APOL1 risk alleles and renal transplant function: time for Mission APOLLO

APOL1 is the newest addition to the list of CKD risk factors- possibly never before in the history of nephrology has a gene associated with such a high odds ratio with disease - above 7 for hypertensive CKD & >10 for FSGS. A gene that confers heterozygous survival advantage when present as a single variant allele, but two variants lead to high CKD risk - APOL1 on chromosome 22. A similar picture of the survival advantage is seen with sickle cell disease. For more on the fascinating story of APOL1 itself, see this open access review, NephMadness coverage from 2015, and the NephJC coverage of a more recent research.

A recent study has shown increased risk of CKD and subsequent ESKD in a population of black kidney donors with high risk APOL1 genotype. High risk is defined as presence of two variants (G1 and G2 – so any combination G1/G1, G1/G2 or G2/G2 is high risk) and was associated with faster progression of renal dysfunction and lower pre- and post-donation eGFR (pre-eGFR 98 versus 108; p= 0.03 and post-eGFR 58 versus 68; p=0.01) over a median follow up of 12 years. The second part of the study involved comparison between these donors and non donors from the CARDIA cohort (Coronary Artery Risk Development in Young Adults), based on APOL1 genotype status. After median 11 years, there was no difference in eGFR decline between the two groups when segregated based on genotype status, indicating that it was the genotype which influenced the eGFR decline and not the donation. Other salient features in the study were:

• 2 donors in the high risk group developed ESRD at 10 and 18 years of donation (11 %, but there were only 19 in this group).
• 78% of the donors were first degree relatives of the recipients. So the fact that a substantial percentage of donors were at risk of subsequent renal disease in this study does raises some valid concerns. Should all black donors be genotyped before transplantation?

An original article published in the Annals of Surgery recently studied eligible kidney donors (n=3438) from the CARDIA cohort of 1985-86 and deduced some risk scores based on the clinical and genetic profile of this population. They projected the 25 year pre-donation risk of CKD (eGFR <60ml/min) or microalbuminuria or macroalbuminuria in an 18 year old and a 30 year old potential donor. This risk is for people with no clinical risk factors (family history/pre-hypertension/diabetes). The risk increases significantly if any of these risk factors are present. See the table for some examples (EA – European American; AA – African American):

How about the risk to the recipients? Case reports have shown development of post transplant FSGS in siblings and monozygotic twins, both in the donor and in the recipient. Data from other studies have shown increased risk of allograft failure in recipients if the donor has a high risk genotype. All these data clearly point to the risk of CKD and subsequent ESKD in AA individuals (both donors & recipients) following transplantation. This brings us back to the most pertinent question, should people of African ancestry be genotyped for APOL1 prior to transplantation? The present studies are not well equipped to answer this question. Though it may seem that one obviously should screen (‘11% of donors with high risk variants develop ESRD!’ ‘High risk variants increase graft failure in recipients!’), lets pause and consider this. We know that live donor transplantation is the modality that offers the best survival. We also know that minorities, in US as well as in UK and elsewhere, have a lower rate of live donor transplantation (see NephJC coverage of a recent JAMA study and the ATTOM study, as well as the NephMadness coverage from 2017 on disparities in transplantation). So, would genotyping worsen the disparity? Is our fate inextricably written in our genes? Enter APOLLO.

APOLLO, APOL1 Long-Term Kidney Transplantation Outcomes Network, is a prospective study aimed at  genotyping donors and recipients in transplants involving recent African ancestry in United States and monitoring long term follow up. This will shed more light on this question and even might have a decisive influence on the present KDRI (kidney risk donor index), replacing the race column with APOL1 genotype. We await this important piece of work with interest.

Post by Sriram Sriperumbuduri

Primary Membranous Nephropathy

The landscape of Primary Membranous Nephropathy (PMN) has significantly changed over the last decade. Most of what we now understand about the pathogenesis of PMN is derived from the Heymann Nephritis model in rats. In 1959, Dr. Walter Heymann published this landmark article, which established the autoimmune nature of the disease. In the late 1970s, two groups (Dr. Couser et al in Boston and Dr. Van Damme et al in the Netherlands) established that the deposits of Heymann Nephritis were not from circulating immune complex trapping, but due to in situ formation. The rat antigen was eventually identified as megalin. The human antigen equivalent remained unknown until much later. Finally, 2009, Salant, Beck et al found that 70% of adult patients with “idiopathic” membranous nephropathy had antibodies against M-type phospholipase A2 receptor (PLA2R), a transmembrane glycoprotein found on podocytes. Soon after, another podocyte transmembrane glycoprotein called thrombospondin type-1 domain-containing 7A (THSD7A) was discovered (See NEJM 2014; 371(24):2277-2287).

