Friday, September 22, 2017

From the Nate Hellman Unpublished Archive: microRNAs and the Kidney

MicroRNAs: one of the sexiest topics in the science community these days! Pick up a copy of Science, Nature, or Cell and you can usually find something to do with microRNAs within. What do these have to do with the kidney? Well, it's still a little premature, but there are certainly microRNAs present in the kidney, and recent studies have demonstrated that specific microRNAs are upregulated in conditions such as polycystic kidney disease and renal cell carcinomas, for instance.

How microRNAs work: microRNAs are single-stranded RNA molecules of between 21-23 nucleotides in length which are partially complementary to regions in multiple mRNAs. Once they bind to these mRNAs, the microRNAs either inhibit translation or completely degrade their target RNAs. A specific enzymatic machinery--comprised of the proteins Dicer and the RISC complex--is responsible for inhibiting mRNAs via microRNAs.

In essence, the power of microRNAs are that a single microRNA can regulate the expression of multiple genes working in parallel to achieve a similar biologic effect. This technology is of particular use to the pharmaceutical industry: one can envision targeting a particular microRNA which inhibit several pathways to prevent a disease process, such as atherosclerosis, renal fibrosis, or cyst formation to think of a few possibilities. The field is still very new. I wouldn't be surprised if a future Nobel Prize came out of this work. Three scientists (Drs. Ruvkun, Baulcombe, and Ambros) working on microRNAs recently won the 2008 Lasker Prize--considered by many to be the "precursor" prize to the Nobel.

Thursday, September 21, 2017

Nephrology Fellows: last call to join an online focus group on palliative care


Calling all Nephrology fellows!

Duke University School of Medicine is seeking to understand barriers and facilitators to palliative care conversations between nephrology fellows and their patients. The study, funded by the Agency for Healthcare Research and Quality, is led by Jennifer St. Clair Russell, PhD, MSEd, MCHES, a social and behavioral scientist in the Division of General Internal Medicine with over 11 years of experience in nephrology.

 If you are eligible to participate in our online focus group (on September 28), you will be compensated for your study participation. It is estimated that the online focus group will only take approximately 120 minutes.

We would be honored to have you participate in this exciting research!

To learn more or complete the eligibility questionnaire, please contact Nikita Shah at Nikita.Shah@duke.edu.

Monday, September 18, 2017

A Primer on Primary Hyperoxaluria

Primary hyperoxalurias are a group of autosomal recessive disorders characterized by excess hepatic oxalate production and reduced kidney excretion.

They are classified into three types based on their enzymatic defect in glyoxylate metabolism
  • Type 1 (80%): alanine glyoxylate aminotransferase (AGT) 
  • Type 2 (10%): glyoxylate reductase/hydroxypyruvate reductase (GRHPR) 
  • Type 3 (10%): mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme (HOGA1)
Variable in presentation and severity, its true prevalence is likely underestimated. While it can occur at any age, the median age of onset is 5.5 years. In Europe, it has an estimated prevalence of 1-3 cases per 1 million, incidence of 1 case per 120,000 live births and account for 1-2% of pediatric ESKD Unfortunately 20-50% of patients have advanced CKD at diagnosis and 10% are diagnosed only after disease recurrence following transplantation.

Excreted almost entirely by the kidney, oxalate can cause kidney tubular toxicity, nephrocalcinosis and obstruction with superimposed infection. In type 1 primary hyperoxaluria as eGFR falls below 30, plasma oxalate rises resulting in oxalate deposition in various organs including the kidney, heart, joints, retina, skin, bone marrow, heart and CNS.

Given its rarity, clinical suspicion is required for diagnosis. Definitive diagnosis requires genetic testing. Clinically it presents with urolithiasis (greater than 95% calcium oxalate monohydrate), recurrent UTIs, metabolic acidosis, acute kidney failure or oxalate crystals on kidney biopsy. Labs can be notable for persistently elevated urine oxalate, serum L-glycerate or serum oxalate. For persons with a family history, prenatal diagnosis can be obtained through genetic screening in the first trimester.

