Wednesday, November 26, 2014

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 

Authored by Eoin O'Sullivan.


There was a fascinating case published a couple of months ago in the American Journal of Medicine. I have a particular interest in this case as it was my clinic mentor, Julian Seifter, who made the diagnosis and published the case. I have waiting for a long time to write a post about it but couldn't until the paper came out.
The case is a 50yr old man with a history of CKD, quadraplegia and an ileal conduit who was being investigated for CKD. His serum creatinine was 3mg/dl and a creatinine clearance was done to estimate his GFR. His urine creatinine concentration was 175mg and his calculated creatinine clearance was only 3 mls/min. At this point, RRT was recommended and the suggestion was that his serum creatinine overestimated his GFR because of reduced muscle mass. 
However, because the urine creatinine still seemed inordinately low and he had no symptoms, an inulin clearance was done which revealed a true GFR of 21 ml/min. What could explain this discrepancy?
A urine culture grew diphtheroids, staphlococcus and streptococcus. Although creatinine, once it is produced in the muscle cannot be metabolized in humans, some bacteria produce creatininase and as a result are able to break it down. Corynebacterium is a diphtheroid that has been associated with the production of creatininase. Dr. Seifter suspected that there was a creatininase-producing bacterium in the ileal conduit that was metabolizing the creatinine leading to a falsely low creatinine clearance. To confirm this, he took a sample of the patient's urine, added a known quantity of creatinine and incubated it for 24 hours at 20 degrees. The results are shown in the figure below.

Our GI tract has some creatininase-containing bacteria but under normal circumstances, the amount of creatinine clearance that they contribute is negligible - less than 2 ml/min GFR equivalent. However, in individuals with advanced CKD, both the relative and total clearance contributed by these GI bacteria increases such that in people with a GFR <10 the contribution of gut clearance can be as high as 4ml/min or approximately 50%. The opposite can also occur. The highest serum creatinine I ever saw was in a 50yr old woman with inflammatory bowel disease. She weighed 40kg but her admission creatinine was 38mg/dl. Despite this, she felt relatively well. She had previously undergone multiple bowel resections and had almost no functional bowel remaining. As a result, she had no gut clearance of creatinine and no upper limit to her serum creatinine concentration.

One final note, the urea clearance was not useful in the above patient either - his urine also contained urease -  the clue to this was a very high urine pH (>9) in the presence of a mild metabolic acidosis and no history of RTA.

Thursday, November 20, 2014


Almost all the formulas we use in the management of the disorders of water homeostasis are derived from the Edelman equation. I am presenting where these formulas come from for the math aficionados.

Edelman equation

·         Original Edelman equation (J Clin Invest. 1958;37:1236-56):
[Na+] = {1.1 x (Nae + Ke)/TBW} – 25.6
Where [Na+] = plasma sodium concentration, Nae=total body exchangeable sodium, Ke=total body exchangeable potassium, TBW = total body water.

·         Simplified Edelman equation: [Na+] = (Na + K)/TBW
·         [Na+] x TBW = Na + K
·         Na + K = [Na+] x TBW

Calculating Free Water Deficit (FWD)

Method #1 (Using baseline weight, certainty about what % of body weight is water)

1.       Assuming only pure water has been lost, the total body sodium and potassium remain constant so the total body sodium and potassium at baseline (Na + K)baseline and the total body sodium and potassium after water loss (Na + K)current are equal:

·          (Na + K)baseline = (Na + K)current

2.       Total body sodium and potassium can be expressed as sodium concentration ([Na+]) multiplied by total body water (TBW):

·         [Na+]baseline x TBWbaseline = [Na+]baseline x TBWcurrent
·         TBWcurrent = [Na+]baseline x TBWbaseline/[Na+]current … (1)

3.       Free water deficit can be expressed as:

·         FWD = TBWbaseline – TBWcurrent … (2)

4.       Then replacing (1) in (2):

·         FWD = TBWbaseline – ([Na+]baseline x TBWbaseline)/[Na+]current
·         FWD = TBWbaseline x (1 – [Na+]baseline/[Na+]current)

5.       If [Na+]baseline is considered normal at 140 mEq/L then:

·         FWD = TBWbaseline x (1 – 140/[Na+]current)

Method #2 (Using current weight, uncertainty about what % of body weight is water)

