A cause and a cure of hyperkalemia? The next #NephJC

There has been a flurry of publications in the field of hyperkalemia with 3 separate trials of oral potassium binding agents within a week of each other (Sodium Zirconium in JAMA, and NEJM and Patiromer in NEJM) and a potentially related observational trial on the risks of co-trimoxazole in patients on RAAS blockade in the BMJ. With all that reading to get through, the next NephJC on Tuesday Dec 2nd will be a double whammy. We will look at the HARMONISE trial of ZS-9, and a large study of co-trimoxazole and potential associations. 

Trim-Sulfa and Sudden Death in patients receiving inhibitors of renin-angiotensin system. 

The first paper for discussion is a large, Canadian, case control series, by the Canadian Drug Safety and Research Effectiveness Network, published in the BMJ. The hypothesis is the risk of sudden death in patients on RAAS blockade is higher following administration of specific antibiotics rather than amoxicillin. To answer their question, they searched 17 years of records representing over 1.6 million patients. They identified 39,879 with a label of sudden death and a subsequent group of 1,027 that had a prescription for the target antibiotics in the 7 days prior to dying. 
The authors write: “In the primary analysis, co-trimoxazole was associated with a significantly increased risk of sudden death within seven days relative to amoxicillin (OR 1.8 C.I 1.5-2.24)” Ciprofloxacin was associated with a somewhat lower risk of sudden death. I found it strange that norfloxacin, which has similar QT prolonging properties to ciprofloxacin, had had no such risk. The authors speculate this observed association may be due to trimethoprim’s activity as an ENaC antagonist. There are a number of important limitations to consider. There was no indication for antibiotics recorded. Also, the cases and controls had some important differences in terms of diuretic use and co-morbidities. Only 8.2% of the cases had renal disease, the stage of which was unclassified. The authors can only speculate about a possible mechanism involving hyperkalaemia as no K levels were obtained for any of these patients, nor any ECG to help explain the effect of ciprofloxacin. 

Harmonise: Effect of Sodium Zirconium Cyclosilicate on Potassium Lowering for 28 Days Among Outpatients With Hyperkalemia. 

ZS-9 is a zirconium silicate, a non-absorbable potassium binding agent. It is an inorganic cation exchanger crystalline with the capacity to bind both potassium and ammonium in the GI tract. Its creators tout its non-absorbable nature as the key to minimising systemic side effects. HARMONISE is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial spanning 44 centres. Inclusion criteria was simply a serum K of ≥ 5.1 on 2 occasions. Initially, 258 patients who met eligibility criteria were given ZS-9 10g three times daily. If they achieve normokalaemia within 48 hours, they were then randomized to a placebo, or increasing doses of ZS-9 once daily. The mean eGFR was 46 ml/min/1.73m2 and no ESKD patients are represented. 
Did it work? The short answer is yes. ZS-9 had a reasonable rapid rate of onset and within 2 hours, serum Potassium has dropped by −0.4 mEq/L (95% CI, −0.5 to−0.4) and was - 1.1 mEq/L by 48hours. Encouragingly, it seems generally well tolerated with some edema and hypokalemia as the doses increased. In conclusion, this is a well executed phase 3 trial and ZS-9 has potential to be a well tolerated and predictable treatment option for hyperkalemia. The authors quite rightly point out we still have no data beyond 4 weeks, nor have we any meaningful endpoint such as mortality or hospital admissions. It is an encouraging study none the less, and should lead to FDA approval and another tool in our kit.

Full post can be seen at www.nephjc.com 

Authored by Eoin O'Sullivan.

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. POSEIDON 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. POSEIDON 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!

