Friday, October 31, 2014

SEVERE CHRONIC HYPONATREMIA: A Pathophysiological Rumination.

PART 4: CONTROL ISSUES

1. Losing Control: In the preceding posts, I explained how sudden emergence of water diuresis as the predominant mechanism by which rapid overcorrection of serum sodium happens in cases of severe chronic hyponatremia.  Few situations or more stressful in nephrology than when we suddenly find that serum sodium has increased by 12 mmol or more within a few hours. The usual scurried response is the immediate administration of 5% dextrose water, DDAVP are both. There has recently been some evidence that using DDAVP with D5W rapidly re-lower the sodium is well tolerated. But, as it was illustrated in this  paper, the response to these therapies is very unpredictable with the usual clinical course being a rather erratic series of rises and falls in serum sodium.


Two mechanisms are responsible for the vast majority of cases of overcorrection due to emergence of water diuresis.  (1) a sudden drop in plasma ADH/AVP levels due either to resolution of a transient source of ADH secretion or repletion of subclinical hypovolemia and (2) in cases of solute depletion hyponatremia, the sudden availability of solute (in the form of saline solutions or protein load) in the setting of an appropriately suppressed ADH. The common feature of both these phenomena is the very low level of plasma ADH which allows water diuresis.

2. Gaining Back the Control:  So how can we prevent the sudden water diuresis which is the hallmark of serum sodium overcorrection? We’ve argued above that the lack of sufficient ADH or sudden turning off of the ADH secretion is responsible for the sudden loss of free water in the urine. To address this issue specifically, in this paper by Sood et al, the Rochester group tested a very simple yet brilliant idea: why not keep the SIADH state from turning off by creating a robust iatrogenic state of SIADH? This was achieved by giving IV DDAVP 2mg every 8 hours (1 mg was tried as well but there was some breakthrough diuresis; also q6hr schedule was also tried). What this does is, by greatly reducing urine output, stabilize the denominator in Edelman’s equation (i.e. almost eliminated changes in TBW, see figure in previous post) and turn the patient into the proverbial beaker, into which now sodium, potassium and water can be added as needed to control the rate of sodium correction. In their series of 25 patients with starting serum sodium of less than 120 mEq/L, quoting directly from the abstract, “Mean changes in serum sodium levels during the first and second 24 hours of therapy were 5.8 +/- 2.8 (SD) and 4.5 +/- 2.2 mEq/L, respectively, without correction by >12 mEq/L in 24 hours or >18 mEq/L in 48 hours and without a decrease during therapy.” There was no difference in the predicted and actual correction of sodium and there were no adverse effects associated with the treatment.
Essentially, by converting the patients into human "beakers" by inducing iatrogenic SIADH and then infusing 3% saline at the desired rate allow for safe and predictable rise in serum sodium without any complications.
Our experience with this protocol has been extremely gratifying.  When this protocol was used very carefully, the serum sodium correction graph was almost invariably an almost straight line: Something that we almost never see with the traditional method of treatment of severe hyponatremia.
Once a serum sodium is between 125 and 130 mmol/L DDAVP can be discontinued while closely watching the patient.

There are a few important points that need to be mentioned here.
#1 --- It has to be clarified to the nursing staff that the DDAVP needs to be given exactly every 8 hours and the dose cannot be missed.  If the dose is missed, there can be breakthrough large volume diuresis in about 10-12 hours from the last dose which can cause overcorrection.
#2 --- The water content of all fluids given/ingested will be retained.  Therefore a very strict fluid restriction needs to be enforced.  In the IV fluids being given to the patient's in the form of infusions with antibiotics etc. need to be accounted for by calculation.
#3 --- in patients with congestive heart failure lasix can be used if it seems like fluid overload is becoming a problem.
#4 --- if a double-lumen PICC line is being used for 3% saline infusion and for drawing labs, the hypertonic infusion should be held for a few minutes before a drawing serum sodium level.  Recirculation can give a falsely elevated sodium level.  An important clue in this situation would be that there would be no large change in urine output that would be expected with a true sudden rise in serum sodium.
This protocol is somewhat opposite of what we have traditionally been taught regarding treatment of severe hyponatremia.  Given how stress-free and easy the management of severe hyponatremia has become with this for me and other colleagues, I expect this protocol to gain more widespread acceptance over the next few years.  I would also like to know if anybody has had experience with this protocol, good or bad.
Hyponatremia remains a clinical challenge but is also fun and stimulating at the same time.  A little time spent on determining the physiology at work and using more quantitative methods of choosing the doses of 3% saline coupled with good results for the patient make it very rewarding as well.