1.       Assuming only pure water has been lost, the total body sodium and potassium remain constant so the total body sodium and potassium at baseline (Na + K)baseline and the total body sodium and potassium after water loss (Na + K)current are equal:

·         (Na + K)baseline = (Na + K)current

2.       Sodium and potassium masses can be expressed as sodium concentration ([Na+]) multiplied by total body water (TBW):

·         [Na+]baseline x TBWbaseline = [Na+]current x TBWcurrent
·         TBWbaseline = [Na+]current x TBWcurrent/[Na+]baseline … (1)

3.       Free water deficit can be expressed as:

·         FWD = TBWbaseline – TBWcurrent … (2)

4.       Then replacing (1) in (2):

·         FWD = [Na+]current x TBWcurrent/[Na+]baseline – TBWcurrent
·         FWD = TBWcurrent x ([Na+]current/[Na+]baseline - 1)

5.       If [Na+]baseline is considered normal at 140 mEq/L then:

·         FWD = TBWcurrent x ([Na+]current/140 - 1)

Calculating Rate of Infusion of Hypertonic Saline

Method # 1: Na deficit formula

Deriving Na deficit formula

1.       Na deficit = Nagoal – Nacurrent … (1)

2.       Since Na + K = [Na+] x TBW, then Na = [Na+] x TBW – K … (2)

3.       Replacing (2) in (1)
·         Na deficit = TBWgoal x [Na+]goal – Kgoal – {TBWcurrent  x [Na+]current – Kcurrent}

4.       Assuming TBW and K remain constant, so TBWgoal = TBWcurrent, and Kgoal = Kcurrent, then TBW = TBWgoal = TBWcurrent and K is cancelled out from equation:

·         Na deficit = TBW x [Na+]goal – TBW x [Na+]current
·         Na deficit = TBW x ([Na+]goal – [Na+]current)

5.       Since now we aim for an increase in [Na+] of 6 mEq/L, so [Na+]goal – [Na+]current = 6 mEq/L then:

·         Na deficit = TBW x 6 mEq/L

Calculating volume of infusate

·         Volume of infusate = Na deficit x (1000 mL/513 mEq)

Calculating rate of infusion

·         Rate of infusion = volume of infusate/24h

Method #2: Adrogue-Madias formula

Deriving Adrogue-Madias formula

1.       [Na+] = (Na + K)/TBW … (Edelman equation)

·         [Na+]current = (Nacurrent + Kcurrent)/TBWcurrent
·         [Na+]current x TBWcurrent = (Nacurrent + Kcurrent) … (1)

2.       [Na+]goal will be the new [Na+] that results when we administer 1L of an infusate containing Nainfusate and Kinfusate, then:

·         [Na+]goal = (Nacurrent + Kcurrent + Nainfusate + Kinfusate)/(TBWcurrent + 1) …(2)

3.       Substracting [Na+]current from both terms of equation (2), then:

·         [Na+]goal – [Na+]current = (Nacurrent + Kcurrent + Nainfusate + Kinfusate)/(TBWcurrent + 1) – [Na+]current

4.       But [Na+]goal – [Na+]current is the same as change in [Na+], then:

·         Change in [Na+] = (Nacurrent + Kcurrent + Nainfusate + Kinfusate)/(TBWcurrent + 1) – [Na+]current
·         Change in [Na+] = {(Nacurrent + Kcurrent + Nainfusate + Kinfusate) – (TBWcurrent + 1) x Nacurrent}/(TBWcurrent + 1)
·         Change in [Na+] = {Nacurrent + Kcurrent + Nainfusate + Kinfusate – ([Na+]current x TBWcurrent –[Na+]current)}/(TBWcurrent + 1) … (3)

5.       Replacing equation (1) in (3), then:

·         Change in [Na+] = {Nacurrent + Kcurrent + Nainfusate + Kinfusate – (Nacurrent + Kcurrent) - [Na+]current}/(TBW + 1)

6.       Cancelling out Nacurrent + Kcurrent then:

·         Change in [Na+] = {Nainfusate + Kinfusate - [Na+]current}/(TBWcurrent + 1)

Calculating volume of infusate

·         Volume of infusate = {1000 mL x (Change in [Na+])goal}/(Change in [Na+])
·         Volume of infusate = {1000 mL x 6 mEq/L}/(Change in [Na+])

Calculating rate of infusion

·         Rate of infusion = volume of infusate/24h

Tuesday, November 18, 2014

SEVERE CHRONIC HYPONATREMIA: A Pathophysiological Rumination.

