]. The FRS, which takes into account age, smoking, serum cholesterol, and blood pressure, is a widely used clinical tool to predict the risk of coronary vascular disease in asymptomatic patients during a 10-year period. Individuals with two or more risk factors are recommended to calculate their FRS, and FRS ≥20% indicates a high risk of coronary heart disease [10].

Further analysis demonstrated that the risk of ATE exceeded 20/1,000 patient-years in most patients with MN with a serum albumin <32 g/L, except individuals that were very young, nonsmoking, and with an eGFR >60 mL·min−1 (1.73 m2)−1 [6, 7, 11]. Consequently, we consider that the patients are at high risk of ATE as long as they have one or more of the following risk factors, including FRS ≥20%, eGFR ≤60 mL·min−1 (1.73 m2)−1, being combined with diabetes or previous history of ATE. Furthermore, the additional risks due to NS need to be confirmed by more studies. For example, the use of prednisone in the treatment regimens for patients with NS increases the risk of thrombosis [6, 12]; therefore, the KDIGO 2021 guideline recommended that prophylactic anticoagulant therapy should not be omitted in patients who start prednisone therapy [4]. However, the absolute risk of ATE in the individual is not established, thus more studies are required to provide guidance.

How to Evaluate the Risk of Bleeding

The bleeding risk assessment tool proposed by the KDIGO 2021 guideline is “GN tools” (https://www.med.unc.edu/gntools/bleedrisk.html), which was developed by Lee et al. [13] in 2014. The tool was derived from a Markov model and can be used to estimate the potential benefit of prophylactic anticoagulation in patients with MN. It was conducted with the data for VTE risk as well as hemorrhage risk. The data of VTE risk were obtained from a cohort of 898 patients with PMN, and the data of hemorrhage risk were obtained in patients treated with warfarin for atrial fibrillation (AF) by reviewing the literature evidence and confirming the approximate validity of these estimates in patients with glomerular diseases and hypoalbuminemia. What is more, the risk of bleeding was stratified into “low, intermediate, and high” according to the clinical characteristics, such as severe renal disease, the history of bleeding, hypertension, advanced age, and anemia. Prophylactic anticoagulation was not recommended for patients at high risk of bleeding, but for patients at low or intermediate risk of bleeding, the serum albumin concentration was taken into account to estimate the probability of benefits and the acceptable benefit-to-risk ratio [13]. Unfortunately, the proposed algorithm (Fig. 1, 2) has missed the “intermediate-risk” category. It can be expected that if the calculated risk of bleeding is “intermediate” by GN tools, it is unable for users to make a choice according to the proposed algorithm. Thus, the “intermediate-risk” category should be added to the “low-risk” category as “low-to-intermediate risk” categories.

Besides the tool adopted by the KDIGO 2021 guideline, the HAS-BLED risk score was also used by researchers to evaluate the risk of bleeding in MN, which was regarded as a better predictor of bleeding in their studies [8, 14]. The HAS-BLED risk score takes into account hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly (>65 years), and drugs/alcohol concomitantly. The HAS-BLED risk score ≥3 indicates a high risk of bleeding [15].

However, it is worth noting that there is no “perfect tool” for patients with MN to date. The two tools both have their own advantages and disadvantages. The GN tools are developed from patients with PMN, thus it is perhaps more appropriate for MN in theory, but the sample size is relatively small and its accuracy needs further validation. In addition, reduced GFR might affect the calculation methods of benefit-to-risk used in this tool, so the application of the decision made in patients with moderate-to-severe renal insufficiency should be cautious [16]. What is more, it was developed for patients with MN, thus its applicability is uncertain for patients with NS due to other underlying diseases. Finally, it used to charge a fee to users, which is maybe one of the limitations of its application. In contrast, the HAS-BLED risk score is easy to obtain, free of charge, and has a better correlation with bleeding risk in the general population compared with other tools, but it is still uncertain whether the bleeding risk assessment tool designed for patients with AF could be directly applied in patients with MN. However, from the perspective of general applicability and availability, the HAS-BLED risk score might be a better choice.