Conservative treatment strategies should be employed early and include aggressive hydration and potassium citrate to inhibit crystallization. Pyridoxine supplementation can be used for primary hyperoxaluria type 1 Gly170Arg and Phe152Ile genotypes. Intestinal oxalate has limited effects on disease progression as oxalate is largely produced endogenously and studies using oxalate-metabolizing probiotics like Oxalobacter formigenes have been disappointing.

In primary hyperoxaluria type 1 conventional HD and PD are ineffective at removing sufficient levels of oxalate for patients with ESKD due to ongoing liver production. While the ultimate management is transplantation, dialysis may be required as a temporary therapy to reduce plasma oxalate levels. Strategies include short daily sessions of high-flux dialysis, nocturnal dialysis, or combinations of hemodialysis and nocturnal peritoneal dialysis.

Isolated liver transplantation corrects the enzyme defect and can be used in early stages of kidney disease. Isolated kidney transplantation can reduced plasma oxalate, but disease recurrence often leads to poor graft survival. Dual liver-kidney transplantation is thus commonly performed for patients with CKD stage 4. Limited data exists for organ transplantation in primary hyperoxaluria type 2 and type 3 has not yet been associated with ESKD.

Sapna Shah, MD
Nephrology Fellow
Mount Sinai, New York

Tuesday, September 12, 2017

Prune Belly Syndrome and Kidney Disease


Prune Belly Syndrome (PBS) is a very rare (3.8/100,000 live births) congenital disease that predominantly affects males.

PBS is characterized by a triad of
  • Anterior abdominal wall muscle deficiency 
  • Urinary tract abnormalities
  • Bilateral cryptorchidism. 
Termed prune belly due to the wrinkled appearance of the abdominal wall at birth, it is a multisystem disease that can affect the genitourinary tract, cardiopulmonary, GI and musculoskeletal systems. Some studies and the inheritance pattern suggest that the disease is due to a recessive X-linked defect.  However, other studies have demonstrated a deletion in the the hepatocyte nuclear factor 1 beta (HFN1B) gene on chromosome 17q12 resulting in defective mesenchymal development, thus suggesting autosomal dominant inheritance. A clear genetic basis for PBS has not yet been established.

As per Seidal et al., nearly one-half of patients surviving infancy will develop CKD and nearly one third will develop ESRD and require RRT. This is thought to occur largely due to incomplete nephron differentiation, dilation of tubules, interstitial fibrosis and eventual glomerulosclerosis. Clinically PBS can be associated with reflux nephropathy and recurrent pyelonephritis.

Often diagnosed at birth or in early childhood, PBS can be diagnosed by antenatal ultrasound between weeks 20-30 with features including hydroureteronephrosis with or without echodense kidney parenchyma, oligohydramnios, hypoplastic lungs and bulging abdomen.

Therapy in childhood remains controversial, but can require early surgery for urine drainage in order to prevent recurrent infections or antibiotic prophylaxis. Maintenance CAPD and HD are equally effective in the management of ESKD and kidney transplantation has been successfully performed with excellent long-term prognosis.

Sapna Shah, MD
@NephShah
2nd Year Nephrology Fellow
Icahn School of Medicine, Mount Sinai, New York


Monday, September 11, 2017

Attn Fellows: Participate in an Online Focus Group on Palliative Care

Calling all nephrolgoy fellows!

Duke University School of Medicine is seeking to understand barriers and facilitators to palliative care conversations between nephrology fellows and their patients. The study, funded by the Agency for Healthcare Research and Quality, is led by Jennifer St. Clair Russell, PhD, MSEd, MCHES, a social and behavioral scientist in the Division of General Internal Medicine with over 11 years of experience in nephrology.

If you are eligible to participate in one of our two online focus groups (either September 17 or September 28, 2017), you will be compensated for your study participation. It is estimated that the online focus group will only take approximately 120 minutes.

We would be honored to have you participate in this exciting research!

