Topic Discussion: Novel anticoagulants in CKD and ESRD

New Oral Anticoagulants(NOACs)	Renal clearance of parent drug	Dosage in ESRD	GFR 15-29ml/min	GFR 30-40ml/min	GFR >-50ml/min	Dialyzable (yes/no)	Reversal agent
Dabigatran( Direct thrombin inhibitor)	80%	Avoid	75mg BID	150mg BID	150mg BID	Yes with 10% rebound rate	Idarucizumab Dialysis
Rivaroxaban(Factor Xa inhibitor)	36%	15mg QD	15mg QD	15mg QD	20mg QD	No	4-factor prothrombin complex concentrate Andexanet Alfa
Apixaban( Factor Xa inhibitor)	27%	5mg BID	2.5mg BID	5mg BID	5mg BID	No	4-factor prothrombin complex concentrate Andexanet Alfa
Edoxaban (Factor Xa inhibitor)	50%	30mg QD	30mg QD	30mg QD	60mg QD	No	4-factor prothrombin complex concentrate Andexanet Alfa

Patients with atrial fibrillations are being treated with NOACs as they are simple to use, no monitoring and excellent safety profile. They are higher in costs and experience still limited. NOAC use in patients with advanced CKD and on dialysis is substantial and increasing, despite AHA, ACC, and HRS and European Heart Rhythm Association guidelines that endorse warfarin as the anticoagulant of choice when CrCl is <30 ml/min. There are few randomized trial data on NOACs among patients with advanced CKD or on dialysis. Most NOACS are dependent on the kidney for elimination. Since most patients with advanced CKD were excluded in clinical trials, this topic is important. 

The above table summarizes what the current data exists on this topic for use of NOACs in CKD patients with Atrial Fibrillation for prevention of stroke.  Bleeding risk is important in patients with CKD and ESRD due to uremic dysfunction of platelets and use of heparin in HD.  Unfortunately, no patients with CKD Stage V or ESRD were not allowed in any of the NOAC trials. Apixaban was the most commonly used NOAC in a recent analysis in advanced CKD patients. Apixaban and Rivaroxaban have renal eliminations around 30% hence most safe in late stage CKD with lower dosing. Dabigatran and Edoxaban ar 80% and 50% renal elimination respectively and should technically avoided in late CKD patients.  Dabigatran is the only NOAC removed by dialysis based on studies thus far.

This review in JACC summarizes the latest uptodate information on use of these agents in CKD and ESRD patients. – A must read!

TOPIC DISCUSSION: Is THSD7A the paraneoplastic marker for Membranous GN associated with cancer?

Two recent papers from Germany have now associated the thrombospondin type 1 domain containing 7A(THSD7A) as a target antigen identified in membranous GN  in association with cancer.   In a large study, the authors screened > 1200 patients for western blot analysis for THSD7A. The incidence was 2.6%. They were mostly women.  In this cohort, the percentage of patients with THSD7A-associated MN and malignant disease significantly exceeded that of patients with PLA₂R-associated MN and malignant disease. In all cohorts, they identified 40 patients with THSD7A-associated MN, eight of whom developed a malignancy within a median time of 3 months from diagnosis of MN. In one patient with THSD7A-associated MN and metastases of an endometrial carcinoma, immunohistochemistry showed THSD7A expression on the metastatic cells and within follicular dendritic cells of the metastasis–infiltrated lymph node. 

In a separate report in NEJM, the same group described a case of gall bladder cancer and membranous GN. The patient had circulating THSD7A antibodies and THSD7A antigen positive membranous GN.  The primary gall bladder tumor and lymph nodes also stained for THSD7A on the immunohistochemical analysis.  Following chemotherapy, the THSD7A antibodies in plasma were no longer detectable and proteinuria improved as well. In that study, when additional 1009 patients with membranous were reviewed, 25 had positive THSD7A antibodies. Of the 25, 7 had malignant tumors.

Patients with THSD7A-associated MN differ in their clinical characteristics from patients with PLA₂R1-associated MN, and more intensive screening for the presence of malignancies may be warranted in those with THSD7A-associated MN.

Topic Discussion: Serology based treatment of Membranous GN

Gone are the days of a kidney biopsy for Membranous GN… Can that happen?   Given the advent of PLAR2 antibody titers availability clinically, can we embark on a serological based approach to diagnosing and treatment of PLAR2 associated Membranous GN.  Here is a proposal from Glassock, Fervenza, Sethi  in JASN( Not evidence based at this point but pathophysiology and common sense based)

I think figures 4,5,6 summarize the entire paper nicely and are good flow charts for clinical use.

1.       Start with measurement of PLAR2 levels and screening for secondary causes.

2.       If PLAR2 is positive and no secondary cause, you have diagnosed PLAR2 associated membranous GN( perhaps no biopsy necessary—my editorial comment)

3.       If PLAR2 is negative, a kidney biopsy is mandatory ( if no contraindications and there should be PLAR2 antigen staining done on it)

4.       If PLAR2 antigen is positive on the biopsy—it’s likely a PLAR2 associated membranous GN and perhaps in immunological remission as PLAR2 antibodies were negative.  If the PLAR2 antigen in kidney is negative,   measurement of THDS7A antibody in serum and it’s antigen staining in the kidney should be performed. If that is positive, you have diagnosed THDS7A associated membranous GN and that has a strong association with cancer and hence  aggressive screening for cancer needs to be done.  IF it is PLAR2 antigen and THDS7A antigen negative but IgG subclass 3 positive, secondary causes need to be considered as this is secondary membranous GN.

5.       Once diagnosed with PLAR2 + membranous GN,  and the titer is in the high range( highest range in the respective lab), and any level of proteinuria,  the titer should be repeated twice a month and if it continues to rise, start cytotoxic agents.  If moderate PLAR2 or low and has nephrotic  or non nephrotic syndrome, again follow the titers and if rising, start treatment.  If titers are down trending or proteinuria is improving, no treatment necessary. There is going to be immunological remission before the proteinuria and clinical remission

6.       If PLAR2 AB response is rapid and >90% reduction in <6 months, consider stopping treatment

7.       If PLAR2 AB is 50% in 6 months or no response, consider changing treatment options

8.       If the response is slow (50-90%) at 6 months, continue treatment for longer time frame.