Now, approximately 85% of PMN is found to be mediated by anti-PLA2R or anti-THSD7A, with still 15% of PMN “idiopathic”. With a serologic test for anti-PLA2R now commercially available as well as a biopsy immunofluorescent stain, the diagnosis and management of patients with PMN has been completely revamped.

For more on this discussion, please join us in the next GlomCon Interactive Fellows’ Curriculum on Tuesday, July 17th at 11 am eastern time. We will be walking through a case scenario as we review several different aspects of PMN.

To join the meeting go to: https://glomcon.zoom.us/ and select 'Join a Meeting'. Enter the Meeting ID into the web site (or connect directly from your Zoom app).

Meeting ID: 394-801-817

You HAVE to be logged into ZOOM to join the session. You may either create a free ZOOM account, or sign in through a Google or Facebook account (if you have one).   

Alternatively, use your institution's 'Polycom' system, enter IP address:

US West: 162.255.37.11

US East: 162.255.36.11

Europe: 213.19.144.110

Then, enter the Meeting ID: 394-801-817

Anemia post-transplantation

A 20-year-old female had Henoch-Schönlein purpura since age 9 leading to ESRD. She underwent kidney transplantation in 2018 from a live donor (mother) and received induction immunosuppression with thymoglobulin (100 mg once) followed by maintenance with tacrolimus (6 mg twice a day), mycophenolate sodium (720mg twice a day) and prednisone (30mg daily). The patient was discharged 5 days after surgery, with creatinine 0.9 mg/dL with tacrolimus trough level of 9.2 ng/mL.

Before surgery, the hemoglobin level ranged from 12.1g/dL to 11.6g/dL. At the time of medical discharge Hb was 9.8g/dL. During the follow-up, the patient was asymptomatic, with no increase in creatinine level and with good trough tacrolimus level (range of 8-12 ng/ml). However, at 2 months post-transplant, she developed worsened anemia with a hemoglobin of 6.1g/dl. At this time, the patient remained asymptomatic. She was then referred to the ED.

The exams at the time showed: hemoglobin 6.2 g/dL; reticulocyte 0.29%; haptoglobin 89 mg/dL; LDH 220 U/L. Subsequently, a bone marrow aspirate was performed and showed a giant pronormoblast with prominent nuclear inclusions, characteristic of parvovirus B19 infection.(FIGURE 1)

The patient received 2 doses of intravenous immunoglobulin (1g/kg/day) and was switched from tacrolimus to everolimus.

Anemia is a very common finding during post-kidney transplant consults. It is not uncommon to have patients that remain with anemia in the first 3 moths after the procedure. Read more here. (FIGURE 2)

The lack of large case series would make us imagine that parvovirus B19 infection after kidney transplant is rare. The incidence in post-transplant is not easy to estimate (range from 1-10%) and mostly occur in the first year, suggesting donor transmission, as described here.  Also, anemia is a common finding after kidney transplant and may have many other differentials that would appear higher on the list, including drug-induced myelosuppression and bleeding. Additionally, parvovirus B19 surveillance is not performed in routine clinical practice.

 A 2006 review from Mayo Clinic showed that among 98 patients with PVB19 infection after transplantation, 54% were kidney transplants, 9% liver transplants, 12% heart or lung transplants and 24% autologous or allogeneic HSCT recipients. The mean age of the patients was 35.2 ± 17.1 years. The majority (58%) were male. The median time to onset of parvovirus B19 disease was 1.75 months (range, 1 week–96 months) after transplantation. Overall, this study suggested that kidney recipients are in particular susceptible to parvovirus infection and that timing of presentation is variable though highest in the early period post-transplant. (FIGURE 3). Finally, it is reasonable to think that the magnitude of parvovirus B19 infection is underestimated.

Dr Felipe Paste
São Paulo, Brazil

Free eBook on Acid Base

Benjamin Abelow's book: The Painless Guide to Mastering Clinical Acid-Base is available again as a free download in recognition of the new class of incoming nephrology fellows. We have highlighted this book in the past. It is a great primer on Acid-Base for trainees - easy to read and very informative. 

The details on how to access the offer are below. It will be available for a limited time only. 

To download a free ebook copy of The Painless Guide to Mastering Clinical Acid-Base, follow the numbered steps below. You will be downloading directly from Amazon, where you can also read editorial reviews of the book. The ebook is a Kindle file type. Apps are available for all devices: phones, tablets, and laptops, including Apple, Android, and Windows. The ebook will be available for free for three days, Sunday, July 8 - Tuesday, July 10. 

To Download:

1.  During the period Sunday, July 8 - Tuesday, July 10 click here: https://www.amazon.com/Painless-Guide-Mastering-Clinical-Acid-Base-ebook/dp/B06XRM56TY

2.  Be sure you’re on the page for the e-book (Kindle) edition, not the paperback. During the three days in questions, it should say, "Kindle Price: $0.00."

