Wednesday, July 19, 2017

Glomcon Teaching Tool

Glomerular Disease Case Conferences from GlomCon on Vimeo.

I would like to introduce you to a new educational project for Nephrology fellowship programs, the Glomcon Teaching Tool. It has been selected as a finalist in this year's ongoing ASN Innovation contest.

This teaching tool has four components:
 1) A Pre-conference 'Glomcon Trivia' webinar : Tuesday 12pm.
-Hour long sessions, led on a rotating basis twice a month by participating Nephrology Programs
-Live audience response polling

2) Live web-based Glomcon Case Conferences, Wednesday 6pm
-Conferences include pathology slides review by a nephropathologist. Discussion is led by a volunteering nephrologist.

3) Web-based archive of de-identified case summaries from past conferences with pathology images

4) Discussion forum questions from the pre-conference webinar will be posted in an online quiz format for users who may have missed it earlier.

We will organize the first Glomcon Trivia session on August 1 with the case conference on August 2.
At this time, 13 programs across the country are participating in it. If you or your program would like to be a part of this endeavor, please email me at If you would like to sign up for the Glomcon case conferences, please email

Thank you very much for your time. I look forward to hearing from you.

Nikhil Agrawal
Nephrology Fellow PGY-5
Beth Israel Deaconess Medical Center/Harvard Medical School

Thursday, July 6, 2017

Treatment of HCV with the new DAAs: Before or After Kidney Transplant?

In the pre-DAA era, the dogma was to treat HCV pre-transplant for two reasons: active HCV increases post-transplant hepatic complications, NODAT, and decreases patient and graft survival and that IFN cannot be used post-transplant because of higher risk of graft rejection. The highly effective and safe newer DAA options have literally eliminated both of these problems making the hitherto unfeasible strategy of treating HCV post-transplant feasible.
Needless to say, pre-transplant treatment can improve the risk of HCV-related morbidity, incidence of diabetes and possibly cardiovascular disease in waitlist candidates but they do have to wait longer (3-5 years) for an HCV negative kidney post treatment. Instead, if they choose to receive a HCV+ kidney and get treatment post-transplant they just have to wait only for 6 months to 1 year. The downsides of waiting longer (after successful HCV treatment) are worsening of their general condition during the wait time and even never getting transplanted at all. Receiving an HCV+ kidney and treating HCV post-transplant is safe, shortens waiting time and is cost effective
Purely on a utilitarian basis, it does make sense to treat HCV post-transplant, unless the wait time is expected to be short i.e. AB blood group, live donor transplant, centers with short waiting time or if liver disease is severe enough to warrant early treatment. For live donor transplants planned within 24 weeks, HCV treatment should not unnecessarily delay the transplant itself as the cure can be obtained with DAAs post- transplant. If the transplant is expected to be delayed (>24 weeks), it is wise to treat GT1/4 pre transplant with renal safe non-sofosbuvir regimens but for non GT1/4, depending on the expected time of transplant, sensitization and risk of rejection, liver status, general condition  and patient preference, the treatment can be performed either pre-transplant with IFN/ribavirin or post- transplant with sofosbuvir based DAA regimen.
Transplanting HCV+ve kidneys into HCV-ve Recipients: solves problems raises questions 
The recent THINKER trial reported successful treatment of HCV in 10 NAT negative recipients transplanted with GT1 positive kidneys, under ATG induction and triple drug (CNI, MMF, steroid) immunosuppression. Although all recipients had viremia on day 3, sustained viral response (SVR) at 4 weeks was 100% with Elbasvir/Grazoprevir. At 6 months none had virological relapse and graft function was excellent (median eGFR at 6 months was 62.8ml/min/1.73m2). The only major adverse event observed was sub-nephrotic proteinuria/FSGS in one patient that occurred after SVR at 12 weeks and so is less likely to be HCV related. Another patient had a transient increase in the class I DSA without any rejection. This D+/R- study provided the recipients with high quality donor kidneys (median KDPI 42%) and significantly reduced the wait time (range between 11 days to maximum of 130 days)Although very successful, this small pilot study raises many questions:
  • Liver outcomes, patient/graft survival in case a SVR does not occur (rare)
  • Cost-benefit ratio if second line DAA is required
  • Potentially increased risk of DSA and rejection
  • Treatment options if donor has non GT1/4 HCV infection
Current challenges in HCV treatment and Future of DAA
Growing RAV (resistance associated variants) and DAA resistance is a threat to HCV treatment. Further DAA treatment for non GT1/4 in renal failure and allograft dysfunction is still a challenge. Pan-genotypic DAAs which are effective and safe in renal failure will hopefully soon be a reality. Glecaprevir/Pibrentasvir is one such DAA now awaiting FDA approval. It has been found to result high SVR irrespective of genotypes, liver status, previous IFN exposure and CKD stage (98% SVR in stage 4/5). The effectiveness in DAA exposed patients is being currently studied by MEGALLAN part 2 study.
Post by Prabhu Kanchi

Tuesday, July 4, 2017

Treatment of HCV with the new DAAs: Part 1

The Burden of Hepatitis C
The estimated global Hepatitis C viral infection (HCV) burden was slashed down to 71 million by the WHO in 2015, from the earlier estimate of 130-150 million, after Rao et all showed that only 51% of patients with positive serology actually carried the virus (detectable RNA by NAT, nucleic acid amplification test). The remaining HCV seropositive have either cleared the virus [spontaneously or after treatment] or have a false positive serology. These NAT negative seropositive patients are considered non-infectious. NAT positive but seronegative individual are always infectious, except for the rare patients with false positive NAT (< 0.2%). NAT is the only reliable way to diagnose HCV in transplant candidates since these patients can be seronegative (due to immunosuppressive state) despite viremia and can have normal liver enzymes despite having liver disease.