Posted by Hashim Mohmand

Tuesday, October 28, 2014

FSGS biomarker updates—suPAR, B7-1, CD40 and more…

FSGS is the most common glomerular disorder causing end-stage kidney disease in the USA with a high post-transplant recurrence rate of 20-50%. Furthermore, the treatment of post-transplant recurrent FSGS is extremely challenging. While reading a recent article on biomarkers predicting post-transplant recurrent FSGS by Delville et al. (discussed below), it seemed a good idea to cover recent advancement in FSGS research. 

 suPAR (soluble plasminogen activator receptor) 
Since the first report by Wei et al. of suPAR as a circulating permeability factor causing FSGS, there has been extensive research to elucidate its role in FSGS. Although administration of suPAR molecule to mice was initially thought to be sufficient to cause proteinuria mimicking FSGS, via activation of integrin beta 3 and derangement of actin cytoskeleton, the situation does not seem that straightforward. As Reiser et al. discussed, there are challenges to overcome: existence of different suPAR isoforms with different disease modifying effects; heterogeneity of FSGS itself, which make it complicated to interpret correlation between levels of suPAR and disease activity; involvement of suPAR in other disease process, including cardiovascular disease (KI 2014). However, suPAR remains an intriguing molecule and potential biomarker in FSGS disease process.

 B7-1 (CD80)
A case series in the NEJM from Peter Mundel’s group in the end of 2013 brought us to an excitement for personalized treatment of a subgroup of B7-1 positive FSGS patients. They found strong B7-1 stain in primary FSGS as well as post-transplant recurrent FSGS. These patients were successfully treated with abatacept (CTLA4-Ig), resulting in complete remission of proteinuria. The hypothetical pathophysiological mechanism was via direct interaction of B7-1 and integrin beta 1 causing podocyte actin cytoskeleton changes. However, it was followed by comments and larger case series (AJKD 2014) questioning specificity of the immunostaining and treatment effect of abatacept. Exploration of this costimulatory molecule in FSGS was just started and further research is needed. 

Micro RNA(s) as biomarkers for FSGS disease activity 
A group from China suggested that certain micro RNAs are associated with disease activity (level of proteinuria) and progression (Zhang et al. CJASN and AJKD 2014). Potential candidates are miR-186 (involved in cell cycle control, AKT and insulin signaling etc.) and miR-125b (involved in NFkB signaling etc.). However, their contribution to pathogenesis is not clear so far.

