Sunday, March 29, 2015

Metformin Guidelines

Metformin is one of the most useful drugs in patients with type 2 diabetes and yet its use in patients with CKD is limited by the perceived association with lactic acidosis. These concerns are due to the association of a prior biguanide, phenformin, with a marked increase in the rate of lactic acidosis. The mechanism for this appears to be reduced peripheral glucose oxidation and increased lactic acid which occurs with even small increases in phenformin levels. The drug was eventually removed from the market because of a number of fatal cases.

Metformin, in contrast, does not appear to be as closely associated with lactic acidosis. Most of the reported cases are in patients who would appear to have other reasons for lactic acidosis (although this case series including patients on dialysis that appears to be reasonably convincing and there are multiple smaller case series in patients on HD). A large meta-analysis of clinical trials if metformin showed no increase in the rate of lactic acidosis in patients on the drug. However, it should be pointed out that these trials did not include patients with advanced CKD.  Metformin is not protein-bound and is largely cleared by the kidneys so there is clearly accumulation of the drug in patients with CKD. However, it is unknown what the real "safe" level is and no studies can ethically be performed to establish this.

As a result, in general, guidelines regarding the use of metformin have been conservative. The insert for the drug suggests that it is contraindicated in individuals with a serum creatinine >1.4mg/dl (women) or 1.5mg/dl (men). Personally, I find these guidelines to be insufficient and frustrating because of course, a creatinine of 1.5mg/dl can mean entirely different things depending on the context (age, weight, race etc.) So it is gratifying to see that the diabetes associations have moved forward with newer guidelines.

The ADA published a paper with new guidelines for the use of metformin in 2011 incorporating eGFR. This paper also summarizes very nicely all of the evidence for and against the use of metformin in CKD. In summary, they suggest that for individuals with eGFR>45, metformin can be safely initiated. For those with an eGFR between 30-45, it can be continued with caution if it is already in use. Finally, it is contraindicated in patients with eGFR<
30. These guidelines make more physiologic sense and although they may still be too conservative, in this era of automatic reporting of eGFR, to me, it is the better approach to take.

Saturday, March 28, 2015

Precision Nephrology

One of our attendings, Dr. Sylvia Betcher, PhD, MD gave an excellent presentation at our renal conference about genetic testing in renal diseases that she learned about at #KidneyWeek2015. There were so many good things I liked about her talk, that I want to share what I learned. On January 30th 2015, President Obama announced in his State of the Union address a Precision Medicine initiative. This will provide researchers in the biomedical field with the necessary tools to define preventive measures and treatment of disease by examining variability in genes, environment, and lifestyle of each patient. Precision Medicine relies on specific molecular and genetic information to classify a certain disease into subsets that allow consideration of focused therapies, which is currently being accomplished through GWAS (Check the #NephMadness genetic nephrology region bracket on GWAS here), whole gene sequence analysis via next generation sequencing (NGS) and VAAST (Variant Annotation, Analysis and Search Tool) which is used to identify damaged genes and their disease-causing variants in genome sequences. The president’s 2016 budget will provide $215 million to the various agencies including the NIH and FDA to accomplish his goals. The objectives of such initiative can be found here.

Most of the budget will go to cancer research and there is no mention of rare diseases or any particular hereditary or genetic disease. In the Nephrology world, are there any diseases in particular that need to be addressed? Yes, for instance Steroid Resistance Nephrotic Syndrome (SRNS), among many others. In this paper, a single-gene cause of SRNS was detected in 526 out of 1,783 families (29.5%), by examining 21 genes. The authors mentioned that screening of these genes is cost-effective and may avoid the undesirable side effects of steroids when a mutation is detected and potentially offer targeted therapy (for example with Coenzyme Q10 in cases of COQ2 nephropathy)

According to the NCBI Genetic Testing Registry as of August 2014, there were approximately 4,500 conditions for which genetic testing is available, many of which will have renal manifestations. Advantages to testing include providing specific therapies, allowing family counseling and to evaluate kidney donors in family members. Diseases that are being considered in Nephrology for genetic testing include: rare autosomal dominant interstitial nephropathies (UMOD, MUC1, REN), Syndromic and Polycystic Kidney Disease, Alport Syndrome and Congenital Anomalities of the Kidney and Urinary Tract (CAKUT). Additionally, I want to emphasize the fact that Genomics England (a company owned by the UK Department of Health) and Illumina (an American biotechnology company based in San Diego, California) have launched a $524M project to create a large genome database. Their plan is to sequence 100,000 whole genomes by 2017 focusing on rare diseases, cancer and infectious diseases. A nephrology consortium has been set up to provide renal patients for this ambitious project.

Let’s say we have screened our patients for congenital kidney diseases. Now what? We have to consider whether the results will influence any change in management, or perhaps we need to screen for extra-renal manifestations. I think that providing family counseling will definitively be helpful. It will also influence the decision on safety of kidney donation. Urine could be an excellent source of genetic information through DNA fragmentation which is a normal process in apoptotic cells to eliminate mutated, damaged or infected cells and is usually highly fragmented whereas in cancer cells the DNA maintains its integrity. So in conclusion, these are exciting times in Nephrology with precise genetic testing now a diagnostic option. Do you see yourself practicing Precision Nephrology in 10-20 years? Let us know what you think!

