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!

Tuesday, December 23, 2014

Tacrolimus Formulations

Tacrolimus comes in oral, intravenous and topical formulations. Prograf is the most commonly used oral tacrolimus formulation and is dosed twice daily.

Prograf pharmacokinetics 

Absorption:
Absorption occurs in the small intestine.
Drug levels reach a maximum concentration in 1 to 2 hrs.
Tacrolimus is poorly soluble and oral bioavailability is about 11 to 20%.

Metabolism:
Cytochrome P450 3A4 metabolizes tacrolimus to at least 10 metabolites, some of which retain significant activity. Biliary excretion is the route of elimination for these tacrolimus metabolites. Gastrointestinal tract mucosal cells also contain CYP P450 3A4 activity and contribute significantly to metabolism.

Elimination:
The terminal elimination half-life of tacrolimus is approximately 12 hours. Elimination is prolonged in hepatic dysfunction.

Poor solubility, first pass metabolism, small bowel CYP450 metabolism and p-glycoprotein activity (pumps drug back into the bowel lumen) all cause reduced oral bioavailability of tacrolimus. Low oral bioavailability is a common pharmacological problem and 30% of marketed PO drugs have poor solubility defined as water solubility below 20ug/ml. An oral drug can only be absorbed once dissolved.

LCP-Tacrolimus 
LCP-Tacrolimus was designed to achieve greater bioavailability by increasing the solubility of tacrolimus. LCP is Life Cycle Pharma, a Danish company now trading as Veloxis Pharmaceuticals. This new tacrolimus formulation uses ‘Meltdose’ technology to achieve this goal. LCP Meltdose technology works by decreasing the particle size of the drug to the molecular scale thus increasing particle surface area. Increased surface area increases solubility. Tacrolimus is heated into a ‘liquid like’ state and then atomized and sprayed onto an inert particle carrier. This then solidifies in a state of ‘solid solution’ into granulates and is compressed into tablets. These granulates retain their particle sizes and dissolution characteristics. Thus, once delivered to the small bowel these very small particles of tacrolimus go into solution easily and are better absorbed.

Phase 2 trials of LCP-tacrolimus in de novo kidney transplant patients have shown a more consistent concentration profile, increased bioavailability of about 30% and reduced peak to peak and peak to trough variation compared with bid tacrolimus (Prograf).


This month in AJT
Budde et al report on a phase III study of LCP-Tacrolimus vs bid tacrolimus in de novo kidney transplants.

This was a worldwide, double blind, double-dummy, randomized study in 543 de novo kidney transplants comparing LCP-tacrolimus with Prograf (bid tacrolimus). It was designed as a non-inferiority trial with a primary endpoint of treatment failure at 12 months (death, graft failure, biopsy-proven acute rejection).

More LCPT patients were in ‘target range’ (6-11) after initial doses. Trough/dose ratio increased (reflecting better absorption) over time with LCPT and was statistically higher than Prograf. Trough levels were similar. Total daily doses were lower for LCPT at 1 and 12 months and the cumulative dose over the whole study was 14% lower for LCPT.

The overall incidence of treatment failure was 18.3% for patients in the LCPT group and 19.6% for patients in the tacrolimus twice-daily group. The treatment difference (95% CI) was −1.35% (−7.94% to +5.27%), well below the noninferiority margin of 10%.

There were no significant differences in adverse events between groups. Interestingly 97% of each group had an AE over the 12 months the most common being diarrhea, anemia, UTI, hypertension and constipation. There was a numerical trend towards more NODAT with LCPT that may be explained by higher LCPT exposure in the first 3 weeks. There was a trend towards a smaller rise in lipid abnormalities in the LCPT group.

This was a well-powered and well conducted trial. LCP-Tacrolimus is safe and as efficacious as Prograf. Cumulative doses are lower and therapeutic range was reached earlier and is more likely to remain stable. This is a promising once daily preparation, however, pricing is likely to determine whether this formulation becomes standard of care in kidney transplantation.

What about Advagraf/Astagraf?
 

Advagraf was approved for the European market in 2007 and the FDA approved Astagraf in 2013. Advagraf contains the same active drug, tacrolimus, as Prograf. Advagraf contains ethylcellulose, which controls water penetration and changes its dissolution properties. The drug also contains a hypromellose protective coat. Both these factors cause the active drug to be released more slowly and further along the GI tract.

In mostly industry sponsored trials Advagraf showed lower peak drug concentrations but equivalent AUC(0-24) and Cmin(trough) concentrations when compared to Prograf. Thus, a 1:1 conversion is suggested in the package insert. However, subsequent experience with Advagraft has demonstrated lower Cmin values and high inter-individual variability leading to the need for higher Advagraft dosing and difficulty with trough interpretation. Furthermore, a phase III study in de novo kidney recipients has shown higher rates of acute rejection with Advagraf, possibly explained by the differing C(max) values achieved with the two preparations. Biopsy-proven acute rejection rate at 24 weeks (primary endpoint, per-protocol analysis) was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment difference 4.5%, 95% confidence interval-1.8%, 10.9%) just outside the prespecified 10% noninferiority margin.