 Pre-transplant antibody panel (including anti-CD40) to predict post transplant recurrent FSGS
Expanding potential FSGS biomarkers is the publication by Delville et al. The authors did a beautiful translational work using human serum in protein arrays, validation of specific auto-antibodies and further experimentation using cell cultures and animals models. The authors elegantly showed that pre-transplant antibody panel, especially anti-CD40 antibody, can predict risk of post-transplant recurrent FSGS.
In more detail, they started by comparing pre-transplant sera of non-recurrent FSGS (nrFSGS) vs recurrent FSGS (rFSGS), identifying 789 autoantibodies upregulated only in rFSGS but not in nrFSGS. Then those antibodies were enriched for those Ab with antigen targets expressed in kidney (151 autoAbs) and more specifically in glomeruli (10 autoAbs). They validated the 7-antibody panel (CD40, CGB5 (chorionic gonadotropin b), PTPRO (protein tyrosine phosphatase receptor O), FAS (TNF receptor superfamily member 6), P2RY11 (P2Y purinoceptor 11), SNRPB2 (small nuclear retinoid X receptor a), and APOL2 (Apolipoprotein 2)) in rFSGS vs nrFSGS cohort, and obtained ROC AUC of 0.92. Surprisingly, anti-CD40 itself had a high ROC AUC (0.77). Then, the involvement of rFSGS-anti-CD40 IgG to enhance FSGS recurrence was confirmed in vitro—rFSGS-anti-CD40 IgG caused actin cytoskeleton derangement in podocyte cell culture—, as well as in vivo—co-injection of rFSGS-anti-CD40 IgG and suPAR molecule markedly enhanced proteinuria (in a suPAR-dependent manner), which was inhibited by CD40-blocking antibody or in CD40 knockout mice. This suggests that by checking pre-transplant anti-CD40 antibody, we may be able to identify a high risk FSGS recurrence group. To manage these patients, current options are: peritransplant plasmaphresis or rituximab. Interesting to see if CD40 antagonist or blocking antibody can play a role in preventing/treating rFSGS in the clinic...

Naoka Murakami

Friday, October 24, 2014

SEVERE CHRONIC HYPONATREMIA: A Pathophysiological Rumination (Part 3)

PART 3: THE DANGERS OF "DEPLETION"

In my previous post concerning chronic severe hyponatremia, I explained how over corrections of serum sodium of large magnitude required a dilute large volume diuresis, often precipitated by resolution of a transient source of ADH secretion.  In this post I will discuss two phenomena which are particularly dangerous as they carry significant risk of producing large volume water diuresis.

1.  Subclinical Volume Depletion: As mentioned in my previous post, we noticed during our review of a large number of cases of severe hyponatremia treated with 3% saline that most of the patients whose serum sodium eventually overcorrected responded to small volumes of 3% saline as if they were volume depleted, with sudden emergence of water diuresis.  Interestingly, most of these patients were initially considered to be euvolemic by experienced nephrologists. 
This very interesting paper reviewed the literature concerning the value of physical examination in diagnosing volume depletion.  The conclusion, rather humbling, was that other than in cases of severe volume depletion our physical exam was quite inaccurate in diagnosing volume depletion.  This is especially concerning considering that establishing a patient's volume status forms the major decision point in the ubiquitous diagnostic algorithm for hyponatremia. 
According to the paper, reliable signs of volume depletion usually are visible with the loss of about 20% of the intravascular volume.  The ADH secretion and response to volume depletion starts with volume losses as low as 5-8% of the effective intravascular volume.  This implies that the patient may have significant ADH secretion, contributing to the relative excess water retention causing hyponatremia, while clinically appearing euvolemic.  It also means small volume bolus may switch off this ADH secretion, causing water diuresis and sudden rise in serum sodium.
Subclinical volume depletion as a contributor to hyponatremia should always be considered a possibility especially when starting therapy with 3% saline.