Saturday, March 21, 2015

#NephMadness Increased MAP in Sepsis Haiku Deck


Increased MAP in Sepsis - Created with Haiku Deck, presentation software that inspires

Post by Hector Madariaga. Go to the AJKD blog NephMadness critical care in nephrology region to read more. Make your picks before March 22nd

Monday, March 16, 2015

#NephMadness Norepinephrine in Sepsis Haiku Deck


Norepinephrine in Sepsis - Created with Haiku Deck, presentation software that inspires


Post by Hector Madariaga. Go to the AJKD blog NephMadness critical care in nephrology region to read more. Make your picks before March 22nd

Friday, March 13, 2015

Is there a benefit in pre-transplant weight loss? #NephMadness

To complement the NephMadness Nutrition in Nephrology obesity match-ups, we thought a post on pre-transplant weight loss was timely. According to a recent report published in JAMA, more than one third of the US population are obese (BMI>30) with an estimated medical annual cost of $147million in 2008. Obesity causes heart disease, stroke, type 2 diabetes mellitus and certain types of cancer. According to a recent policy statement of ASCO, obesity is predicted to overtake tobacco as the leading modifiable cause of cancer in the United States in the near future.
In the Nephrology world, we are all aware of the survival advantage of obesity in dialysis patients with the so-called “reverse epidemiology” or “obesity paradox” (While obesity, hypertension and hyperlipidemia are indicators of high cardiovascular risk in the general population, in dialysis patients these conditions are associated with a survival advantage). This was demonstrated in several well-conducted studies (ref, ref, ref) in the United States and Europe.

But is there any survival advantage for obese patients while they are waiting for a kidney transplant? Obesity is not an absolute contraindication for transplant listing although some transplant centers do not evaluate patients with BMI >30-35 kg/m2. At our center, we recommend patients should aim for a BMI < 35kg/m2; however we have performed kidney transplants in patients with higher BMIs. Approximately 60% of kidney transplant recipients are overweight, which represents a 116% increase from 1987. But is BMI an accurate reflection of obesity in adults? The answer is no. The accuracy is limited and although a BMI cutoff of >30 kg/m2 has good specificity, it misses more than half of people with excess fat. Newer techniques to evaluate obesity include abdominal circumference, waist to hip ratio, hydrostatic weighing and body fat measuring.

There are concerns about allograft survival, weight gain after kidney transplantation and wound healing. Two retrospective analyses in obese patients undergoing kidney transplantation reported higher rates of delayed graft function, acute rejection, peri-operative complications and worse renal function with higher BMIs.
On the other hand, there is evidence that higher BMIs do not influence outcomes. A study of >164,000 patients demonstrated that low pre-transplant BMI, low pre-transplant serum creatinine (which could be due to sarcopenia), were associated with worse post-transplant outcomes. Bariatric surgery is becoming more popular prior to kidney transplantation and according to this study of USRDS data that evaluated the safety of the procedure, bariatric surgery provides substantial weight loss to kidney recipients. However, it also reported more peri-operative complications and increased mortality in comparison to patients undergoing the same procedure without kidney disease. Significant pre-transplant weight loss (>10kgs) may be a risk factor for peri-operative complications, particularly wound problems. Another study reported that weight loss during transplant listing had no effect on long term outcomes after transplantation and rapid weight loss was associated with subsequent post-transplant rapid weight gain. According to this analysis, the rate of mortality before and after transplantation is unchanged despite weight loss.

In conclusion, there is no evidence that weight loss before transplantation improves long-term outcomes following transplantation although much of the evidence is retrospective and observational in nature. The absence of significant central obesity certainly helps with wound healing and it is intuitive that a ‘healthy weight’ augers well for long term morbidity. How we measure this ‘healthy weight’ however is debatable including where BMI fits into this assessment, if at all.

Hector M. Madariaga,
SUNY Upstate Medical University

Wednesday, March 11, 2015

Scleritis and Kidney Disease - More than meets the eye...

Scleritis is a severe inflammation involving the deep episclera and sclera. Symptoms include moderate to marked pain, hyperemia of the globe, lacrimation, and photophobia.

Scleritis tends to recur and is frequently associated with an underlying systemic illness, such as rheumatoid arthritis, lupus, IgA vasculitis, polyarteritis nodosa and granulomatosis with polyangiitis.   A few cases are infectious in origin and about half of the cases of scleritis have no known cause.

 In Renal Grand Rounds on Tuesday, Patrick McGlynn presented a case of 30 year-old healthy female who came to clinic complaining of pain and redness on her right eye. Blood pressure was elevated at 155/90 mmHg. On exam, right eye had redness on sclera. No involvement of left eye. No papilledema on fundoycopic exam. Ophthalmology was consulted and thought the exam was consistent with sectoral scleritis inferotemporally on right eye (representative figure above). Labs showed a creatinine of 1.79mg/dL and urine sediment analysis revealed few WBC casts. Based on acute presentation with renal failure and active urine sediment, a kidney biopsy was performed, revealing IgA nephropathy.

 Ocular involvement in patients with IgA nephropathy is infrequent, but may lead to uveitis, episcleritis, scleritis or retinal vasculitis. For sure worth keeping an eye…

Accepting Applications to the Origins of Renal Physiology Course

Nate Hellman, in front of the "Kidney Shed" at Mount Desert Island
The National Course for Renal Fellows: Origins of Renal Physiology course will run from August 30 to September 5, 2015 at the Mount Desert Island Biological Laboratories. Each year renal fellows come to the Acadia coastline to explore the fundamentals of renal physiology with a distinguished faculty drawn from top institutions around the world. Funded by the National Institutes of Health (NIDDK), the course covers the costs of instruction, food and housing for the week.

The application link is here. Applications will close at the end of April.

"The MDIBL Renal Fellows course gave me the opportunity to learn renal physiology from the experts in their fields, in a place where so many important discoveries were made by the giants of nephrology. Collaborating with my peers from programs all over the country, we re-created the experiments that helped characterize ENaC structure and function, osmoregulation, and the complex proximal tubular in a supportive yet intellectually stimulating environment. And when our lab presentations were finished, we enjoyed Acadia National Park and the coast of Maine, by foot and by bike, making great new friends along the way." - Jeffrey William, Fellow, Beth Israel Deaconess Medical Center

This course is a fantastic offering and was life changing for myself and I know many others. Where else can you go to learn about the kidney with fantastic faculty and fellows from all around. This was where I met the late Nate Hellman back in 2008, founder of RFN. You can read some nice blog posts from Nate from the actual course here and if you scroll down here. I would not only highly recommend this course but I would urge you to go. Now that it is supported by the NIH you really have no excuse not to go.

