#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.

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

#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.

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 

#bestmentors What Makes a Mentor Great- Storify

#NephWorkForce TweetChat on 2014 ASN Fellows Survey

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

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