In Europe where this formulation has been approved since 2007 use of the drug is still minimal. It will remain to be seen whether the same trend occurs in the US. Experiences so far make it unlikely that this formulation will become first line therapy in kidney transplantation.

Wednesday, December 17, 2014

The future of nephrology training: A fellow's perspective


Much is being said about the steady and dramatic decline in applications to nephrology training programs. The recent match shows a continuation of this trend: 67.9 percent of offered positions filled, leaving 50% of US programs unfilled on match day. The writing is on the wall: the number nephrology training positions needs to shrink. However, there is going to be no agreeable and easy way to decide which program should reduce size or close its doors. Should we let programs decide what to do individually or should we defer decisions to some governing body? Should programs that go unfilled be forced to reduce numbers or shut down, the so-called “survival of the fittest” model? Or should we create an algorithm to decide how to reduce positions more equitably?

Tejas Desai posted a paper that describes a more equitable model by allocating training positions according to ESRD prevalence in US states/jurisdictions. In his model, he estimates that fewer jurisdictions would reduce in size under an equitable model compared to the “survival of the fittest” model. An “equitable” process using an algorithm is attractive because it would distribute the allocation of positions based on some objective measure, like ESRD prevalence. This would benefit training programs that have a harder time recruiting. An equal proportions model may “share the pain” so certain regions are not affected disproportionately than others, thus retaining program directors and training infrastructure for when applications rebound (assuming they will).

As a fellow in training, I worry that any algorithmic approach to this problem will be focused too heavily on the needs of the training program and not the applicants. In that sense, the “survival of the fittest” model is more oriented to a fellow’s actual needs. Program desirability is likely driven by a mix of perceived program quality and factors unrelated to quality like geographic region, cost of living, or job opportunities for spouses, for example. In this thin market with so few applicants, program quality is not as much of a distinguishing factor. I think it’s safe to assume that fellows will work hard everywhere and that training program directors and faculty truly care about fellow education at all programs. In that sense, these factors not directly related to program quality will likely influence an applicant’s decision. I think it’s safe to assume that if these factors matter today, then they will likely be valued again by applicants in future years. If we are truly on board with a mission to increase interest in nephrology, we can start by paying attention to where people want to train and why. The NRMP Match rank list is a reasonable way to understand this.

Simply allocating positions based on ESRD prevalence or any other equitable algorithm favors at-risk programs, but it does not take into account trainee preferences. Many trainees desire specialized training in transplantation, glomerulonephritis, interventional nephrology, clinical research, basic science research, medical education, quality improvement, or health informatics. Some programs are more desirable because they can provide these individualized opportunities for career development. Access to one of these programs might be more limited through an algorithmic approach to training position allocation. Who knows, if word got out that positions have been weighted to regions based on ESRD prevalence alone, it may perpetuate the stereotype among residents that nephrologists are nothing more than dialysis technicians, missing the breadth and depth of actual practice. If fewer positions are made available in highly desirable programs, then it would be wrong to assume an applicant will be just as happy or available to train elsewhere. Given that some applicants desire certain locations due to factors like job opportunities for spouses, reducing positions in those desirable locations may be enough to convince the applicant to choose an alternative career like hospital medicine for example, where opportunity is abundant.

The nephrology community should remember that the primary issue is lack of interest. Efforts to increase interest should be at the center of the discussion. Deciding how to reduce positions will be controversial and it will be tough to find agreement. Maybe the best solution will need to consider everyone’s needs equally: considering applicant choices/preferences and also minimizing program dissolution. One model for position allocation could be based on an incentive for producing more nephrology applicants: You get fellowship training positions if you contribute to the applicant pool by mentoring/developing the residents and students at your institution. This would actually address the underlying problem wouldn't it? I applaud Dr. Desai for starting this conversation. Even if some final complex algorithm is required, I just hope that applicant and fellow preferences are not ignored.

Friday, December 12, 2014

Effects of Intensive Low-Salt Diet Education on Albuminuria: CJASN e-Journal Club

This month’s CJASN e-journal club was hosted at the Department of Nephrology at the Royal Infirmary of Edinburgh. It discussed a trial designed to investigate the efficacy of an intensive low salt diet intervention (weekly 30 minutes phone feedback by a dietary consultant) on albuminuria in non-diabetic hypertensive patients already on an ARB. This study is an open-label, case-control, randomized clinical trial based in South Korea. 

It is important to note that selected patients were a relatively healthy, homogenous population with good blood pressure control and an already low urinary sodium excretion. Very few were active smokers and many took regular exercise. All RAAS antagonists and diuretic agents were stopped for an 8 week run in and blood pressure was controlled with alternative agents. At week 0, Olmesartan was then commenced, and at 8 weeks, subjects were randomised to control or intensive education groups. 
The primary endpoint was the decrement in albuminuria by week 16 and was reached in the intensive salt reduction group. They demonstrated a significant reduction in albuminuria (278 mg/d to 178 mg/d) compared to the conventional therapy group (258 mg/d to 231 mg/d). There was a greater reduction in urinary sodium excretion in the intensive education group than the conventional group, but no change in blood pressure or renal function. In subgroup analyses, the authors examined those that received a reduction of > 25% of their dietary salt and those who did not, irrespective of treatment group. Notably, only 60% of those who achieved this reduction came from the intensive group. 