Matt Sparks

Saturday, March 7, 2015

#NephMadness Furosemide Stress Test Haiku Deck #CCRegion


Furosemide Stress Test - Created with Haiku Deck, presentation software that inspires

Post by Hector Madariaga. Go to the AJKD blog NephMadness critical care in nephrology region to read more.

Wednesday, March 4, 2015

Is Matching at the HLA Epitope Level the Holy Grail of Longer Graft Survival?

All HLA antigens are composed of strings of several polymorphic sites, which may serve as targets, or epitopes, for antibody binding. An important consideration is that HLA antigens have multiple epitopes that can be recognized by specific antibodies. The current nomenclature of the HLA system does not take into account the nature or identity of these epitopes. Elucidation of three-dimensional molecular structures and amino acid sequence differences between HLA antigens has made it possible to define the structural basis of HLA epitopes (reviewed by Tambur, Claas AJT 2015).

Why could this be important?
For certain HLA phenotypes a given mismatch has no or few mismatched epitopes and for other phenotypes, the same HLA antigen has many mismatched epitopes and is therefore, structurally highly incompatible. Altogether, the degree of structural compatibility of a donor HLA mismatch is largely determined by the HLA type of the recipient. Therefore, the level of epitope match may help identifying the best compatible donor. Furthermore, it may identify epitopes that are most immunogenic and lead to a greater risk of antibody generation post-transplant (Wiebe et al. AJT 2013).

How can you do this?
HLA Matchmaker, a computer algorithm available for free at www.hlamatchmaker.net, determines histocompatibility at the epitope rather than antigen level. Therefore, it can provide an estimate of the degree of epitope matching or mismatching.

Who would benefit the most?
Highly sensitized patients with difficult matches and younger patients to minimize risk of de novo DSA development post-transplant.

Monday, March 2, 2015

#NephMadness Early Goal Directed Therapy Haiku Deck #CCRegion



Early Goal Directed Therapy - Created with Haiku Deck, presentation software that inspires

Check out the NephMadness Critical Care Nephrology region.

Post by Hector Madariaga

Thursday, February 26, 2015

#NephMadness 2015: It’s almost here

It’s almost March, time to fill out your bracket. No not college hoops, it’s time for the annual Nephrology SoMed educational phenomenon that is NephMadness. The brainchild of Matt Sparks and Joel Topf has grown legs in its 3 years of existence and now represents a highlight of the Nephrology #FOAM calendar.

NephMadness is a homage to the NCAA Basketball Tournament, March Madness, but instead of matching up college basketball teams, NephMadness throws some of the most important concepts in nephrology together to battle it out. This years theme is Nephrologys interaction and cross-over with other specialties. See the current editorial in AJKD by the NephMadness team for the complete low-down. The overall regions/specialties, each with 8 Nephrology topics, for 2015 are:

1.         Obstetric Nephrology
2.         Infectious Disease and Nephrology
3.         The Heart and Kidney Connection
4.         Nephrology and Nutrition
5.         Genetic Nephrology
6.         Critical Care Nephrology
7.         Nephrology and Vascular Surgery
8.         Onconephrology

The game will progress throughout March with winners and losers announced along the way via ongoing blog posts. My own (extremely biased) view is that the winner will come from the strong Genetic Nephrology region! Let us know what you think when the brackets are published on March 1 on the AKJD blog. Also follow along on Twitter using the hashtag #NephMadness.


Wednesday, February 25, 2015

Blood pressure target in diabetes mellitus

Hypertension in diabetic patients increases the risk of microvascular and macrovascular complications. It is quantitatively and qualitatively different from the non-diabetic population and characterized by disturbed circadian rhythm of blood pressure (BP) with increased variability. It also features frequent nocturnal hypertension with high 24 hour BP load and impaired auto-regulation of blood flow leading to microvascular injury.

A large meta-analysis of 1 million individuals followed for 14 years showed a continuous decrease in cardiovascular risk with reduction in BP to as low as 115/75 mmHg. In the absence of RCT data, presuming “lower is better”, BP targets of < 130/80 mm Hg were traditionally recommended in diabetic patients. However the hypothesis of a J-shaped relationship with risk challenges the lower BP targets suggesting that benefits of extreme BP reductions are smaller than moderate reductions. This seems logical as physiologically there is a low (as well as high) BP threshold for organ blood flow auto-regulation. Two diabetic statin trials (TNT and PROVE IT-TIMI) reported a J-shaped relationship between BP and adverse cardiovascular events, although there were no BP lowering interventions.  Recently, JNC 8 (based on the ACCORD trial, where the SBP target of < 120 mm Hg could have produced J shaped curve) and ESH/ESC 2013 (diastolic target based on HOT trial) recommended a relaxed BP target of < 140/90 mmHg in diabetic patients. These conflicting recommendations on hypertension targets, from various professional bodies have created confusion in the minds of physicians.