Top nephrology-related stories of 2013

The votes are in! Hard to believe that another year has come and gone. RFN has presented the top 10 stories as voted by the readers of RFN since 2010. 2013 proved to be another interesting year. This years list is almost completely dominated by clinical trials. Basic science was snubbed this year (unlike other years). New this year was the active participation of the nephrology blogosphere in promoting different stories. Eleven different people posting on six different blogs and discussed why some of the stories were worthy of the top 10 list this year. These bloggers included Joel, Christos and Ed El Sayed over at PBFluids. Myself and Edgar at eAJKD. Adrian at Red Beans. Kenar at Nephron Power. Pascale at WhizBANG. Andrew, Paul and Gearoid here on RFN. This was a lot of fun and a great learning opportunity. Going into greater detail and hearing about different perspectives about how each of these stories might impact the field of nephrology was nice. This year set a record in voting at 155. Thanks to all who took the time to vote. As always this is not by any means a comprehensive list. If you have additions, feel free to add your story below as a comment. Now lets get to it...

First, a review of the top stories for the last several years can be found below.
Top stories of 2010
Top stories of 2011
Top stories of 2012

Hold up, stop the press, we have a last minute addition..
Honorable Mention- The much awaited hypertension guidelines (JNC 8 aka JNC late) was finally published in JAMA. I guess it is fitting that JNC 8 was published AFTER the year-end poll. The recommendations were a vast simplification to the JNC 7 report. In a nutshell, the JNC 8 committee recommended to treat blood pressure to 150/90 (JNC 7- 140/90) in patients greater than 60 yrs old and 140/90 (JNC 7- 130/80) for everyone else including patients with CKD, diabetes and those less than 60 years old. The new guidelines also recommend black patients take either a thiazide diuretic or a calcium channel blocker (CCB) as initial Rx. They recommended non-black patients to take thiazides, ACEi, ARB or CCB. Patients with CKD should be on ACEi or ARB. JNC 8 will still be fair game for next years top nephrology-related story.

10. Controversial cholesterol guideline published by AHA/ACC (14%)- Coming in at number 10 is the new cholesterol guidelines published in JACC by the AHA/ACC. There was much debate about the calculator that accompanied these guidelines as many felt that it was flawed and over-estimated the risk of cardiovascular disease. This over-estimation (75-150%) would place many more people on statins that would not be warranted. Joel over at PBFluids has a nice discussion about this. For a review on treating cholesterol in patients with kidney disease check out Andrew's post at RFN.

9. A novel potassium binder ZS-9 presented at ASN (14%)- This was a big surprise for just about everyone at ASN this year. However, the study is not published yet. The medical community is sorely in need of a better potassium binder for treating hyperkalemia. This is a frequently encountered problem with life threatening implications. Sodium polystyrene sulphonate (kayexalate) has been put through the ringer as of late. Many have been calling into question its effectiveness and potential risks (bowel necrosis). For another view on SPS check out Joel at PBFluids. The company ZS Pharma presented results from a phase II clinical trial and demonstrated that ZS-9 was capable of lowering potassium with minimal side effects. This could be a huge breakthrough and a much needed drug to treat a common medical condition. This is a well-deserved top story of the year in my opinion.

8. APOL1 risk alleles linked to CKD progression in AASK and CRIC cohorts presented at ASN and published in NEJM (15%)- The story of APOL1 risk alleles continues to gain traction in the medical literature. This year at ASN the story deepened with a study by Parsa et al. I discussed this on eAJKD. The authors showed that having 2 APOL1 risk alleles was associated with faster decline of kidney function in both the AASK and CRIC cohorts. The original APOL1 study published in Science was the #4 RFN top story of 2010. This is an exciting avenue of investigation as a target for APOL1 could have huge ramifications in treating kidney disease. However, this could be a long way off.

7. JASN paper by DeSilva et al showing that Fistula First perhaps not best for Elderly CKD patients (16%)- Coming in at number 7 is a very interesting paper from DeSilva et al in JASN. The Fistula First campaign has largely been seen as effective in decreasing the number of patients initiating dialysis with either a catheter or a graft. However, the benefit of performing dialysis with a fistula over a graft might not be apparent until several years. Is is possible that the survival benefit of a fistula over a graft is lost in the elderly? This group showed that in patients over 80 years old mortality did not differ between patients with a fistula versus a graft. Furthermore, they show that patients receiving a fistula were much more likely to require a catheter at some point as compared to a graft. An accompanied editorial states that we should shift our focus from a "fistula first" to a "patient first" approach. A one size fits all approach to medicine can be dangerous. This is an important study and worthy of the top 10 list.