2.  Solute Depletion Hyponatremia: The so called "Tea and Toast Diet " hyponatremia and "Beer Potomania" are examples of solute depletion hyponatremia.  As nicely described by Dr. Berl, our solute intake limits our ability to excrete free water.  Even with a maximally dilute urine of around 50 mOsm/L, a person consuming a 300 mOsm/d diet can only excrete 6 L of urine (300/50=6).  Such a person will become hyponatremic with drinking more than 6 L of fluids a day because any water in excess of 6 L per day excretory capacity will be retained in the body.  It is important to note that this water retention is not due to ADH secretion.  ADH is often suppressed in such patients.  The renal danger of this pathophysiological mechanism is that whenever such patient is "presented" with solute (IV normal saline, high-protein meal which would generate BUN or even 3% saline!), without a high ADH level to prevent it, the added solute is used to rapidly excrete free water that has been "trapped" in the body. 
As an example, consider the case of the 26-year-old female that I briefly alluded to in the previous post.  She presented with a serum sodium of 108 mEq/L after being on an exclusively alcohol diet for the last 2 weeks.  She received 2 L of normal saline in the ER (154 mEq x2 = 308 mEq of Na). Using the Edelman equation (see figure) and an initial total body water of 32 L, if we do not account for urine output, that amount of added NaCl would have raised the serum sodium to about 111 mEq/L. But the actual rise of serum sodium was to 131 mEq/L in about 5 hours accompanied by almost 7 liters of dilute urine output. Her kidneys used the roughly 300 mEq of sodium in the NS bolus to excrete more than 6 liters of maximally dilute urine (300/50=6 L, remember the earlier calculation?) and almost perfectly accounts for the 23 mEq/L rise in serum sodium (by reducing the denominator, TBW).
This would have also happened if she had received the same amount of NaCl in the form of 3% saline as in such cases the volume of infusate matters less than the amount of solute delivered.
I hope this case illustrates how dangerous solute depletion hyponatremia can be and how easy it can be to precipitate an overcorrection of serum sodium in such patients. This raises a very important question: if even treatment with 3% saline is so unreliable in patients with chronic severe solute depletion hyponatremia, how can we safely treat such patients? That will be the subject of my next post.
In conclusion, subclinical volume depletion and solute depletion pose a particularly tricky challenge in the management of chronic hyponatremia as sudden rises in serum sodium level can happen rather easily in these patients with, what would otherwise seem to be, rather innocuous treatment with saline solutions.

Posted by Hashim Mohmand

Monday, October 20, 2014

SEVERE CHRONIC HYPONATREMIA: A Pathophysiological Rumination (Part 2)

PART 2: THE PEE IS THE KEY
I mentioned in the previous post that severe hyponatremia is multifactorial and that the contributing etiological factors in any given case may be transient and reversible.  In this post I would like to stress the importance of closely monitoring the urine output of the patient in addition to frequent monitoring of the plasma sodium.  Urine output is an extremely important clinical parameter that needs to be monitored closely but is not really mentioned in textbooks and handbooks.
Overcorrection by more than 12 mEq/L in 24 hours is not easy to achieve if the patient has a stable state of antidiuresis.  In an anuric patient with total body water of 32 L and a starting serum sodium of 108 mEq/L would require an infusion of more than 750 mL of 3% saline: a prescription not many of us would order.  In fact, during our review of cases of severe hyponatremia we found that the very popular Adrogue-Madias equation grossly underestimated the sodium correction in the majority of patients.  Most of the patients' sodium corrected far in excess of what the equation predicted.
The reason for that is that these equations treat the patients as if they were beakers that we can add sodium to and watch the plasma sodium rise as predicted.  However, unless the patient is on dialysis or in oliguric renal failure, they also lose free water in the urine, a fact that the equation does not take into consideration.  In fact, in our case series every patient that had an overcorrection of sodium beyond the desire goals, and had adequate documentation of ins and outs, had a documented large volume dilute diuresis.  Invariably, such large-volume water diuresis emerged suddenly as if an ADH switch was turned off, suggesting resolution of a transient source of ADH secretion.
While small, sudden increases in serum sodium are certainly possible with the addition of too much sodium to the system, very large and dangerous increases require simultaneous loss of free water.  A very illustrative case is one of a 26-year-old female I managed a couple of years ago.  She presented with a serum sodium of 108 mEq/L and received the inescapable 2 L of normal saline bolus in the ER and about 5 hours later her serum sodium was 131 mEq/L. With an estimated total body water of 32 L (and using the Edelman equation, see figure), if we considered her oliguric and try to account for the rise in serum sodium slowly on the basis of addition of sodium chloride to the system, we would require about 1.9 L of 3% saline to be infused in a 5 hour period!  However it is perfectly explained by the almost 7 L of water diuresis that emerged with the 2 L saline bolus.  More on this case in a later post.