To learn more or complete the eligibility questionnaire, please contact Nikita Shah at Nikita.Shah@duke.edu

Saturday, September 9, 2017

Origins of Renal Physiology at MDIBL Continues to Inspire Nephrology Fellows

2017 MDIBL Origins of Renal Physiology National Renal Fellows Course
I first discovered the Origins of Renal Physiology course on Renal Fellow Network as a medicine intern, and ever since that time, dreamt of going to the course as a renal fellow. Nate’s picture in front of the “Kidney Shed” was seared in my mind. The dream finally came true two weeks ago when I set foot on the Mount Desert Island Biological Lab (MDIBL) in Coastal Maine, and the first place I visited was indeed the Kidney Shed.

In his opening address to the fellows attending the course, Dr. Ziedel rightly said “Physiology is the pride of Nephrology”. He went on to mention the names of several luminaries who have worked at the MDIBL leading to many important discoveries. The lab has been a cornerstone of nephrology research and has been a home for the work of Homer Smith, E.K Marshall, David Evans, Franklin Epstein, and many others who have spent years working on and elucidating the fundamental concepts on kidney physiology.

In modern day practice of nephrology, we are less exposed to these fundamentals of kidney physiology that initially piqued our interest in nephrology. The Origins course is one of the many efforts made by the renal community to reconnect nephrolgoy fellows to physiology. It’s a very unique course which gives the fellows an opportunity to rub elbows with senior and distinguished renal physiologists from esteemed institutions and work with them on experiments to understand the different aspects of kidney biology.

The course consisted of 7 modules, each focusing on a functional unit of the nephron- the glomerulus, proximal tubule, thick ascending limb, distal tubule, acid-base, water homeostasis, and chloride secretion. We studied animals like zebrafish, turtles, and toad bladders. We also explored how ENaC and NKCC channels work. We delved into discussion about morpholinos and so much more. Over the duration of the course, we developed a new-found appreciation for the beauty and wonder of exploring how the kidney regulates homeostasis. We also got a sense for the profound impact MDIBL has had on the field of nephrology and physiology.

As MDIBL is in such close proximity to Acadia National Park- one of the most beautiful national parks in the world, nature is inherently embedded in the process of learning here. Most days started off with a refreshing early morning short hike which energized us to spend the entire day in the lab. On alternate days, amazing outdoor activities were planned for us after presentations of the earlier day’s work. My week at the MDIBL during this course was very memorable.

I was honored to be working closely with great mentors and met nephrology fellows from all over the US and abroad, shared interests and future aspirations and found new friends. 

All in all, an incredible experience! I would wholeheartedly endorse this conference for future fellows.

Manasi Bapat
@manasib33
2nd year Nephrology Fellow
Mount Sinai Hospital, NY

Tuesday, September 5, 2017

September Wash U Nephrology Webisode available - an unusual case of AKI!

Another great episode on the road, as I packed up my gear and headed to Rush University Medical Center in Chicago, IL.  Discussants joining me for this case are Dr. Roger Rodby, Dr. Pravir Baxi, and Dr. David Cimbaluk.  More complicated histology in a very unusual case of AKI:

"73 year old Caucasian female with hypertension, remote history of breast cancer, and NSAID use, presents with incidental AKI"


Tuesday, August 22, 2017

A few months ago, we posted about an acid-base primer that was being offered free for fellows in the US.

During the 5-day period from Wednesday, August 23 - Sunday, August 27, you can get a free copy of this ebook (kindle) edition of The Painless Guide to Mastering Clinical Acid-Base. Simply go to Amazon, search the title of Amazon ID number (B06XRM56TY), or click here, and you will find the ebook priced at $0.00 during those 5 days. Once you "purchase" the book, it will remain permanently in your Amazon library and you will be able to load it onto any device that has a Kindle app linked to your account. Feel free to notify students, residents, nurses or any others who might benefit. There is no limit to the number of persons who can get the download.