6. Tolvaptan fails to gain approval from FDA for ADPKD (18%)- Number 6 is #TeamTolvaptan. Joel pushed for this story to be the number one story of the year over at PBFluids. Patients with CKD and in particular ADPKD have few pharmacological weapons to combat the relentless decline of renal function. The results of the TEMPO3:4 trial was the number 1 story of last year and the nephrology community was hopeful tolvaptan would gain FDA approval for ADPKD this year.  However, this was not the case as the FDA focused on liver toxicity and lack of hard outcomes (no ESRD outcomes only change in cyst size and slope of creatinine). I hope we see the tolvaptan story making the number 1 story of 2014 with approval from the FDA. We will see.

5. Abatacept in B7-1 Postivie Proteinuric Kidney Disease presented at ASN and published in NEJM (22%)- This was a small case series published in NEJM of abatacept (fusion protein composed of the Fc region of IgG1 fused to CTLA-4 inhibiting B7-1 binding) in patients with FSGS. Five patients with FSGS underwent immunostaining for B7-1 and showed positivity. These patients were subsequently treated with abatacept. All had either a partial or a complete remission. The thought is that B7-1 activation leads to podocyte dysfunction and abnormal motility through its interaction with beta-1-integrin. Paul discussed the utility of abatacept in FSGS, Lupus Nephritis and Diabetic Nephropathy on RFN. I hope a large trial will be underway soon as these are encouraging results.

4. RAVE Trial showing Rituximab as effective as conventional immunosuppression as induction agent in ANCA vasculitis reported in NEJM (25%)- The use of rituximab has continued to gain popularity treating a variety of autoimmune-related diseases. The difficulty in treating ANCA vasculitis is that the toxicity of the meds can sometimes be worse than the disease itself. Enter the RAVE trial. This was a randomized trial originally published in 2010 and demonstrated non-inferiority of rituximab as compared to oral cyclophosphamide for remission of severe ANCA associated vasculitis at 6 months. The follow-up to RAVE was reported in NEJM and discussed by Paul at RFN in December. In the RAVE trial the experimental group received rituximab and those who had remission only recieve placebo therafter. Whereas the comparison group received continued immunosuppression with cyclophosphamide followed by azathioprine (conventional group). Overall results showed that the rituximab group was non-inferior to the conventional group at 18 months. Rituximab was also superior to conventional immunosuppression in relapsing patients over the first 12 months. Interestingly and surprisingly, adverse events were similar between the two groups. These are encouraging results and adds to the armamentarium of drugs for ANCA vasculitis.

3. JASN paper by Maduell et al showing Online Hemodiafiltration reduces mortality compared to standard HD (27%)- Online hemodiafiltration continues to gain traction in Europe but its use the US has been slow to catch up. Online hemodiafiltration is a technique that involves the addition of convective clearance (hemofiltration) to the diffusive clearance of hemodialysis. This gives better middle molecule clearance of uremic toxins. Maduell et al reported in JASN this year a multicenter, open-label, randomized controlled trial with 906 patients on HD with either hemodialysis versus online-hemodiafiltration. After 2-years the online hemodiafiltration group had a 30% reduction in mortality (P=0.01). Paul at RFN reviews the evidence for why online hemodiafltration has gained momentum in Europe. Lets hope the big dialysis groups catch on and start offering this therapy to patients on hemodialysis. 

2. NEPHRON-D trial presented at ASN and published in NEJM (27%)- Number 2 is the NEPHRON-D trial. Edgar covered this at eAJKD and Ed Al Sayed at PBFluids. This trial effectively put the nail in the coffin of combined ACEi/ARB therapy for diabetic nephropathy. In short the trial was stopped early due to adverse events such as  hyperkalemia and acute renal failure, but still didn't show a difference in CKD progression or death. Even though this was a negative trial it answered an important question about the use of combination therapy and appears that readers agree as it is the number 2 story of the year.