In conclusion, very close monitoring of urine output should be an important and integral part of the early management of severe hyponatremia.  The sudden emergence of water diuresis is often the earliest sign of a rising serum sodium and should prompt a stat plasma sodium check. I have often relied upon a well documented q2hr urine output in ICU setting more so than the q2-4hr sodium levels which are fraught with the issue of delayed venipuncture and delays in reporting.

Posted by Hashim Mohmand

Monday, October 13, 2014

SEVERE CHRONIC HYPONATREMIA: A Pathophysiological Rumination (Part 1)


INTRODUCTION:
Severe chronic hyponatremia (<120 mEq/L) remains the #1 reason nephrologists lose sleep on call nights and rightly so.  The fear of overcorrection and the risk of central pontine myelinolysis (CPM) or osmotic demyelination syndrome (ODS), however uncommon they actually might be, has been drilled into our brains since the beginning of medical school.
In this post and the few that follow, I will attempt to address some aspects of chronic severe hyponatremia which have traditionally not been included when hyponatremia is taught or written about or have only recently been backed by some evidence and have not yet made their way into the textbooks. The recently released guidelines also did not address some of these issues. 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.

PART 1: THINK OUTSIDE THE ALGORITHM
The Schrier-Berl algorithm for diagnosis of hyponatremia has been used successfully for decades for teaching, and for reasoning through the differential diagnosis at the bedside.  It is an integral part of every medicine textbook and pocket handbook. It takes us to our diagnosis through 3 decision points: Plasma osmolarity, volume status and urine sodium sequentially.  While the algorithm holds true for the garden variety mild to moderate hyponatremia, it almost invariably breaks down in case with very severe hyponatremia.

During our extensive review of cases of severe hyponatremia treated with 3% saline, we seldom came across a case in which there was only one isolated cause for hyponatremia.  Rather, they were almost always two or more possible etiologies.  In addition, many patients that were initially considered to be euvolemic by experienced nephrologists, responded to 3% saline as if they were volume depleted.  Lastly, the clinical course of these patients during the hospitalization seemed to suggest many of these causes of inappropriate release of ADH were transient and reversible (SSRIs, acute nausea, postop state etc.). The patients' physiology seemed to change from time to time, with overcorrection of sodium invariably accompanied by large-volume water diuresis as these transient sources of ADH were "switched off."
It was, however, the paper by Sood et al that finally looked at the possible different etiologies for cases of severe hyponatremia as shown in the table (see image), which I consider the single most important table in all of recent hyponatremia literature.  They showed for the first time for multiple etiologies and processes are at play, some fixed and some transient in generating severe hyponatremia.

It is of paramount importance, that in the workup of hyponatremia, especially severe cases, we do not limit our reasoning through the differential diagnosis to comply with the algorithm that we have so familiar with but constantly look for multiple etiologies and transient causes of SIADH, especially subclinical volume depletion (low urinary sodium can be helpful here), as often it is the resolution of these causes that leads to the large-volume water diuresis and overcorrection. 
Posted by Hashim Mohmand


Wednesday, October 8, 2014

No more folic acid

Although tangetial to nephrology in some ways, I believe a recent study published in JAMA Internal Medicine has important lessons for anyone involved in clinical medicine and should make us think about the things that we do reflexively without really thinking about the reasons.

In 1998, the US government mandated that all cereals be fortified with folic acid. Prior to this point, folate deficiency was a real problem. Now, not so much. In fact, folate deficiency has pretty much disappeared as an important clinical problem. Researchers at the Beth Israel Hospital in Boston examined their clinical database to see whether or not this change had lead to any difference in the number of folic acid tests performed and if the number of low serum folate diagnoses was substantial. The results are fascinating. There was no change in the pattern of ordering this test over the 11 year period covered by the paper. In total, 84,000 tests were performed of which 47 (0.056%) were low. The cost if this test to the institution is $2, the charge is $128 while medicare reimburses $20 per test. Thus, the cost per positive result was $35,800.