Posted by Ben Abelow

Tuesday, August 8, 2017

August Wash U Nephrology Web Episode now available

The monthly nephrology webisode from Wash U is posted and available for your viewing pleasure!  For August, we went on the road and recorded with some special guests from Rush University Medical Center in Chicago.  Try your hand at unraveling this tricky CPC with some complicated histology:

"32 year old African American male with uncontrolled hypertension, HIV, and a positive RPR presents with AKI and shortness of breath."


Monday, August 7, 2017

Midwest Point of Care Ultrasound Workshop

Washington University School of Medicine 
Point of Care Ultrasound Workshop  
Sunday, September 10, 2017
 Institute of Public Health
600 S.Taylor Ave.



Dear Friends. 
Point of care ultrasound has emerged as a powerful tool to assess volume status. This workshop will be part of the Midwest Nephrology + Transplant Symposium.  In this workshop we will review the fundamentals of beside US including heart, lung, and IVC assessment along with US-guided line placement and solid organ biopsy (kidney). 
For more info.

Thursday, August 3, 2017

Panda Eyes

I recently saw an elderly woman in clinic. She had a background history of migraine headaches and had been investigated over the past 18 months for recurrent syncopal episodes. She had at least 5 episodes that began with palpitations usually on minimal exertion. Apart from these episodes, she was fit and active. Her ECHO showed only mild LV hypertrophy and mild pulmonary hypertension. EKGs were unrevealing.

Two years ago she had been seen by a dermatologist for sun-related skin lesions and had mentioned that she had recurrent bruising around her eyelids. She had taken a photo of these lesions and they were noted to be purpuric. They would come and go and usually last for a couple of months when they were there.

She was referred to my clinic for investigation of mild albuminuria. She had ~500mg albumin for approximately 5 years with no significant change. Her renal function had always been otherwise normal apart from one single increase in creatinine was unexplained and returned to normal in a few days. She had no significant risk factors for kidney disease apart from long term NSAID use for her migraines.

As part of her investigations, she had an SPEP and free light chains. The results showed that she has an IgG lambda paraprotein likely related to an underlying multiple myeloma. Re-review of her ECHO images showed that they were consistent with infiltrative disease and she is currently undergoing work-up for AL-amyloidosis.

Periorbital purpura is a rare finding in patients with amyloidosis occurring in about 15% of patients. It is thought to be a result of Factor X deficiency due to binding of Factor X by the amyloid fibrils. It is generally atraumatic and tends to recur without treatment of the underlying amyloid. It is almost pathognomic of amyloid and its presence should prompt testing for AL amyloid.

Image from NEJM

Dialysis for dementia?


When I first began learning about Nephrology, I came across ‘dialysis dementia’, a progressive and fatal condition described in hemodialysis patients. Several studies in the 1970s implicated aluminium found in phosphorus binders and dialysate water as the cause. However, owing to modern techniques of water purification and the use of non-aluminium phosphorus binders, ‘dialysis dementia’ is now considered a rare adverse effect of dialysis, with a current estimated prevalence of 0.6–1.0%.

Nonetheless, moderate to severe cognitive impairment may affect 30–60% of patients undergoing hemodialysis (HD), and two-thirds of patients undergoing peritoneal dialysis (PD). The current pathophysiology of cognitive impairment in patients on dialysis might be mediated by traditional risk factors, such as older age, sex, diabetes mellitus, hypertension and cardiovascular disease; non-traditional factors, including hyperparathyroidism, elevated FGF-23 levels, vitamin D deficiency, anemia, malnutrition, inflammation, and oxidative stress; and dialysis-associated factors, such as adequacy, dialysis modality, hemodynamic instability during the procedure and solute shifts.