            Overall, genotypes GT1 followed by GT3 are the most common strains and have a global prevalence compared to GT 2,4 and 6. GT5 is the least common of all having prevalence of <1% and limited to southern Africa. In the United States, approximately 70% of chronic HCV infections are caused by GT1 (55% of 1a, 45% of 1b) followed by GT2 (15 to 20%) and GT3 (10 to 12%). GT 1 is the more aggressive of all and also more resistant to interferon therapy but GT2 has greater risk of CKD progression than GT1.
Serology, NAT and HCV Transmission in the Transplant Setting
Transmission of a virus in eclipse phase (see below) is a well-known phenomenon with HIV and HBV. The eclipse phase is the time lag for the NAT to detect viremia after an acute infection. Even with the new generation HCV PCR tests, there is an eclipse phase of about 5-7 days. The first ever report of transmission of HCV from a NAT negative donor was reported in 2015. Notably in all the reported cases, the deceased donors had high risk behavior. The HCV infection being missed in a potential transplant recipient or a live donor in the eclipse phase has not been reported yet but is theoretically possible, especially in centers/countries with high HCV prevalence. 

Direct Anti-Viral Agents (DAAs) and renal disease
DAA in Chronic Kidney Disease
The introduction of DAAs was met with excitement by nephrologists, see previous RFN coverage. The treatment of GT1/4 in CKD is quite straight forward as non-Sofosbuvir regimens are available i.e.  Elbasvir/Grazoprevir (EG) and PrOD (Paritaprevir, ritonovir, Ombitasvir, Dasabuvir +R(ribavirin in GT1a). See here for coverage of the C-SURFER on the blog. These combinations can be used even in CKD4/5D as they are metabolized by the liver.
In contrast Sofosbuvir has renal excretion, accumulates in renal failure (eGFR < 30ml/min/1.73m2) and unfortunately further worsens the renal failure and hence contraindicated in CKD 4/5D. Since a Sofosbuvir-based DAA regimen (Sofosbuvir plus Velpasvir or Ledipasvir or Daclastasvir or Simeprevir) is the only approved treatment for non GT1/4 ,patients with eGFR< 30ml/min/1.73m2  should be treated with pegIFN/ribavirin and those with less severe CKD can be still treated with Sofosbuvir without any dose reduction. This might change after the results of the study looking at effectiveness of low dose Sofosbuvir/ Velpatasvir in non GT1/4 HCV patients with CKD5D, are available.
DAA in renal transplantation
Paritaprevir (effect of which is enhanced by ritonavir) inhibits the CYP3A4 enzyme causing 4-6 fold elevation in cyclosporine levels and nearly 60-80 fold elevation in tacrolimus levelsmaking use of the PrOD regimen less desirable in transplant setting. Even though PrOD was effective in liver transplant studies and no rejection reported with CNI dose changes, it has been never used in renal transplant studies. Since there is little direct data in allograft dysfunction, the data from CKD may be extrapolated to the transplant setting.

HCV Positive Donors
D+ donor kidneys are non-inferior
Outcomes of HCV D+ R + was considered inferior to D- R+ since the early viral replication with immunosuppression was thought to increase the risk of the liver disease, graft failure and patient mortality. It was even considered that transplantation outcomes with HCV+ donors not different from HCV+ patients remaining on dialysis. In reality, the risk was later found to be very small from 13 year UNOS data published in 2012. The risk of receiving a HCV+ kidney translated to only <1% lower survival at 1 year and a 2% lower survival at 3 years. Also, recently Morales showed that 10 year patient and survival graft survival was not different between D+ and D- to R+ patients.
HCV+ Donor Kidneys are underutilized
Increasing IV drug abuse in the past two decades has increased the prevalence of HCV in the young. Many of these newly infected population are unaware of the infection and so unlikely to get treatment but more likely to die due to drug over-dosage and hence are potential donors of  high quality kidneys. About 300-500 unrealized opportunities exist each year in US and nearly 4100 HCV positive good quality kidneys (with average KDPI 70%) were discarded between 2005- 2014.
In the following post I will deal with treatment issues including whether to treat with DAAs pre or post transplant.

Post by Prabhu Kanchi, Nephrology Fellow, Ottawa

Monday, July 3, 2017

New Wash U Webisode - Part 2/2 on Vascular Access

The July 2017 nephrology webisode is part 2 of a series featuring vascular access expert Dr. Dirk Hentschel.  In last month's episode we went to the bedside to examine the access of 2 patients on chronic hemodialysis.  This episode is a more traditional lecture that reinforces several concepts about pressure, flow, and how to approach some common vascular access problems that are often encountered.