Comparison of BP targets (in mm Hg) by different guidelines

 

Age 

Diabetes

Chronic Kidney disease

JNC 8 (2013)

<60 y: <140/90
≥60 y: <150/90

<140/90

<140/90

ESH/ESC (2013)

Elderly < 80y:
SBP 140-150SBP < 140 in fit patientsDBP < 90
 Elderly > 80 y:
SBP 140-150DBP < 90

<140/85

<140/90

ASH/ISH (2014)

< 80 y: <140/90
≥ 80 y: <150/90

<140/90

<140/90

AHA/ACC/CDC (2013)

<140/90
Lower targets may be appropriate in some patients including the elderly

<140/90
Lower targets may be considered

<140/90
Lower targets may be considered

KDIGO BP guidelines in CKD (2012)

No recommendation for general population. For Elderly with CKD ND
Tailor BP target based on age and co-morbidities

CKD ND with or without diabetes

Albuminuria < 30 mg /24 hr
≤ 140/90
Albuminuria > 30 mg /24 hr
≤ 130/80 

CKD ND = non-dialysis-dependent CKD
A recent meta-analysis in JAMA has reignited the debate of BP targets in patients with diabetes. Emdin et al analyzed 45 RCT`s (100,354 participants), conducted between Jan 1966 and October 2014, of BP lowering treatment in patients with diabetes (regardless of presence or absence of defined hypertension). Trials with predominantly type 1 diabetes patients were excluded. The researchers examined the associations between BP-lowering treatment and vascular disease in type 2 diabetes. They found that:
  •  Each 10-mmHg lower systolic BP was associated with a lower risk of mortality, cardiovascular disease events, coronary heart disease events, stroke, albuminuria and retinopathy.
  • All outcomes, including mortality, were reduced when SBP was lowered from elevated baseline of >140 mm Hg and higher to a range of 130-140 mmHg. 
  •  Further reduction of SBP below 130 mm Hg yielded lower risk of stroke, retinopathy and progression of albuminuria.
  •  Irrespective of drug class, the associations between BP-lowering treatments and outcomes were not significantly different except for stroke and heart failure.

The authors recommended that for patients at high risk of stroke, retinopathy or progression of albuminuria, BP treatment should be commenced at initial SBP level of 140 mmHg and target SBP below 130 mmHg.
The lower risk of stroke with reduction of SBP below 130 mmHg has been previously reported in the TNT trial, this meta-analysis and a subgroup analyses from the ONTARGET trial. However, the bigger question is if such lower SBP target can be achieved without any adverse events in the elderly diabetic population. The rate of serious adverse events reported in ACCORD trial in intensive treatment group (achieved BP 119 mmHg) was 2.5 times that of the control group (achieved BP 133 mmHg). While there is clear benefit in BP sensitive outcomes like stroke, it is unclear why lower SBP target below 130 mmHg does not benefit other outcomes like heart failure and renal failure. This could be due to the fact that hypertension trials have a short follow up and these outcomes occur too late in the disease process to see early benefits. Or could this be due to J-shaped relationship?
As summed up in a recent commentary titled “Hypertension Guidelines in need of Guidance”: We should be more worried about hypertension, not hypotension. Surely, one would avoid excessive or unwanted degree of BP lowering in patients with hypertension; it needs only common sense, not guideline committees.
Which hypertension guidelines do you follow? And what BP target do you set for your diabetes patients? Will you try to target these lower SBP if your patient tolerated them? Leave your comments below.

Amit Langote
Nephrology Fellow, Ottawa



Friday, February 6, 2015

#MyNephroStory: A Rewarding Journey

There is a lot of discussion about the recent nephrology Match in the US and everyone is discussing what’s wrong with nephrology? Why is the interest in Nephrology waning? Like most people I took a unique journey to nephrology and maybe by sharing my tale it will inspire others to take up nephrology. I went from a small town, Jalgaon, in India to nephrology fellowship in Canada.

Screen Shot 2015-02-05 at 7.27.54 PM.png
My journey to renal enlightenment began on a wet monsoon night in Pune, India where I was on call in the ICU during residency. We had a patient dying of multi-organ dysfunction and he desperately needed dialysis. The only dialysis machine available was a vintage Drake Willock beast that had sprung a leak. We called the on-call nephrologist, a new recruit at the time, for help. After a we saw this dripping wet, unassuming guy carrying not a stethoscope but a screwdriver. This nephrologist gets down on his hands and knees, pulls out the section of the Drake Willock, identifies the leak and fixes it, all in about 15 minutes. The patient survived and I knew right then, I wanted to be a nephrologist. From that moment on I was wide eyed boy in the candy shop for anything nephrology.

The rain soaked nephrologist was Dr Valentine Lobo, and he took me under his wing, and guided me through residency and then through nephrology fellowship. He was the mentor that was always there, teaching me to place lines, do biopsies, place PD catheters. We covered the widest swath of nephrology, we did pediatrics, electrolytes, transplant, pathology. We went to the lab to measure creatinine and do HPLC drug levels. I remember placing a dialysis line in a man receiving chest compressions for a hyperkalemic arrest. I remember doing plasmapheresis for aHUS and staring at the foley tube waiting for the first trickle of urine after a transplant. I sprinted from the clinic to the lab with containers of warm urine to search for dysmorphic RBC and RBC casts. He was the best mentor, knowledgeable, excited and encouraging. He made nephrology not just my vocation but my destiny.