It was with interest then that I read recent research suggesting that peripheral clearance of amyloid-β (Aβ) by PD could help to reduce the amyloid plaque burden in the brain, potentially representing a new therapeutic approach for Alzheimer disease (AD). In this study, plasma Aβ levels before and immediately after PD in patients with CKD and in APP/PS1 mice (a standard animal model of AD) were measured. In both cases, plasma Aβ40 and Aβ42 levels were significantly reduced after dialysis. In the animal model, PD resulted in a decrease in Aβ levels in the brain interstitial fluid with reduced deposition even if plaque formation was well underway. The dialysis-treated mice showed reduced levels of hyperphosphorylated tau in the brain, suggesting a slowing of neurodegeneration along with decreased inflammation and increased microglial phagocytosis of Aβ in the brain. Attenuated cognitive decline was demonstrated by improved performance on the Y-maze and open-field tests.

According to the authors, this was a proof-of-concept study that restoration of the AD brain microenvironment and clearance of brain Aβ could be achieved by peripheral approaches. Yet how do we reconcile this promising experimental model with the high incidence of dementia in our PD patients? Although the USRDS data reports the risk of incident dementia to be lower for patients who started on PD than for those who started on HD, it still higher than the age-matched non-dialysis cohort. The tentative conclusion that we may draw from this is that vascular dementia is likely a far greater contributor to cognitive impairment in this population than AD.

In this study PD was very potent in removing Aβ from the blood in CKD patients. The authors highlight key differences in the PD procedure used in this study compared to standard practice. While CKD patients usually receive continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) with long dwell times of 8 hours or more, the AD mice received only 2 hours of dialysis per day. This suggests that CAPD may be even more effective at depleting the brain Aβ burden in AD patients. Similarly brain Aβ deposition appears to be lower in patients who receive hemodialysis. 

What are the implications of this study for us as nephrologists? Will we be dialyzing people for ‘dementia’ in the future? Or for other neurodegenerative diseases that may benefit from peripheral clearances such as Huntington disease or motor neuron disease?  More research is definitely needed and there will be side-effects that non-nephrologists may not appreciate but it could be an exciting area in the future.



Post by Dearbhla Kelly

Thursday, July 27, 2017

Training in ABPM, the “Renal Biopsy” of Hypertension


24 hour Ambulatory Blood Pressure Monitoring (ABPM) is the gold-standard for diagnosing sustained, white coat, and masked hypertension. It’s a better predictor of cardiovascular events than office readings and carries a Grade A recommendation by the United States Preventative Services Task Force (USPSTF).
The evidence is unequivocal and yet not all nephrologists perform ABPMs.  Fellows have even less exposure to implementation, interpretation, and reimbursement.
Last year, Raymond Townsend of U Penn and Daichi Shimbo of Columbia-Presbyterian created a course to address the above deficiencies. In addition to reviewing the evidence and billing aspects, the course focuses on practical considerations such as learning about the software and monitoring protocols, and correctly educating the patient on the dos/don’ts while wearing the monitor. The hands-on session allows attendees to familiarize themselves with the various models and wear an ABPM for the afternoon.
After attending last year, I not only gained a deeper understanding of ABPM but now have a resource for future questions. This year’s course (1 day) will be held on Monday, September 11th, in San Antonio, TX. 
I have no financial or formal relationship with the organizers.
Hillel Sternlicht, MD

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 nagrawa2@bidmc.harvard.edu. If you would like to sign up for the Glomcon case conferences, please email conferences@glomcon.org.

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.