It is clear based on this that routine testing of folic acid levels is inappropriate and yet it is still often ordered as a routine test in working up individuals with anemia, dementia and neuropathies. Alan Wu, in an accompanying editorial suggests that clinical laboratories should retire this test and in fact his institution, San Francisco General, now includes this as a send-out only that has to be clinically justified.

The reflexive ordering of laboratory and other tests is a problem that has only gotten worse with computerization. When I started working, as interns we had to write individual lab requests on paper and leave them on patient's wards. There was an explosion in testing when interns were finally able to order labs with just a click of a button. I wonder what tests in particular in nephrology we should be ridding ourselves of or at least ordering far less often?

Thursday, September 25, 2014

Renal Physiology PenCasts

Improving preclinical nephrology education during medical school is a hot topic in nephrology these days. John Roberts, a nephrology fellow at Duke, recently produced a collection of short (10-15min) videos on renal physiology in an effort to do just this. These videos are geared towards 1st year medical students and are meant to compliment other learning styles such as book reading, group learning or standard didactic lectures. Take a look at the videos and offer any comments or suggestions. These are fantastic videos that really break down the essence of basic renal physiology that is the foundation of our field. Kudos to John for taking on this project. They look great! Mike Berkoben of Duke Nephrology makes an appearance as well.

Tubular Transport 1 
Tubular Transport 2
Regulation of Body Fluid Osm 1 
Regulation of Body Fluid Osm 2 
Body Fluid Compartments: Regulation of ECFV 1 
Body Fluid Compartments: Regulation of ECFV 2 
Potassium 1
Potassium 2
Acid Base Physiology 1 
Acid Base Physiology 2 
Acid Base Physiology 3

Link to all of the videos

Tuesday, September 16, 2014

NephroCheck®—can we predict AKI in the ICU? And then what?


Nephrologists have been looking for sensitive biomarkers to predict AKI. Efforts have been made and the idea of “renal angina” was proposed by Goldstein and Chawla in 2010, but still there has been no reliable biomarker commercially available to detect AKI early enough. 
Well, the FDA has just approved a point-of-care biomarker assay, NephroCheck®, for predicting risk of AKI. Interestingly, none of the most studied biomarkers such as KIM1 and NGAL are included. NephroCheck® uses two urinary biomarkers : insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases (TIMP-2).

IGFBP7 and TIMP-2 were selected as biomarkers to predict AKI using a 522-patient cohort (median age 64, 91% Caucasian) of critically ill patients admitted with sepsis, shock, major surgery and trauma—though inclusion criteria differed based on the facilities (Crit Care 2013). Over 340 biomarkers were screened, including urine kidney injury molecule-1 (KIM-1), plasma and urine neutrophil gelatinase-associated lipocalin (NGAL), plasma cystatin-C, urine interleukin-18 (IL-18), urine pi-glutathione S-transferase (pi-GST) and urine liver fatty acid-binding protein (LFABP).

IGFBP7 and TIMP-2 are both inducers of G1 cell cycle arrest and showed the highest AUCs on the above cohort (0.76 and 0.79 respectively, and 0.80 when combined). The results were then validated using another 722-patient cohort, without evidence of AKI on admission. Primary outcome was AKI stage 2-3 (KDIGO) within 12-18 hours post-test. There was also another validation study published earlier this year (AJRCCM 2014), using 420 patient from 23 facilities in the US, demonstrating sensitivity of 92% (95% CI 85-98), and specificity of 46% (95% CI 41-52) with cut-off value of 0.3 (ng/ml)2/1000. AUC was 0.82 (0.76-0.88).
Although NephroCheck may have potential advantage to rapid response to developing AKI, still there is substantial limitations of the study including: heterogeneity of the validating cohorts, Caucasian racial predominance, focusing on septic AKI and reflecting more ischemic/hemodynamic-related AKI/ATN.
 So, what should we do next, based on the early detection/ risk prediction of AKI? What interventions or drugs could we use to prevent AKI development in those high-risk patients? Specific treatment strategies for AKI are now warranted for this biomarker to be in full use in the fight against AKI.
Figure from Crit Care 2013 paper: Proposed mechanistic involvement of the novel biomarkers in AKI.