In 2009, I was a final year nephrology fellow and was looking for some information on the net and stumbled across UKidney, Initially I thought it was some renal-inspired spoof of YouTube, but as I explored the site I saw the structure and vision of it’s creator, Dr Jordan Weinstein. and I wrote him about who I was and what I was doing. Specifically, I asked him about nephrology training in Canada and what were the possibilities. I never really expected a reply, but once again a senior nephrologist noticed my enthusiasm and took the time to write back with encouraging words to give Canada a try. 
So, that is what I did, and three years later I landed in Edmonton at the University of Alberta with my pediatrician wife and 3 -year old daughter, to start another renal roller coaster ride. We arrived in November and until that moment, my experience with snow was limited to defrosting the freezer. I had never seen so much white stuff in my entire life. But when you are excited about nephrology what’s a couple of feet of snow? 
The fellowship was in renal transplant and was wonderful. I continued at U of A as a nephrology Fellow after my Transplant Fellowship. Every moment is a new learning experience, every staff is loaded with #NephPearls, and everyone is eager to teach. I bet it is a two way street, probably my “kid in a candy store” attitude helped. Recently, with the help and urging of my program director, Dr Mark Courtney, I began exploring social media. He sent me a #NephJC link saying this is something I would be interested in, and once again I launched myself into another facet of nephrology education with the same wide eyed zeal that made me choose this beautiful specialty. 
Looking back, honestly, I would change nothing. I would still go to medical school and still select nephrology. It has everything that a branch can offer and enough unknowns that I remain that “wide eyed boy in the candy store”. I remember the excitement with which I opened my brand new copy of Schrier’s text in 2008 and it is with the same tingling excitement I open my twitter account every day. New research, new people, new thoughts, new ideas, all geared to improve the life of the kidney patient – why wouldn't I choose nephrology, It ROCKS!

Authored by Nikhil Shah 
NMSC Intern & Nephrology Fellow at University of Alberta Hospital 

Tuesday, February 3, 2015

Update from Cardiology Literature: Antithrombotic therapy in Atrial Fibrillation and CKD

In 2015 I hope to blog on articles from non-renal journals that are of interest to nephrologists. First up is cardiology and a topic that has been covered in previous RFN posts (here, here, here). The optimal management of atrial fibrillation in patients with CKD is controversial as they are at both a higher risk of stroke and higher risk of bleeding than the non-CKD population; this is particularly true of patents on dialysis. Warfarin is well established in reducing the risk of stroke in patients with atrial fibrillation but the trials excluded patients with a creatinine clearance of < 30ml/min. Thus we have had to rely on, often contradictory, observational studies to guide us in this area.

A study in the Journal of the American College of Cardiology in December is the latest to investigate the net clinical benefit (or harm) of antithrombotic therapy in these patients. It was a retrospective cohort study using nationwide Danish registries to identify all patients discharged from hospital with a diagnosis of non-valvular AF between 1997 to 2011. Out of the 154,259 patients identified; 11,128 (7.2%) had non-end stage CKD and 1,728 (1.1%) were receiving dialysis. They used the CHA2DS2-VASC score to stratify the patients into high and low/intermediate risk of stroke groups. Briefly the score is calculated by adding one point for heart failure, hypertension, diabetes, vascular disease, age 65-74 and female sex and 2 points for age over 75 and a previous stroke. A score of ≥ 2 is considered high risk.
They found that among high risk patients on dialysis, warfarin was associated with a significantly lower risk of all-cause mortality (HR 0.85, CI 0.72-0.99) and there was a non-significant trend toward a reduction in cardiovascular death and a composite end point of hospitalization or death from all stroke/all bleeding. There was no benefit of warfarin in low-intermediate risk dialysis patients; indeed there was a trend toward higher all-cause mortality (HR 1.36, CI 0.96-1.94). Analysis of a sample of the non-end stage CKD patients found 19.1% were CKD stage 1-2, 20% were CKD 3, 36.4% were CKD 4 and 24.5% were CKD 5. Warfarin was associated with significantly lower risk of all-cause mortality in both high risk (HR 0.64) and low-intermediate risk groups (HR 0.62) in patients with non-end stage CKD. One caveat, highlighted in the journal’s editorial, is that certain components of the CHA2DS2-VASC score (diabetes, hypertension and heart failure) were identified based on filled prescription data, meaning the frequency of these risk factors may have been underestimated and therefore overestimating the number of patients classified as low-intermediate risk. We should therefore interpret the mortality benefit for this group with caution.

The most recent NICE guidelines in the UK, published in June 2014, do not recommend aspirin as monotherapy for the prevention of stroke in patients with AF. This study suggests the same should apply to patients on dialysis as aspirin was not associated with a lower risk of any outcome.
Analysis of the newer anticoagulants such as Dabigatran, Rivaroxaban and Apixaban, were not included in this study. They are contraindicated in patients with ESRD as they are cleared via the kidneys and drugs levels can accumulate and precipitate bleeding though their use in this setting has increased nonetheless. A study from the U.S. out this month in Circulation found that 5.9% of anticoagulated patients with AF on dialysis are started on dabigatran or rivaroxaban and that these drugs were associated with a higher risk of hospitalisation or death from bleeding compared to warfarin.

Balancing the risks and benefits of anticoagulation in patients with AF and ESRD remains complex. The current evidence suggests that warfarin remains the best anti-thrombotic available but it also has a significant potential for harm and the decision of whether or not to start treatment needs to be an individualized patient choice.

Authored by David Baird
Royal Infirmary of Edinburgh

Sunday, February 1, 2015

ESAs in Patients with CKD and Cancer: Is the Risk Worth the Benefit?

Anemia is a common manifestation of CKD. Currently, there are no guidelines for nephrologists regarding erythropoietin stimulating agents (ESAs or Epo or Darbe) use in patients with CKD with previous or active malignancy. Recently an excellent review of this topic was published in Kidney International by Hazzan et al. Let’s go over some of the key points.

