Thursday, November 24, 2016

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)
75mg BID
150mg BID
150mg BID
Yes with 10% rebound rate

Rivaroxaban(Factor Xa inhibitor)
15mg QD
15mg QD
15mg QD
20mg QD
4-factor prothrombin complex concentrate

Andexanet Alfa
Apixaban( Factor Xa inhibitor)
5mg BID
2.5mg BID
5mg BID
5mg BID
4-factor prothrombin complex concentrate

Andexanet Alfa
Edoxaban (Factor Xa inhibitor)
30mg QD
30mg QD
30mg QD
60mg QD
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!

Wednesday, November 9, 2016

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.

Tuesday, November 8, 2016

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.

Tuesday, October 25, 2016

Topic Discussion: AKI following LVAD

Image result for LVADLeft ventricular assist devices (LVADs) are used increasingly as a bridge to transplantation or as destination therapy in end-stage heart failure patients who do not respond to optimal medical therapy. Many of these patients have end-organ dysfunction, including advanced kidney dysfunction, before and after LVAD implantation. Kidney dysfunction is a marker of adverse outcomes, such as increased morbidity and mortality.The incidence of AKI after LVAD implantation varies considerably: between 4 and 38 %. 

Risk factors:
INTERMACS score 1 or 2 (
Kidney <10 cm in size
Older age
ACE-I or ARB therapy immediately prior to surgery
High central venous pressure
Low LV end-diastolic dimensions
Long CPB time
Higher intraop bleeding
Need for re operation
Liver dysfunction
Need for blood transfusions
RV failure

Factors such as acute blood loss, volume shifts, arrhythmias, and the effect of multiple vasoactive medications influence renal hemodynamics. The sudden change in renal blood flow characteristics due to continuous flow-LVAD support can lead to AKI. Patients with preoperative RV failure and patients with INTERMACS scores of 1 or 2 are at higher risk of AKI.  The RV function is of vital importance after LVAD placement since postoperative RV failure and idioventricular arrhythmias have been associated with AKI . An RV dysfunction can result in a reduced LV preload, low LVAD speeds, reduced forward flow, increased arrhythmias, and liver as well as kidney congestion.

It appears that the cause is hemodynamic vs ATN. No study has really defined the mechanism. Given the LVAD devices have pro thrombotic risk , renal vascular thrombosis and or anticoagulation related AKI should be in the differential. As always, AIN from any medication is to be considered. Hemolysis related injury could be leading to pigment nephropathy as well.

Wednesday, October 12, 2016

Tuesday, October 4, 2016

In the NEWS: Lung Ultrasound and volume assessment in ESRD

Your new device- the lung ultrasound has made its way in Europe. A recent trail in CJASN discusses the value of using lung ultrasound in assessing volume status of a patient.  Lung water can be used in a way in clinical practice as it is being used in critical care and cardiology to assess volume in ESRD patients.  Few prior studies that have looked at the role of ESRD and lung ultrasound in clinical practice and training of fellows/faculty  are here:

This new study in CJASN looked at >1000 patients pre and post HD via lung ultrasound simultaneous to standardized lung exams ( crackles ) and peripheral edema.  What the investigators found was that the lung congestion by crackles, edema or a combination was inferior to ultrasound B lines in various analysis.  Using the knowledge of B lines might guide us in better managing volume status in our ESRD patients. 

In the editorial with it in CJASN, Dr. Rich Sherman writes “I believe that lung US will prove to be of value in improving the care of patients on dialysis . From a practical standpoint, I hope that this technique can provide us with at least one simple benefit. If a routine lung US on the previous Friday before dialysis might make these events less likely, then sign me up!

I concur with Dr Sherman! I think Nephrologists should get familiar with the science and technology and embrace this change to help their patients. Dialysis units ( large and small) should consider carrying US machines to help guide volume exam and make clinical decisions. It will decrease hospitalizations, less radiation exposure( X rays) and hopefully less ER visits.

Image courtesy:

Monday, October 3, 2016

Concept Map: Electrolyte Disorders and anti cancer agents

Most electrolytes disorders are "hypo" that are drug induced from anti cancer agents. Mechanism is mentioned where there is evidence.

The two references are:

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