Naoka Murakami

Monday, September 8, 2014

CJASN Activities

Two ASN-related activities to mention happening in the next couple of months. First, CJASN eJC will be hosting a twitter conversation about the recently published commentary "Training the Next Generation's Nephrology Workforce. This will be hosted by Amar Bansal, a fellow at UPenn who is the author of the article. It will take place on September 10th at 9pm and the hastag is #CJASNeJC.

The second event is a fellows luncheon at the ASN annual meeting on November 13th from 12.45 to 1.45pm. This is titled "Improving the journal club experience for fellows" and will be moderated by Drs Gary Curhan and David Goldfarb. An email will be sent in September/October to all registered fellows with the ASN.

Thursday, August 28, 2014

Kidney Organ Allocation in the USA - Upcoming Changes!

This is a short video describing the current and new policies regarding deceased donor kidney allocation in the USA. These policies may significantly affect certain groups of patients and physicians must be aware of those in order to best represent their patients. For more details, also check prior blog.

Link for the video here

Hypokalemic Periodic Paralysis

A recent renal consult I encountered was a Cantonese gentleman with a classical symptomatic history for Hypokalemic Periodic Paralysis (HPP). He presented with a serum K of 1.4 mmol/l and profound weakness. Initially beginning in his teenage years, he had intermittent attacks of weakness lasting hours and affecting proximal muscle groups. Emergency department admissions invariably revealed low serum K.
Many of us will know the classical features to look for in the history:
  • High risk Asian and Hispanic population groups, particularly males less than 20 years old.
  • High carbohydrate meals triggering insulin release or  B-adrenergic surge from exercise or volume depletion.
  • Thyrotoxicosis: A major subgroup of patients, usually men. The mechanism is thought to involve a combination of up regulation of Na-K-ATPase, loss of function of the inward potassium rectifying channel Kir2.6, and a feed forward effect in certain variants of the sulphonylurea receptor 1, culminating in dramatic intracellular potassium shifts. It is important to note is that rarely the paralytic episodes can predate the thyroid disease by many years.
The genetics of hypokalemic periodic paralysis have been discussed previously on Renal Fellow Network.

Management: More Questions than Answers
Acute management is relativity straightforward – administration of K, either IV or orally. Case control series demonstrate up to 70% of patients having rebound hyperkalemia of >5mmol/l if  KCl doses of over 90mmol/ are administered. Lower doses may potentially be used if concomitant B-blockade is deployed in conjunction. Oral KCl rescue is more suitable for home use.  As a rule of thumb, 40 to 60 mmol/l of oral  Kraises plasma potassium concentration by 1.0 to 1.5 mmol/L, and 135 to 160 mmol/l Kraises plasma potassium by 2.5 to 3.5 mmol/l.
Besides avoiding obvious environmental triggers, therapeutic interventions and prophylaxis are more unclear. Patients have normal total body potassium with no chronic GI or renal loss, thus the drop in serum levels is mediated via a transcellular shift. Despite this, prophylactic K supplementation remains a traditional cornerstone of therapy, although one would imagine a normally functioning cortical collecting duct should excrete this quite rapidly, particularly with chronic dosing regimens.
The “highest quality” of evidence comes from a Cochrane review of 3 very small studies, the largest examining the utility of dichlorphenamide, a carbonic anhydrase inhibitor, in 34 patients. Self-reported quality of life improved in 15 patients, and attack frequency dropped. This is in line with a more recent study in 2011 which quote a 50% improvement in symptoms in a larger group of patients on dichlorphenamide. This is unusual as the additional HCO3 in the collecting duct should increase intraluminal negative charge, and encourage potassium excretion, as should the volume depletion and increased RAAS activity. Furthermore, volume depletion could theoretically induce increase sympathetic output, worsening K loss. The most plausible explanation I found was a paper from 1975 suggesting the metabolic acidosis induced by the carbonic anhydrase inhibitor buffers the transcellular shift of K+.
Despite aldosterone levels being normal during attacks, reports suggest aldosterone antagonists may benefit patients as a second line therapy via their K+ retaining effects, although their action appears to be opposite to that of dichlorphenamide. It is curious these agents with supposed diametric effects on renal K handling both have positive effects on K balance in HPP.