[This is the final post in the five-part series covering some important and often overlooked (and under-published) issues and concepts in the management of severe hyponatremia. While this is not, by any means, an exhaustive discussion of the topic, I hope that these posts will not only help the readers enhance their understanding of the pathophysiology of severe hyponatremia but also help them manage it more effectively with a lot less stress and mental anguish.]

In this video post, I discuss --- what I find to be --- an extremely useful method of calculating the dose of sodium chloride based infusions and predicting response to therapy while treating chronic severe hyponatremia.

Posted by Hashim Mohmand

Monday, November 17, 2014

Michelle P Winn Endowed Lectureship, ASN 2014

At this year's ASN Kidney Week in Philadelphia Andrey Shaw, MD, presented the inaugural Michelle P Winn Endowed Lectureship. Dr Shaw was not only a longtime collaborator of Michelle’s but also a very close personal friend making him the perfect choice for this inaugural lectureship. Dr Shaw delivered an excellent talk interweaving highlights from Michelle’s stellar career with examples of Michelle’s fun loving and genuine kindhearted nature. I was lucky enough to work in Michelle’s lab from 2012 to 2014. She cared greatly about all her mentees both professionally and personally. She was a huge inspiration and a friend.

Michelle did her undergraduate studies at the University of North Carolina before going to medical school at East Carolina University. She then entered Duke University for residency and fellowship before joining the Duke faculty. Despite spending most of her career at Duke she remained a true Tar Heel (UNC) fan!

She received her training in classical human genetics from Drs Jeffery and Peggy Vance at the Duke Center for Human Genetics. In collaboration with another longtime friend and collaborator and early mentor at Duke, Dr Peter Conlon, Michelle began investigating the genetic heterogeneity of FSGS.
  • Together Drs Winn and Conlon collected what is now one of the largest Familial FSGS datasets in the world.
  • Michelle’s early work linked familial FSGS in one large family from New Zealand to a locus on chromosome 11.
  • Following this she identified TRPC6 as the cause for FSGS in this family. This was a seminal paper published in Science and introduced an ion channel and calcium into the burgeoning field of podocyte biology. 
  • Michelle’s further work on TRPC6 made a huge contribution to the understanding of the biology of TRPC6 in kidney disease. 
Michelle was also very interested in other inherited kidney diseases.
  • She described linkage of a gene causing MPGN type III, 
  • identified TNXB mutations causing vesicoureteral reflux, 
  • was involved in studies of genetic factors influencing the development and progression of IgA nephropathy 
  • a hybrid CFHR3-1 gene causing familial C3 glomerulopathy. 
  • Her work also helped to define the disease burden and impact of other FSGS causing genes such as INF2, NPHS2 and PLCe1
Towards the end of her career and even while fighting her illness she remained very involved and continued to contribute in a huge way to the field we all love.
  • She discovered Anillin a new gene causing FSGS, 
  • a new mutation in the WT1 gene 
  • added further insights into the function and regulation of TRPC6 in podocytes. 
Michelle was a leader in her field of podocyte biology and renal genetics. In 2007 Michelle won the ASN Young Investigator Award. I am sure that if her life had not been tragically cut short she would have been awarded the highest honors our specialty has to offer. The creation of the Michelle P Winn Endowed Lectureship is testament to this probability. Michelle was a beautiful person and will be missed by all who knew her.

Tuesday, November 11, 2014

Blogger night at #KidneyWk14 on Thursday

Thursday night at 8:30 pm, Blogger Night (after the ASN Presidents Reception). If you like the Neph Social Media Crew from Twitter, Renal Fellow Network, AJKDblog or NephJC, join us for drinks at Field House Philly sports bar. Look for Joel in his AJKD hat.