Overall this is an interesting, well-performed study which successfully demonstrates that lower salt excretion correlates with lower albuminuria. This occurred despite no effect on BP in a cohort with already excellent BP control. It may be better to interpret this as a “proof of concept” that salt restriction in humans could influence albuminuria. For clinical practice however, there are issues around the generalizability of these findings to everyday patients, given this was a highly selected, compliant group of patients. Also, as we know in the nephrology community from previous trials, an improvement in a relatively soft endpoint like albuminuria will not necessarily translate into improvements in renal/cardiovascular events or mortality. 

Check out the full text of the paper, our complete post and discussion over at the CJASN eJC website.

Authored by Eoin O’Sullivan & Paul Phelan

Wednesday, December 3, 2014

SHROOM3, Making sense of GWAS risk alleles

In this months edition of JCI a group led by Dr B Murphy from Icahn School of Medicine at Mount Sinai describe a beautiful set of experiments that explain the mechanism by which the CKD and eGFR risk allele rs17319721 causes chronic kidney allograft damage.

The single nucleotide polymorphism rs17319721 is in intron 1 of a gene called SHROOM3. The risk allele A (major allele G) of rs17319721 was found in large GWAS studies of European ancestry to be associated with GFR (p=1*10−12), incident CKD (p=0.005) and GFR in type 2 diabetic patients (P= 3.18E-03). The risk allele, A, frequency is about 40% in caucasian populations but is less frequent in non-caucasian populations.

The authors decided to investigate the effect of rs17319721, the SHROOM3 risk genotype, on kidney allograft fibrosis and chronic allograft nephropathy (CAN). Furthermore, they sought to determine what role, if any, SHROOM3, plays in allograft fibrosis. The risk locus was genotyped in over 500 allograft recipients and 500 allograft donors from the GoCAR transplant cohort. Also, SHROOM3 transcript levels in 3month protocol allograft biopsies were recorded in some of these patients. Donor genotype carrying one risk allele A (A/A or A/G) was associated with higher 3month SHROOM3 expression levels compared to the normal donor G/G genotype. Interestingly, correlation occurred only in Caucasian donors when analyzed separately and there was no association with the recipient risk genotype.

The authors then looked at 12month allograft GFR and chronic allograft dysfunction index score at 12 months (CADI-12). 3month SHROOM3 expression levels were inversely related to 12 month GFR, predictive of CADI-12 and were predictive of worsening CADI score (3m to 12m)(termed ‘progressors’). These associations were not found in non-Caucasian donors.

To assess whether 3M SHROOM3 levels could predict CAN they generated logistic models that included recipient age, sex, race, AR and CIT with or without 3M SHROOM3 levels to predict 12M CADI ≥2 or 3-12M CADI change (ΔCADI) of ≥2. AUC for prediction of high CADI-12 and ΔCADI were improved in each subgroup when SHROOM3-3M level was added. For Caucasian donors AUC for ‘progression’ was 0.81 with SHROOM3 and 0.74 without SHROOM3. Furthermore, the A allele in the donor was associated with greater risk of CADI-12≥2 in all allografts (OR 1.98; CI, 1.10–3.59), indicating a higher risk of CAN with the risk allele.

This work demonstrates that the A risk allele (rs17319721) in donors is associated with higher 3M SHROOM3 levels and increase risk of CAN. Also, 3M SHROOM3 levels predict CAN and 12M GFR.

So what is the mechanistic consequence of having the A allele vs the G allele? rs17319721 is located in a transcription factor binding motif. The authors found that the transcription factor TCF7L2 binds more strongly to this motif when A is present vs when G is present. Wnt agonist increased TCF7L2/β-catenin complex binding to the A allele binding site but not the G allele site. TGF-β1 is a known key growth factor regulating renal fibrosis. The authors found that TGF-β1 induced increases in SHROOM3 expression via the Wnt/β-catenin/TGF-β1 pathway in renal tubular cells.

Then they showed SHROOM3, in turn, enhances the TGF-β1/SMAD3–induced expression of profibrotic genes including CTGF, Vimentin, and Collagen IV (downstream targets of TGF-β1/SMAD3 signaling) and these genes were significantly upregulated in allografts within the highest quartile of SHROOM3 expression. Finally the authors verified these data in a mouse model of fibrosis.

Taken together, this data suggest an increased profibrotic program in the presence of the enhancer function of the risk allele and/or increased SHROOM3 expression. This schema is illustrated below.

This paper nicely describes the mechanism of action conferred by a single risk allele found in large GWAS studies. Until recently there has been little data to explain the relevance of the many risk SNPs described in GWAS studies. Without an understanding of the mechanism through which these SNPs confer disease there can be no progress towards identifying potential therapeutic targets. This study has identified SHROOM3 as a potential therapeutic target for chronic allograft nephropathy.