Friday, June 30, 2017

An Under Recognised Cause of Metabolic Acidosis

The MUDPALES mnemonic for raised anion gap acidosis was drilled into me from medical school.  However recently after working through each category I became stumped when nothing ticked the box to identify the cause. 
The lady I had been asked to see was in her 80s and had fractured her hip.  On admission she had normal renal function and acid base status.  Post-operatively she was started on regular analgesia including paracetamol (acetaminophen) and developed a Staphlococcus Aureus wound cellulitis treated with flucloxacillin.  Over the following 2 weeks she developed a raised anion gap acidosis and positive urinary anion gap.  Renal function, lactate and ketones were normal.    
A cause of metabolic acidosis not in MUDPILES is pyroglutamic acidosis.  Pyroglutamic acid (also called 5-oxoproline) is a by-product in the gamma-glutamyl cycle.  This pathway is involved in the synthesis of glutathione, and is shown above from a recent paper.
Glutathione provides negative feedback on the cycle by inhibiting the enzyme gamma-glutamyl-cysteine synthase.  An acquired deficiency in glutathione, as with alcohol or paracetamol, results in loss of this negative feedback and increased production of 5-oxoproline leading to a metabolic acidosis.  Other drugs affect the cycle at different points including flucloxacillin which inhibits 5-oxoprolinase similarly resulting in build-up of 5-oxoproline. 
Urine amino acid screens show high levels of 5-oxoproline, though this test is not always available.  Our patient improved with withdrawal of paracetamol and flucloxacillin and oral bicarbonate which was stopped after a week.  Some cases have been treated with N-acetylcysteine to replenish glutathione levels. 
I think this is probably an under-recognised cause of metabolic acidosis with many of the risk factors being prevalent in our inpatients (poor nutrition, chronic alcohol use, renal failure, infection, paracetamol use).  A different mnemonic for causes of raised anion gap metabolic acidosis may be helpful like GOLD MARK:
·         G – glycols (ethylene and propylene)
·         O – 5-oxoproline (pyroglutamic acid)
·         L – L-lactate
·         D – D-lactate
·         M – methanol, ethanol
·         A – aspirin/salicylates
·         R – renal failure
K – ketones 

Post by Ailish Nimmo

Monday, June 12, 2017

The evidence behind the use of plasmapheresis in glomerular diseases

Therapeutic plasma exchange (PLEX) is a type of therapy where a patient’s plasma volume is removed over a period of a few hours, through a process of centrifugation of blood with subsequent separation of its constituents, and replaced by different types of colloid fluids, most commonly Albumin or Fresh Frozen Plasma (FFP). Its most frequent use in nephrology is for certain glomerulopathies such as ANCA-associated vasculitis, anti-GBM disease, recurrence of idiopathic FSGS post-transplant and atypical HUS. The data with regards to PLEX use for these indications is mostly historical and based on mechanistic concepts which led to multiple observational studies and reports claiming efficacy. There are very few randomized trials directly comparing PLEX to other therapies and a review of the data (see table summary of KDIGO recommendations) has really brought me a new perspective on what justifies our use of PLEX for renal disease.
Table: KDIGO recommendations on PLEX use for glomerular disease

KDIGO recommendation
Grade
Anti-GBM disease
We recommend initiating immunosuppression with cyclophosphamide and corticosteroids plus plasmapheresis in all patients with anti-GBM GN except those who are dialysis-dependent at presentation and have 100% crescents in an adequate biopsy sample, and do not have pulmonary hemorrhage
1B
Start treatment for anti-GBM GN without delay once the diagnosis is confirmed. If the diagnosis is highly suspected, it would be appropriate to begin high-dose corticosteroids and plasmapheresis while waiting for confirmation
Not graded
ANCA-associated vasculitis
We recommend the addition of plasmapheresis for patients requiring dialysis or with rapidly increasing SCr
1C
We suggest the addition of plasmapheresis for patients with diffuse pulmonary hemorrhage
2C
We suggest the addition of plasmapheresis for patients with overlap syndrome of ANCA vasculitis and
anti-GBM GN, according to proposed criteria and regimen for anti-GBM GN
2D
Post-transplant FSGS
We suggest plasma exchange if a biopsy shows minimal change disease or FSGS in those with primary FSGS as their primary kidney disease
2D
Atypical HUS
Not mentioned in KDIGO guidelines
Adapted from: Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Nov;9:S1; and Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA, Green MD, Jha V, Josephson MA, Kiberd BA, Kreis HA. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney international. 2010 Feb 2;77(4):299-311.