Sunday, November 9, 2014

Nephrology fellows events at ASN #KidneyWk14

Welcome Reception: Nov 12th: 6-7PM
Marriott Downtown, Grand Ballroom, Salon H

Fellows In Training Bowl (Mystery Case Debate): Nov 14th 2-3PM
Convention Center, Room  119A

Fellows In Training Bowl (Jeopardy game Nephrology Challenge): Nov 14th 3-4PM
Convention Center, Room  119A

Meet the Experts Session Nov 15th  9:30AM - 10:30AM (Meeting the ASN Award Winners)
Convention Center, Hall D

Fellows Forum Nov 15th 10:30-11:30AM
Convention Center, Room 203

Fellows Poster Discussion Section Nov 15th 2-3PM
Convention Center, Room 112

h/t Kenar Jhaveri

Thursday, November 6, 2014

NephJC Live at ASN Kidney Week 2014

The Nephrology twitter journal club will come to life on Saturday 15th November at Kidney Week in Philadelphia. NephJC co-founders Dr Joel Topf and Dr Swapnil Hiremath will co-host the event at the Double Tree hotel.

There will be 2 live presentations on the day, both of which are sure to stimulate active discussion. There will be a study, presented by Dr. Deirdre Sawinski of University of Pennsylvania, looking at transplanting HIV positive kidneys into seropositive donors. Dr Francis Wilson will also present his RCT on acute kidney injury.

The event is filling up so please visit before this Sunday November 9th to register. For those of us who cannot make it to Philadelphia, the event will, as ever, be live tweeted using #NephJC.

Wednesday, November 5, 2014

Preventing PD Peritonitis: What's the Evidence?

Peritoneal dialysis associated peritonitis is the second commonest cause of death among PD patients (35/1000 years) and the most common cause of treatment failure. It confers a CV risk of 7 times normal for 6 months following the bacteremia, so we need to remain ever vigilant when dealing with PD patient, and its worth refreshing our knowledge on how to prevent this feared complication. There is a paucity of high quality evidence for many of the most fundamental questions in PD. Such is the lack of evidence, the International Society for Peritoneal Dialysis (ISPD) have issued a consensus document where they state they are unable to issue formal guidelines.

The best resources I have found on the topic are a Kidney International supplement from 2006, and the ISPD document already mentioned. In the first instance, which patients are at risk of developing peritonitis? The best described risk factors are hypoalbuminemia (similar to the association in haemodialysis patients), Staph aureus  carriage at inception of dialysis (HR 1.53), initiation of PD early after catheter insertion (HR 0.98/day), PD after transplant failure (HR 2.18), lower hemoglobin (HR 0.88/gram/l), faster PD transport rates (HR 2.92) and previous peritonitis. A special risk group to consider are those PD patients undergoing invasive procedures such as endoscopy or IUD insertion. There is evidence that antibiotic prophylaxis using cephalosporins may help reduce peritonitis rates.

The cornerstone of peritonitis prevention is minimizing contamination risk with effective hand washing and immaculate exchange technique. Specialized nurse-led training is key. If peritonitis occurs, retraining and re-education are the most important interventions. Home visits by PD nurses can cut recurrence rates in half, and should be performed where possible. A Cochrane review could find no RCT data to support any particular insertion technique, catheter type, number of cuffs or positioning. It demonstrated that of all catheter-related interventions designed to prevent peritonitis in PD, only disconnect (twin-bag and Y-set) systems have been proved to be effective. Topical antibiotic prophylaxis is a standard of care and there are multiple RCTs demonstrating the efficacy of mupirocin cream application at the exit site. Ointment is to be avoided as it can erode the catheter polymer.  In contrast, nasal mupirocin is more difficult to justify. Cochrane point out that while there is trial data that nasal mupirocin reduces exit-site/tunnel infection, it has no effect on peritonitis rates. Preoperative intravenous prophylaxis reduces early peritonitis but not exit-site/tunnel infection. 

Recent published trials in the area of antimicrobial prophylaxis have been disappointing. They include the Honeypot study, discussed previously on RFN, which demonstrated the application of honey to exit sites approximately doubled the risk of developing peritonitis in diabetic patients. The MP3 study published in JASN in 2012 found polysporin to increase rates of fungal exit site infections without any improvement in primary outcomes of exit site infection or peritonitis. Finally, a special mention goes to cats, who are responsible for at least 25 case reports of pastuerella peritonitis, as well as an assortment of other bugs. Not to be outdone, rodents feature  in the case reports also, coining the term “hamster bite peritonitis” caused by pastuerella aerogenes.
In summary, technique and continuing re-education are of fundamental importance, as are topical antibiotics to prevent exit site infection.  Beyond this, trial data are severely lacking and local opinion and consensus must guide practice.

Authored by Eoin O'Sullivan