Erythropoietin Biology and Relevance in Malignancy
  • Besides stimulating erythropoiesis, Epo has been shown to have both anti-apoptotic and pro-proliferative actions in endothelial cells, brain +/- spinal cord, kidney and heart. Furthermore, Epo has also been shown to promote angiogenesis in endothelial cells. These non-erythroid functions of Epo are not fully understood.
  • Epo mediated angiogenesis appears to be physiologic and driven by hypoxia but may play pathological role in proliferative diabetic retinopathy.
  • Because angiogenesis is important for tumor survival and progression, it is important to know if cancer cells express the EPo receptor (EpoR). Initial evaluations for the EpoR on cancer cells, tested either for the Epo- receptor antibody (the antibodies used were non-specific) or mRNA transcripts (which were potentially contaminated by other cell types from blood or stromal tissue) and were less informative. Recent development of first specific antibody to the EpoR (A82) with both positive and negative controls will allow more rigorous testing for the EpoR protein on cancer cells. Swift et al. studied 66 cell lines and found either no or very low levels of the EpoR protein. Although current data does not show strong evidence of presence of functional EpoR on cancer cells, we need more evidence to draw a definite conclusion.
  • In absence of EpoR, Epo induced supra-physiologic Hb levels would increase oxygen delivery to cancer cells and potentially stimulate proliferation.
  • Also, hypothetically, binding of Epo to EpoR expressed on activated macrophages can suppress NF-kB activation and proinflammatory genes, resulting in an immunosuppressive effect. 
Nephrology Literature on ESA usage in Patients with CKD and Cancer
  • The TREAT trial was a landmark study in the field of nephrology which was published in 2009 in the NEJM. The TREAT (and CHOIR) trials changed how we treated anemia. In this study, more than 4000 diabetic CKD patients with anemia were randomized to either higher hemoglobin (Hb) target (13 g/dl) with darbepoetin or lower hb target (9 g/dl) in placebo arm. Surprisingly, there was a trend towards increased risk of death due to cancer in the Epo group (darbepoetin alfa group 39 deaths, placebo group 25 deaths, P=0.08). Also, in patients with a previous history of cancer, there was increased mortality due to malignancy in Epo group (darbepoeitin alpha 14/188 deaths, Control 1/160 deaths, P=0.002). These results, for the first time, raised concern regarding possible association of Epo with cancer.
  • However, a year later in 2010 Japanese study in CKD stages 4 and 5, failed to show an increased incidence of cancer with Epo. But this study targeted lower Hb (10.1 g/dl) and had a short follow up period.
  • Seliger et al found that Epo increased the risk of stroke, only in CKD patients with diagnosis of cancer. But cancer group received higher initial ESA dose even though the pre-ESA Hb was similar in both groups.
Oncology Literature on ESA use in Patients with CKD and Cancer

Head and neck cancer trials had used Epo to increase tumor oxygenation in an effort to increase efficacy of radiotherapy.
  • ENHANCE TRIAL 2003 was conducted in head and neck cancer patients given ESAs while under-going only radiotherapy (no chemotherapy). Surprisingly, locoregional progression-free survival was found to be poorer with epoetin (where patients were treated to Hb 14–15 g/dl) than with placebo.
  • Similar results were found by DANISH RCT which reported 10% difference in 3-year local/regional control in favor of the control group (P=0.01) compared to darbepoetin group 
Meta-Analysis of Outcomes of Mortality with ESAs
  • Cochrane database analysis- Dec 2012 , found strong evidence that ESAs increased mortality during the active study periods (death occurring up to 30 days after active study protocol) (hazard ratio 1.17; 95% CI 1.06–1.29), and borderline evidence that ESAs decreased overall survival (hazard ratio 1.05; 95% CI 1.00–1.11). The increase in mortality risk was seen in studies where patients had Hb higher than 12 g/dl before Epo treatment. 
  • Mortality risk was higher in patients who received Epo without concurrent chemotherapy but these trends in patients receiving Epo and concurrent chemotherapy are not clear.
  • There is insufficient evidence to know if the risk is dependent on the cancer type. 
Clinical Implications and Recommendations for ESA use in Patients with CKD and Cancer 
1. The nondialysis CKD/ESRD patient with current cancer:
  • Only FDA indication for ESA treatment is for anemia caused by current myelosuppressive chemotherapy; there is no indication for patients with cancer not receiving chemotherapy.
  • If acute severe, symptomatic anemia is present, then blood transfusion is the treatment of choice. 
  • Suggest generally limiting the Hb target to an upper level of 10 g/dl to prevent risk of stroke and mortality with higher Hb targets.
  • For the occasional patients who still have anemia-related symptoms, a slightly higher Hb target may be considered. 
  • Intravenous iron may be given to minimize total ESA dose exposure.
  • The FDA and some oncology guidelines recommend against the use of ESAs if chemotherapy treatment is with curative intent.
  • Hazzan et al feel that ESA treatment is probably reasonable for the advanced non-dialysis CKD/ESRD patient receiving chemotherapy with curative intent but with an upper Hb target of only 10 g/dl. However patient counselling of the risk and benefits is mandatory before Epo use. 
2. The nondialysis CKD/ESRD patient with a previous history of cancer:
  • Discuss with patient`s oncologist if the cancer is cured. Ask about risk of recurrence and the risk for other tumors related to the primary malignancy or its treatment.
  • For up to 5 years after potential cure, treat with ESAs as if active cancer was present, maintaining an upper limit of Hb of 10 g/dl.
  • Even after confirmed cure with very low risk for recurrence, make efforts to reduce ESA dose exposure by ruling out other treatable causes of anemia. (Remember TREAT trial) 
3. The nondialysis CKD/ESRD patient with no active or previous cancer:
  • If high risk for cancer such as strong family history of colon cancer or breast cancer or if the patient is a smoker, or past exposure to cyclophosphamide, use conservative Hb targets to minimize any potential risk of ESA, if any.
  • If no risk factors for malignancy then treat as per usual CKD/ESRD protocols. 
The article does not discuss situation where patient with active cancer have metastatic disease and limited life expectancy. If patients are on palliative chemotherapy or have stopped cancer treatment, then I feel that in such patients it is reasonable to give them Epo to improve quality of life, after a detailed discussion of the risk involved. This may be one situation where the benefit outweighs harm. These seem to be practical recommendations to me until we have new data on this topic. How do you deal with your patient in this situation? What is the practice pattern at your Centre?