Anti-GBM disease
Anti-GBM disease has always been regarded as a sine qua non indication for PLEX.  I still remember my first teachings on anti-GBM disease in medical school which were were it causes lung hemorrhage, it causes acute kidney injury and it is treated with plasmapheresis. When reviewing the literature, I was surprised to find only a single randomized trial on the use of PLEX in anti-GBM disease. This a study published in 1985 in Medicine by Johnson et al where they randomized 17 (yes, only 17!) patients with biopsy and serology proven anti-GBM disease to either Prednisone + PO Cyclophosphamide (N=9) vs PLEX + Prednisone + PO Cyclophosphamide (N=8). Patients at baseline were not equally matched as the patients in the conventional group had higher serum creatinine (SCr) at start of therapy and had more severe disease on biopsy. Indeed, 5/8 biopsies available had >70% gloms with crescents in the conventional group vs only 1/7 in the PLEX group had > 50% gloms with crescents. They did find that more patients were dialysis dependent at the end of the study in the conventional group (6/9) vs the PLEX group (2/8). Four patients in the PLEX group had improvement in their renal function vs only 1 in the conventional group. These patients who had improvement were the ones with lower SCr at presentation. Eight patients had pulmonary hemorrhage (4 in each group) and all these episodes were treated with IV Methylprednisone pulse and responded promptly. There were only 3 deaths in all, 1 in conventional and 2 in PLEX group. Anti-GBM titers became undetectable much more quickly with PLEX, after about 2 months. Overall, it is somewhat surprising that what we consider such a strong indication for PLEX is supported by only 1 randomized trial showing improved renal survival with PLEX, where the groups were unevenly matched. What is also important to consider with anti-GBM disease is the possible futility of treatment in patients with most severe disease. A review of anti-GBM disease in the UK from 1980-1984 by Savage et al looked at outcomes for 108 patients. There were 69 patients who were dialysis dependant on presentation. At 8 weeks, none were off dialysis (51 on dialysis and 18 dead). Out of 12 who presented with a SCr>600umol/L, only 1 had improvement in renal function (other 11 either on dialysis or dead). Another British study published in 2001 in the Annals of Medicine by Levy et al retrospectively looked at all anti-GBM disease treated at the Hammersmith hospital in since 1975. They had 71 patients, 39 of which were dialysis-dependant on presentation. Only 2 were off dialysis at 1 year follow-up. When looking at outcomes based on biopsies, they found that 23% of patients with >50% crescents survived off dialysis and that 3 patients survived off dialysis despite >70% crescents. However, no patients with 100% crescents recovered renal function. Together, these results certainly seem to suggest that patients with severe anti-GBM disease presenting dialysis dependent have very little chance of recovery and may not benefit at all from immunosuppressive therapy and PLEX. While a trial of treatment may still be indicated, I believe a rapid re-assessment of the patient’s condition and need for continued immunosuppressive therapy is indicated given the high infectious risks with treatment. Patients with 100% crescents on an adequate biopsy are very unlikely to get any benefit and should probably just be managed conservatively.