3.  Click on “Buy now with 1-Click.” (Do not click on “Read for Free,” as that leads to the “KindleUnlimited” program, which has a monthly fee.)

4.  If you don’t already have a Kindle app on your device, you can easily download one. Just go to your usual on-line source for apps and search “Kindle.” The apps are available for all types and makes of devices. You can download to multiple devices associated with your Amazon account.

Congratulations New Fellows

Congratulations to the incoming class of Nephrology fellows!

I’m one of you! I went to way too many interviews and had the pleasure of meeting several passionate nephrologists and fellows. I’m confident that there are a lot of amazing, talented physicians among us.

While we may not meet each other again until our 2nd year of fellowship, I was hoping we could plan to build a stronger social network to stay abreast of the year ahead of us and affect change.

As a start, I wanted to point out a few resources available for us to use once we’re fellows in July of 2018: 1. Societies: Sign up to ASN, NKF and ISN. It’s free for fellows and gives you access to journals [Like JASN and CJASN through ASN; KI through ISN], NephSAP and grants for travel and research. ASN allows you to sign up for free as a resident, so, you could start there for now. 2. Travel Grants: Once you enter your second year, you’ll be able to go to several conferences. Here’s a running list of courses and conferences, several of which offer travel grants for fellows. [P.S: If you’re a medical student/resident, ASN and NKF have travel grants for conferences for you too!] 3. Grants. As your research interests develop, feel free to look here for opportunities for funding. 4. Social media. Please join the Renal Fellow Network blog [this one right here!], twitter and the NSMC [Nephrology Social Media Collective]. While the NSMC has already enlisted their amazing group of interns, applications will be open again for the next year. For this year, NSMC was accepting applications till January 1st, 2018.

There are several challenges that I’m aware of facing us in nephrology today. I’m going to list a few in the hopes that you will find some of these areas to be worth your while to work on in the near future.

As I write this, health policy in the field of nephrology is changing. For instance, a bill was introduced in October, 2017, which, on the surface appears to provide integrated care for dialysis patients. However, I have some concerns related to the bill pertaining to its ability to limit small and medium sized dialysis organizations from functioning, in addition to further severing the transitions of care between CKD and dialysis for patients. We need more physicians discussing bills like this in private and in public to help advocate for the future of our profession as well as our patients. As a group, we can make a difference.

The reputation of nephrology among medical students and residents has also changed over the last few years. Currently, I do not believe there are consistent websites or resources for interested applicants to look at to make an informed decision on nephrology. While there are a lot of negative things that are being said about our field, you are all here for a reason. I hope that we can use this blog to reinforce our reasons and convince future applicants to make the right choice for their career, whatever it may be.

One of the easiest and productive ways for us to make a difference in health policy, education, recruitment, clinical research and our career as nephrologists is to improve our collective social presence. This is why I think it’s important for you to consider joining this blog or the NSMC, if you haven’t already. [links above]

The Renal Fellow Network blog was created to be by the fellows and for the fellows. I hope you will join me in keeping that promise. Posted by Yuvaram Reddy

A Nephrology Fellow’s Guide to Billing/Coding

Nephrology fellows - you don’t want to miss the Siegfried & Roy of Billing & Coding @ParinMakadia @drirfanagha at Nephrology Business Leadership 2018 https://t.co/2GtrF6hBCM @NBLUniv @Nephro_Sparks @DiMiRenalMD @DallasRenal pic.twitter.com/XaD2gmuJ1U

— Samir Nangia MD CPE (@SamirNangia) January 19, 2018

I'm a second year Nephrology fellow and have been very fortunate to receive dedicated education on the business of medicine. During my time at Baylor, I was the inaugural fellow of the business track; a track designed by our program director Dr. Raghavan for fellows interested in learning key concepts of business of nephrology.

A part of the business track curriculum, it requires fellows to attend a national conference on the topic of business. I chose to attend to Nephrology Business Leadership University (NBLU) in August of 2017. This conference is a crash course into understanding key concepts on how to be a successful nephrologist in private practice.

Personally, one of the most interesting courses at NBLU was on Billing/Coding taught by Dr. Parin Makadia and Dr. Irfan Agha. This course was effective and unique as it was taught from coder’s point of view. After returning from my time at NBLU, I was inspired to write a billing/coding guide as my scholarly project for the Baylor Business Track. Using this link below - you will be able to view each section of a physician note and the necessary documentation needed to bill at an appropriate level.

Click here for the document

I hope this guide help all graduating fellows/residents going into practice, good luck!

Natasha N Dave
Baylor Nephrology Chief Fellow
Houston, TX