How to Make a Choice of Anticoagulants for Prophylaxis

As is shown in Figure 2 [4], the prophylaxis regimen of low-molecular-weight heparin (LMWH) in combination with aspirin is regarded as a good alternative for warfarin. Figure 1 [4, 7], on the contrary, only proposed warfarin, which is consistent with the commentary [7]. It is no doubt that warfarin is a preferred agent of choice for prophylaxis owing to its long-term experience [4]. However, the regimen of LMWH combined with aspirin might be an inappropriate proposal to some degree. We have challenged the rationality of the combination regimen in a “Letter to the Editor” [17] published in Kidney International. We consider that it is illogical to use any other regimens except warfarin because the bleeding risk assessment tool is developed from AF patients treated with warfarin only, and there is no evidence supporting this prophylaxis regimen according to the reference cited by the KDIGO 2021 guideline; moreover, we have showed our concern over the safety of the combination regimen. We are very pleased to receive the reply [18] fromthe experts for the KDIGO Membranous Nephropathy Working Group. We agree that LMWH is one of the anticoagulants for prophylaxis in NS [8, 19, 20] and has been used in studies in women with miscarriages [18]. But, it cannot be ignored that the efficacy of LMWH for prophylactic anticoagulation is uncertain due to antithrombin III urinary loss in NS, which may potentially cause heparin resistance and, furthermore, the optimal dose of LMWH is not established [4, 19-22]. In our opinion, LMWH should not be used in patients with severe NS and severe renal insufficiency because there is a contradiction between requirements of a dose increase for antithrombin III deficiency and a dose reduction for impaired renal function. Last but not the least, there is little evidence of the regimen of LMWH combined with aspirin in NS or MN, due to the fact that it has not been reported in such individuals.

With respect to direct oral anticoagulants, there is a lack of evidence in MN and NS as well. Case reports exist of successful use of factor Xa inhibitor in adults with NS [23]. Meanwhile, case of failure use of factor Xa inhibitor reported the recurrent VTE in PMN, indicating that additional studies are required for the pharmacokinetics and pharmacodynamics, safety, and efficacy in patients with NS and hypoalbuminemia [24, 25]. In a word, warfarin is the current anticoagulant of choice until pharmacokinetics and pharmacodynamics studies are performed with newer agents.

In summary, there are still many controversial issues in the field of prophylactic anticoagulation in patients with MN. The evidence of other pathologic classification, which mainly derived from MN, is even more lacking. The KDIGO 2021 guideline and other studies have provided some guidance for us; however, a general consensus cannot be reached due to a lack of high-quality RCTs evidence. It is estimated that 972 participants are required to conduct an RCT, assuming that prophylactic anticoagulation could reduce the incidence of VTE by 75%, and 2,618 participants are required if the ratio is 50% [26]. Meanwhile, more than 6,000 patients would be required to conduct an ATE risk-related RCT [7]. Obviously, it is a hard work. It can be expected that the situation of lacking guidance from high-quality evidence in this field is going to continue for a long time, therefore, it is necessary to carry out other meaningful research, such as multicenter, large-scale retrospective studies based on existing databases or multicenter prospective studies to provide more evidence for prophylactic anticoagulation in MN and NS of other pathologic classification.

Conflict of Interest Statement

All the authors declared no competing interests.

Funding Sources

This work was supported by the National Natural Science Foundation of China (No. 81570612 and No. 81870497); the Jiangsu Province Key Research and Development Program-Social Development (BE2021737); and the Nanjing Health and Scientific Technology Development Program (YKK20237; YKK21268).

Author Contributions

Xiaomin Li drafted the manuscript; Xiaotong Xie and Yu Zhao analyzed the data; Guihua Wang made revisions; Hua Shao and Xiaoliang Zhang approved the final manuscript version.

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