1. CORAL trial for Renal Artery Stenosis presented at AHA and published in NEJM (33%)- Coming in at number 1 is the CORAL trial. This was presented at AHA Scientific Sessions and published in NEJM. As with combo ACEi/ARB therapy this is another nail in the coffin for this time stenting renal arteries in hypertension associated with renal artery stenosis. The CORAL trial was a large trial of 947 patients with renal artery stenosis. There was no difference in any of the outcomes most notably death, MI, stroke, progression of CKD or need for RRT. Jonathan has a nice discussion about this trial at RFN. There still could be a small subset of patients who might benefit from stenting (e.g. flash pulm edema). However, this could be the end of routine stenting in renal artery stenosis.

Again, quite a busy and exciting year in the world of nephrology in 2013. 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 2014 has in store!

The Role of the Gut for Potassium Homeostasis in CKD

Recently the FDA approved one of the newer exchange resins (Lokelma, ZS-9) for the treatment of hyperkalemia. (Veltassa, Patiromer), a calcium based cation exchange resin, was recently developed and approved since 2015 for the treatment of hyperkalemia. These two new drugs, which each have large randomized placebo controlled trials confirming their effectiveness, now seem bound to replace the ancient but much experienced Kayexalate (Sodium Polystyrene Sulfonate; SPS) for the management of hyperkalemia. However, they are not approved in Canada and their cost makes them less enticing options in a publicly funded health care system. Also, what about safety concerns? SPS has been used since the 1950s, however it took decades for case reports to come out possibly linking fatal colon necrosis to Kayexalate use. This association remains hotly debated. A systematic review in 2013 found a total of 58 cases of biopsy confirmed bowel injury that were “possibly” related to SPS use based on the WHO causality criteria. Interestingly, these cases were not limited to patients using SPS with sorbitol, nor to the post-operative population as was once thought to be the major risk factors for adverse GI events from SPS. On the other hand, a retrospective single-centre review over a 10 year period found only 3 cases of colon necrosis among 2,194 patients having received SPS. When they compared this incidence of colon necrosis to control patients having not received SPS, they found a non-significant RR of 2.10 (0.66-6.64; P=0.2). Many nephrologists will argue that SPS has a long standing proven track record and that colon necrosis is such a rare side effect that it is unlikely to be related. While no one knows if this is truly the case, the uncertainty surrounding this issue is one of the major reasons that led to the development of the newer exchange resins: ZS-9 and patiromer.

Before praising and widely accepting these newer, expensive products, would it not be wise to use the same caution we would for SPS? It can take years for such a rare adverse event as colon necrosis to manifest itself, how do we know we won’t be facing this GI safety issue 5 to 10 years from now?

Perhaps we could look for other ways of trying to enhance GI elimination of potassium.