Amit Langote MD
Nephrology Fellow
Ottawa, Canada

Saturday, January 17, 2015

NSMC Inaugural Internship Class Announced

The Nephrology Social Media Collective (NSMC) is proud to announce the inaugural class of the 2015 internship. This is a new initiative with the goal to help foster individuals interested in finding their voice in social media.
The 2015 internship class is:

The collective consists of: Swapnil Hiremath, Joel Topf, Edgar Lerma, Kenar Jhaveri, Paul Phelan, Joshua Schwimmer, Matt Sparks, Jordan Weinstein. Interns will rotate through the various blogs (UKidney, RFN, NephJC, NephronPower) and projects (NephJC, NephMadness, NephPearls) and complete projects related to medical education and nephrology. Go to the NSMC Internship Blog to follow their progress. Congrats to the new intern class. This will be a fun and exciting year.

Monday, January 12, 2015

#NephWorkForce TwitterChat on Tuesday January 13 at 9pm EST

Join Mark Parker (@kidneyfuture), Chair of the ASN Workforce Committee on Tuesday, January 13th at 9pm EST for the discussion about the recently released ASN-GWU Nephrology Fellow Survey. This will be an excellent opportunity for everyone to discuss the recent trends and future of nephrology training. Joel Topf has a nice interview with Mark Parker and summarizes the results of the study over at PBFluids. Take a few moments on Tuesday night to watch the discussion and voice your opinion.

Thursday, December 25, 2014

Top nephrology-related stories of 2014

Another year has come and gone. 2014 featured some novel therapies for hyperkalemia and the notable failure of the SYMPLICITY-3 trial for renal denervation in resistant hypertension. ASN Kidney Week continues to grow and each year includes more and more social media. Its fun to be a part of it.

I also want to make a last minute honorable mention:

The new US Kidney Allocation System- This had been in the works for several years and was implemented on December 4th of this year. Some of the highlights of the new system are; 1. credit is given for time on dialysis prior to listing 2. patients with blood type B will be able to receive a blood type A2 kidney and highly sensitized patients will receive points to allow for more of a change for transplant. 3. an attempt to match kidneys based on "longevitiy". 4. increased sharing across the country. These changes are supposed to level the field so kidney transplants are allocated equitably across socioeconomic lines. It also attempts to find ways to offer more kidneys to patients that are highly sensitized while pair a kidney with the right donor. How this plays out across the US will be the true test.

Below are links to the last 4 years of the top nephrology stories polls

2010
2011
2012
2013

And now for the top 10 of 2014 and the 5th straight year of top nephrology stories on RFN...

10. POSEIDEN Trial showing fluid administration guided by LV end diastolic pressure reduced contrast-induced AKI (6%)- Coming in at number 10 this year was an interesting study reported in the Lancet. This was also covered during NephJC journal club as well. POSEIDEN was a single center study with ~400 patients with high risk for contrast-induced AKI undergoing coronary angiography. Patients were randomized to either control (0.9% NS 1hr before and 4hr after cardiac cath) or the intervention arm (the same 1hr pre NS dose but gave NS post cath based on LVEDP). The strategy was to maximize fluid administration while minimizing volume overload in order to prevent AKI. The patients in the intervention ended up getting more fluids and thus a reduction in AKI from ~16% to ~7%. How can these results be translated to other settings (such as CT scan with contrast)? Measures of LVEDP are more difficult to obtain when you are not performing a heart cath. My take away from this study is that patients at high risk for AKI need significant volume expansion and the more you can safely give the better. Strategies to minimize fluid overload will be needed to mitigate the risk of volume overload .

9. Gestational HTN or preeclampsia was more common in kidney donors (6%)- This was an interesting study reported in the NEJM in November. This group utilized a retrospective cohort of 85 healthy women in Ontario, Canada who underwent kidney donation who later became pregnant. These women were compared in a 1:6 ratio with 510 healthy non-donors in the general population who became pregnant. They reported that gestational hypertension or preeclampsia were more common in the donor population compared to healthy controls (11% versus 5%). This finding comes on the heals of several reports linking kidney donation to small by statistically significant increase in ESRD. Paul has a nice review on RFN. The caveat to each of these studies is that they are retrospective case-control studies. While kidney donation might confer some risk, the benefit conferred to the recipient in terms of quantity and quality of life are substantial.

8. Patiromer OPAL-HK trial for hyperkalemia (7%)- It is likely that patiromer and ZS-9 will be in a death match for potassium binding supremacy. The OPAL-HK trial (reported in NEJM) studied 243 patients with mild (av 5.3 mmol/l) and moderate-to-severe (av 5.7 mmol/l) hyperkalemia to treatment with patiromer (a nonabsorbed polymer that binds potassium in exchange for calcium). The study showed remarkable efficacy in lowering potassium in both groups. During the randomized withdrawal phase the majority of patients assigned to placebo had recurrent hyperkalemia. Safety signals include mild to moderate constipation. It will be interesting to see how this drug will stack up against ZS-9. Having 2 drugs in the fight could equal a win in the pricing war. We will see.

7. IgA Nephropathy GWAS implicates genes involved in helminth immune response (7%)- This was the surprise of the year in my opinion. This was a genome wide association study (GWAS) in IgA Nephrology and was reported in Nature Genetics. This group performed GWAS on ~2,700 patients with biopsy proven IgA Nephropathy and ~3,900 controls of European and Chinese ancestry. They found 6 new associations, 4 in ITGAM-ITGAX, VAV3 and CARD9 and 2 new independent signals at HLA-DQB1 and DEFA. "Most loci were either directly associated with risk of inflammatory bowel disease or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The risk alleles were highly suggestive of helminth diversity adaptation". So it appears that yet another kidney disease could be linked to infectious pathogens (see APOL1 and Trypanosoma brucei rhodesiense).