ANCA-associated vasculitisAnother frequent indication for PLEX in glomerular disease is ANCA-associated vasculitis and thankfully there is a bit more data to guide us here. The best data comes from the MEPEX trial by Jayne et al published in JASN in 2007 where 137 patients with biopsy/serology proven ANCA vasculitis and SCr > 500umol/L were randomized to either PLEX (7 exchanges in 14 days) or IV methylprednisolone (1g IV daily x 3), both in combination with oral Cyclophosphamide and Prednisone. Patients with severe lung hemorrhage requiring mechanical ventilation were excluded. Just over 2/3 of patients were dialysis-dependent on presentation. They found that treatment with PLEX had a better renal recovery (alive and off dialysis and SCr<500umol/L) at 3 months than IV steroids (70% vs 49% respectively, P=0.02). The HR for ESRD at 12 months for PLEX vs IV steroids was 0.47 (0.24-0.91, P=0.03). Survival however was not significantly different (19 deaths in PLEX group vs 16 in IV steroids group) and most deaths were due to infections (19), lung hemorrhage (6) or cardiovascular disease (4) and very few due to vasculitis. A sub-study of the MEPEX trial by Van Wingaarden et al found that for patients requiring dialysis on presentation and with severe tubular atrophy on biopsy, the point at which patients would get more benefit for renal survival from treatment over risk of death from treatment was when they had 18% or more normal glomeruli for IV steroids group as opposed to only 2% normal glomeruli for PLEX. This suggests that patients with most severe disease are more likely to reap renal benefit from treatment when they are given PLEX. In 2013, Walsh et al published the long term follow-up data from the MEPEX trial and found that the short term benefit seen in MEPEX was lost. Indeed, for patients treated with PLEX there was no significant improvement in the composite of ESRD or death (HR 0.81, 0.53-1.23; P=0.32) nor in the outcome of ESRD (0.64, 0.40-1.05; P=0.08). At final follow-up, half the patients died and 2/3 were either dead or on dialysis, reaffirming the poor prognosis of severe ANCA vasculitis. A meta-analysis of all randomized trials looking at PLEX for ANCA vasculitis by Walsh et al in 2011 found PLEX to be associated with a 20% risk reduction in the composite of ESRD-death (HR 0.80, 0.65-0.99) and a 36% reduction in ESRD (HR 0.64, 0.47-0.88) but no effect on death (RR 1.0, 0.71-1.42). The authors did warn though that overall most trials were small, none of them individually found a significant result for the composite of ESRD-death and they had notable methodological flaws such as randomization concealment was only performed in 4/9 trials and the methods of concealment weren’t described in any. Hopefully, the PEXIVAS study which is now nearing completion and should be presented at the upcoming ASN Kidney Week 2017 (hopefully as a late-breaking trial) will help clarify the role for PLEX in ANCA vasculitis. For now, it would seem that PLEX is indicated for patients presenting with severe renal failure due to ANCA-vasculitis as it improves renal survival, without a mortality benefit though.

Post-transplant FSGS
It is sad to say that there are unfortunately no other prospective trials studying the role of PLEX for glomerular disease. While the use of PLEX for recurring idiopathic FSGS post-transplant is recommended (the rationale being the removal of some as of yet unidentified pathogenic plasma permeability factor), the data is purely observational. A review of 77 case-reports and case-series, totalling 423 patients with recurrence of FSGS post renal transplant, published in BMC Nephrology in 2016 showed that overall 71% of patients achieved complete or partial remission. Factors most associated with response were male sex and starting treatment within 2 weeks of recurrence. However, the lack of control group prevents us from establishing a clear benefit from PLEX itself. Also, the treatment regimens were extremely varied and it is unclear exactly how much PLEX, for how long should it be given and which replacement fluid to use. Finally, the frequent use of PLEX in these patients who are already on immune-suppressing drugs may predispose to even more infections given the removal of Immunoglobulins by PLEX.

Atypical HUS
Similar to FSGS, the use of PLEX for atypical HUS is based purely on observational data (case reports and case series). The rationale behind its use for this indication certainly makes sense by removing defective complement factors and replacing properly functioning complement factors to halt the overactivity of the alternative pathway. Patients diagnosed with TMA are often started on PLEX promptly while awaiting results of diagnostic testing (Shiga toxin E. Coli cultures, ADAMSTS13 level and complement pathway factor levels and mutations). If diagnostic tests suggest an alternative complement pathway disease, it will be maintained until Eculizumab is available. Unfortunately, while most observational studies suggest an initial response around 60% to PLEX, this is mostly a hematologic response and patients will often become dialysis dependent.

Conclusion
Overall the evidence to support the use of PLEX for the treatment of glomerular diseases is not great. While anti-GBM disease and lung hemorrhage are considered some of the strongest indications for PLEX, this is not firmly supported by good prospective data. The best evidence is for its use is in severe ANCA-vasculitis and with the upcoming PEXIVAS study results hopefully this will further help us in our decision making. I think it is great that such a large study such as PEXIVAS (over 700 patients) for such a rare disease has been able to come to completion and this highlights the importance of proper collaboration to conduct prospective studies in GN. Hopefully this will inspire us to continue to strive for well-designed studies to guide us in the treatment of our patients.

David Massicotte-Azarniouch
Nephrology Fellow, University of Ottawa