--> BK-channel in colon enterocyte (Source: Sandle et al. QJM. 2010 Feb;103(2):85-9)    
The colonic enterocyte has an ability to excrete potassium in stool. This may be an important physiologic property in patients with advanced CKD who lose the ability to renally excrete potassium. In fact, patients with ESKD are known to have a greater excretion of potassium in their stool compared to individuals with normal kidney function. An important transporter involved in this process is the BK-channel located on the apical side of the colonic enterocyte within the colon crypts (see Figure). This channel is responsible for actively secreting potassium in the GI lumen. Aldosterone stimulates this channel, enhancing K secretion in the stool, similar to its effect in the kidneys. In fact, a study in the 1970s of patients suffering from acute cholera showed that within 12 hours of receiving a single dose of 100mg of spironolactone, there was a significant decrease in stool loss of potassium and an increase in stool loss of sodium. This likely is a major reason explaining why anuric patients with ESKD may still have from hyperkalemia if given RAAS blockade. The BK channel will also be stimulated by various diarrheal states such as Ogilvie’s syndrome, villous adenoma and certain laxatives such as bisacodyl. Bisacodyl is a stimulant laxative which enhances peristalsis through parasympathetic nerve activation, but also stimulates cAMP production within the colon enterocyte. This cAMP is thought to enhance K excretion via the BK-channel. A study performed in 2005 used immunohistologic analysis of colonic enterocytes in patients with ESKD and showed that BK-channels are upregulated in these patients compared to controls with normal kidney function. The upregulation of BK-channels probably represent an adaptation to chronic potassium load in order to maintain homeostasis. Interestingly, a small study in 2003 tested the effect of Bisacodyl on potassium in patients with ESKD. Eight controls normal kidney function and 13 patients with ESKD were given Bisacodyl 5-10mg PO titrated to achieve 2 soft bowel movements per day and these were compared to 5 ESKD patients given lactulose 10ml PO titrated also to 2 soft bowel movements per day. After 2 weeks of treatment, they found that the ESKD patients with Bisacodyl had a significant decrease in potassium from 5.9 to 5.4mmol/L whereas the controls given Bisacodyl and the ESKD patients given lactulose had no change in potassium values after 2 weeks of therapy. This suggests that Bisacodyl increases potassium excretion in the stool in patients with ESKD through a mechanism not simply related to its laxative effect, but likely through stimulation of the BK-channel of the colonic enterocyte. It is unfortunate that no further studies have looked into this therapeutic option for maintaining potassium homeostasis in patients with advanced CKD. Unfortunately, we don’t know if Bisacodyl would work as well in the non-dialysis population since we could expect these patients may not have as upregulated BK channels as in ESKD who are faced with more chronically elevated potassium loads. However, this would be an interesting study to pursue since Bisacodyl would be a cheap and safe way of controlling potassium in patients with advanced CKD by enhancing the body’s natural adaptation to potassium handling.

David Massicotte-Azarniouch
Nephrology Fellow
University of Ottawa

NephMadness 2014 Part 7 - Electrolyte Bracket

The electrolyte bracket contains a mixture of the old staples of nephrology mixed with some new kids on the block trying to muscle in on established territory, Vaptans vs hypertonic saline and ZS-9 vs Kayexalate. Hypertonic saline is well established and works when used correctly. In my experience inadequate monitoring and insufficient lab testing always complicates the correction of severe and acute hyponatremia. Severe hyponatremia has potentially devastating consequences and so should be managed in an ICU setting where frequent labs can be drawn and most importantly acted upon. The role of Vaptans is probably more in the chronic setting, in particular for longstanding hyponatremia in the setting of heart failure. In fact the SALT 1+2 trials excluded patients with acute symptomatic hyponatremia. Dr Berl wrote a nice review in KI.

Bicarbonate is center stage in the 2 and 7 seed match up. Bicarbonate for acute acidosis such as lactic acidosis, when extreme, is widely used I would imagine. This is despite lack of good evidence to suggest it improves outcomes. However, when faced with severe acidosis it makes physiological sense to give alkali. Another area were iv bicarbonate has fallen out of favor is in cardiopulmonary resuscitation. The 2010 ACLS guidelines recommended against the routine use of iv bicarbonate. This was due to fears of it causing intracellular acidosis, hypernatremia, respiratory depression and metabolic acidosis once perfusion is restored. One study from the 1990s looked at 273 successful out of hospital cardiac arrest outcomes. 58 patients got no HCO3 and had short CPR times (7.4 +/- 5.5 minutes). 215 patients did receive HCO3 and had significantly longer CPR times (23.3 +/- 13.5 minutes, (P =< 0.001). Initial emergency department blood gas results of both groups were not significantly different. No patients in the no HCO3 group had hypernatremia (sodium [Na]+ greater than 150), whereas four patients (2%) in the HCO3 group were hypernatremic. Eight patients (14%) in the no HCO3 group and 37 patients (17%) in theHCO3 group were alkalotic with pH values greater than 7.49 (P = NS). Six patients (10%) of the no HCO3 group and 24 patients (11%) of the HCO3 group had a metabolic component to the alkalosis as defined by a positive base excess value (P = NS). These are interesting findings given that these patients are the sickest and probably most acidemic you will encounter!

Despite this entire blurb I went for serum anion gap in this bracket!Very useful equation.