The most intuitive treatment is B-blockade, demonstrated in a number of series to be effective, but almost always in those whose HPP occurs in association with thyrotoxicosis.

Authored by Eoin O'Sullivan

Sunday, August 24, 2014

mTOR Pathway in Anti-phospholipid Syndrome

Antiphospholipid syndrome (APS) is an autoimmune hypercoagulable disorder characterized by small-to-large vascular (both arterial and venous) thrombosis with end-organ damages, in presence of circulating antibodies against phospholipid binding proteins.

Kidney transplantation in patients with APS is challenging because  post-transplant thrombosis, vascular complications and requirement of anticoagulation during peripoperative period. Let’s start with a brief review of recent advances in transplantation in APS.

For post-transplant TMA due to recurrent APS nephropathy, Canaud et al. recently explored the use of eculizumab. Eculizumab, a humanized mAb that binds C5, prevents cleavage of C5 into C5a and C5b, thereby preventing generation of the membrane attack complex (MAC). At a molecular level, the pathogenesis of endothelial damage in APS is in part via complement activation; C5b-9 MAC deposition on endothelium, leading to cell lysis and/or activation of other proinflammatory pathways, so the use of eculizumab is reasonable. Three patients, maintained with steroids, CNI and MMF, were treated with eculizumab for posttransplant TMA with robust improvement of allograft functions after several doses, and all three patients were successfully withdrawn from maintenance eculizumab treatment after 3-12 months of initial dose. Interestingly, although biopsy showed improved TMA lesions, C5b-9 depositions were persistent for as long as 3 months as “foot prints”. The authors also noticed that eculizumab treatment did not prevent the chronic vascular lesions seen in 12-month protocol biopsies.

Preemptive use of eculizumab in kidney transplant in APS-related ESRD was also attempted in another case series. Three patients, two with CAPS (catastrophic APS), received 1,200 mg of Eculizumab on day 0, 900 mg on POD 1, and weekly thereafter until week 4. After week 5, they received 1200 mg every 2 week. Despite one  biopsy proven cellular rejection successfully treated with pulse steroid, graft function and survival was acceptable without recurrence of APS during follow-up of 6 months to 4 years. In the setting of no specific treatment other than systemic anticoagulation, eculizumab seems potentially promising treatment, however, the sufficient treatment length of this drug needs to be optimized, especially due to high cost. Also, there is no description of immunosuppressive regimen either for induction nor maintenance, and it is unclear these patients were on sirolimus or not.

 In a recent NEJM article, Canaud et al.  indicated the beneficial effect of sirolimus in proliferative vascular changes associated with APS and CAPS, which were not reversed by eculizumab in their previous study. They demonstrated that the chronic vascular changes in APS patients were induced by activation of mTORC via phosphorylation of Akt-S6K pathway, using immunohistochemistry of renal biopsy samples and in vitro signaling studies with HIMEC-1, a human microvascular endothelial cell line, as well as autopsy samples of CAPS. Furthermore, using a cohort of kidney transplant patients with APS (10 treated with steroids+sirolimus+purine inhibitor and 27 with steroids+CNI+purine inhibitor), their nested-case-control study demonstrated that posttransplant allograft functions were better preserved at 144 months post transplant in the sirolimus group compared with CNI group (7 of 10 vs 3 of 27 patients with functioning grafts) and this effect was observed only in patients with APS and not in patients without APS. Other variables including cold ischemia time and immunologic risk profile were comparable between sirolimus and CNI groups. Although this is a relatively small case-controlled study, the use of mTOR inhibitors for the prevention of APS post-transplant seems very promising.

Naoka Murakami