6. HALT-PKD Trials of low BP target and ACEi/ARB combo (10%)-  The much awaited dual release of the HALT-PKD trials were presented and simultaneously reported in NEJM at kidney week this year. HALT-PKD consisted of 2 trials: the first study was termed "early" in which patients had preserved renal function and the other termed "late" in which patients had a decline in renal function. They both tested dual ACEi/ARB blockade and the "early" study had an additional focus on blood pressure reduction. 120/70 to 130/80mmHg (Standard BP) and the low blood-pressure target group was quite low at 95/60 to 110/75 mm Hg (Low BP). Both the "early" and "late" trial dual ACEi/ARB combo groups had no additional benefit over monotherapy. However the "low BP" arm of the "early" study had benefits in LVH, kidney size and urinary albumin excretion at the expense of dizziness and light-headedness. However, this did not confer eGFR benefit. How these results would translate into clinical benefit is uncertain. It is clear that combo ACEi/ARB therapy is done in this patient population as it is for diabetic kidney disease (see Nephron-D). Will it be feasible to push blood pressure this low in patients with PKD. Without changes in eGFR or another solid end-point my guess is no.

5. Anti-Phospholipase A2 receptor assay licensed for commercial testing (13%)- Another exciting development in the field was the news that the anti-phospholipase A2 receptor assay gained clearance for commercial use by the FDA. This test has the potential to really help guide therapy in patients with membranous nephropathy. A recent paper in CJASN and covered in CJASNeJC discusses the potential application of this assay in membranous. Much is still to be learned about how the measurement of anti-PLA2R will affect treatment but this could be a much needed non invasive insight into the disease process. 2015 will surely be filled with more research into the topic. Some questions that remain to be answered. 1. Would you re-initiate immunosuppression if titers increase in absence of worsening proteinuria or worsening renal function in a patient with biopsy proven membranous? 2. Could this test bypass invasive biopsy in select patients? 3. How often should you measure titers? 4. Could anti-PLAR2 offer another index to gauge prognosis and potentially lengthen or intensify therapy?

4. ZS-9 trials for hyperkalemia (14%)-  Coming in a number 4 is ZS-9. Another "potassium buster" drug for hyperkalemia. The company ZS Pharma reported the results of 2 trials, the HARMONIZE trial in JAMA and a phase 3 trial in NEJM. Both these studies showed efficient potassium lowering versus placebo and rebound once the drug is discontinued. NephJC hosted a lively twitter discussion about the HARMONIZE trial. Concerns for how ZS-9 will be tolerated long term and why it was compared to placebo and not kayexalate or diet. Also, in the high dose group more patients had peripheral edema. ZS-9 has the potential to really change the landscape of hyperkalemia treatment, but long term safety data is needed. The other positive from all of the hyperkalemia trials is that the medical community is finally actually starting to study this.

3. SYMPLICITY-3 trial for renal denervation in resistant HTN (19%)-  Probably the biggest disappointment of the year was the SYMPLICITY-3 trial. An introduction isn't even needed as the results have been widely publicized and critiqued. You can read a summary from NOD Kidney Konnection. The SYMPLICITY-3 trial was performed in response to the FDA who requested a sham procedure group be used as a control against renal denervation in patients with resistant hypertension. The results have reverberated across the medical community. Both the sham and denervation groups had impressive drops in blood pressure by ~15 mm Hg. This was the problem. What went wrong? Was it ineffective denervation? Was it a powerful placebo effect? Was it the Hawthorne effect? Bottom line is this trial didn't achieve a significant benefit in renal denervation. Questions remain as to the effectiveness of the actual denervation technique. Will industry put money back into this technology after the results of SYMPLICITY-3? We will see.

2. JNC8 Hypertension Guidelines published in JAMA (22%)- Coming in at number 2 and the winner of NephMadness 2014 is JNC-8. This was an honorable mention in 2013 as it was published online after the end of the year poll. These guidelines were much anticipated and sometimes referred to has JNC-late. JNC-8 attempted to answer questions using randomized controlled data while carefully adjudicating the available evidence. JNC-8 is far narrower in scope than JNC-7 and was not a “how to” document. JNC-8 explicitly states places where we do not have evidence for and what we really need to know. Lastly, the document simplifies the blood pressure goals. Some have expressed concern about raising the systolic blood pressure target in patients over 60 (without DM or CKD) from 140 to 150 mm Hg. For a review of the major changes with JNC-8 see the NephMadness champion post.

1. Perivascular Gli1+ progenitors contribute to myofibroblast pool leading to fibrosis in multiple organs including kidney (57%)- Coming in at number 1 this year is an interesting report from Cell Stem Cell. I'll have to add an asterix to this win though. It appears the stem cell community really got the word out to vote for this one. It is still deserving of a top story of the year as it paves a new paradigm in the pathogenesis of fibrosis. In a real tour de force Kramann et al not only define this process in kidney fibrosis but also look at lung, liver and heart fibrosis. They utilized lineage tracing to show that tissue-resident (not circulating) Gli1+ cells (pericytes) proliferate after kidney, lung, liver, or heart injury to generate myofibroblasts. This has been a hot topic and covered in detail in this years NephMadness. Next, they genetically ablated these cells and induced organ injury in various mouse models. They showed that kidney and heart fibrosis was substantially less compared to controls. These are exciting studies that have the potential to open new therapeutic targets for chronic kidney disease and other chronic disease such as cirrhosis, lung fibrosis and heart failure. This could be a candidate for the next basic science NephJC discussion. An exciting development and it will be fun to watch where this goes.

Another busy and exciting year in the world of nephrology in 2014. Thanks to all of the contributors and readers for keeping the site fun, interesting and educational.

Thanks for supporting RFN and happy holidays. Can't wait to see what 2015 has in store!