Vote for the Top Nephrology Stories of 2014

This is the 5th year RFN has hosted the Top Nephrology Stories of the year poll. This is an attempt to look at the year in nephrology voted by the readers of RFN. Take a few moments and vote for any of the stories you feel are worthy of making the top 10 list. You can vote for as many as you wish. Write a quick blog post about a story you think deserves the vote. If we missed anything please feel free to comment below. Note, the story must be published after the year end poll of 2013.

Please go to the right hand side -----> of the RFN page and make your selection until Dec 12th. Results will be posted on Dec 25, 2014

Below contains links to each of the stories for more information.

JNC8 Hypertension Guidelines published in JAMA (this was published online after the poll last year)

ZS-9 trials for hyperkalemia in JAMA and NEJM (Nov 2014)

Patiromer OPAL-HK trial for hyperkalemia in NEJM (Nov 2014)

The PREDIAN Trial: pentoxifylline for diabetic kidney disease in JASN (June 2014) 

SYMPLICITY-3 trial for renal denervation in resistant HTN in NEJM (March 2014)

Mesoamerican nephropathy continues to unfold

Dendritic cell isoketals activate T cells and promote HTN in JCI (October 2014)

Sustainable Growth Rate legislation in March 2014 pushed inclusion of oral only meds (phos binders) in ESRD out of bundle until 2024

α–Intercalated cells defend the urinary system from bacterial infection in JCI

Peritoneal dialysis solution shortage 

IgA Nephropathy GWAS implicates genes involved in helminth immune response in Nature Genetics (Sept 2014) 

Anti-Phospholipase A2 receptor assay licensed for commercial testing

Co-trimoxazole and sudden death in patients receiving RAS inhibitors in BMJ (Oct 2014)

Identification of thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy in NEJM (Nov 2014)

Perivascular Gli1+ progenitors contribute to myofibroblast pool leading to fibrosis in multiple organs including kidney Cell Stem Cell (Nov 2014)

HALT-PKD Trials of low BP target and ACEi/ARB combo in NEJM (Nov 2014) 

CORONARY Trial of on-pump versus off-pump CABG and subsequent CKD (June 2014)

POSEIDEN Trial fluid administration guided by LV end diastolic pressure in Lancet (May 2014)

Gestational HTN or preeclampsia was more common in kidney donors in NEJM (Nov 2014)

Please go to the right hand side -----> of the RFN page and make your selection until Dec 12th. Results will be posted on Dec 25, 2014

Novel hyperkalemia treatments – practical points

I was quite excited to see the development of novel agents to help us manage hyperkalemia in our kidney patients in place of kayexalate, which is extremely unpleasant for patients, is associated with diarrhea and have reported severe side effects such as intestinal necrosis. As previously reviewed, recent trials were published on two major drugs: Patiromer (Veltassa) and ZS9.

 Patiromer is a polymer that binds K in exchange for calcium (NEJM 2015). FDA recently approved this agent for treatment of chronic hyperkalemia (not acute) though it included a black box stating that patiromer can significantly affect the absorption of many orally administered medications and therefore it should be taken 6 hours apart from any other medication (a significant limitation). This decision by the FDA was based on some in vitro data (could not find the actual data on the recent papers) so it is unclear which drugs may significantly be affected if taken in close proximity. The company is now performing a number of studies to elucidate that. Currently, Patiromer is available to patients but it is only dispensed in subspecialty pharmacies and most hospitals don’t have this medication on formulary yet, in part related to the cost of $30 per pill. The main side effects reported with Patiromer were hypomagnesemia and constipation. Duration of trials were up to 52 weeks.

ZS9 is a crystalline compound of zirconium silicate that exchanges Na+/H+ for K+. Based on its mechanism of action, patients will have about 300mg of extra Na+ intake per day (Kayexalate has the same issue). The main side effect of ZS9 was edema (~7%). Duration of trial with ZS-9 was only 4 weeks. FDA has not approved ZS9 yet but it is likely that once approved, it will be the leading drug in the market, especially if the black box from FDA remains for patiromer.

 These first trials excluded patients on dialysis and patients with potassium greater than 6.5 mmol/L. Let us know if you have used Patiromer in the real world so that we can start gaining more knowledge outside of a controlled clinical trial.

Figure from Nephcure.org