Therapeutic misadventures in rhabdo

There are three commonly promoted strategies used in the treatment and prevention of AKI in rhabdomyolysis: 1) Normal saline 2) Bicarbonate containing solutions 3) Mannitol.

Volume resuscitation is clearly paramount when treating rhabdo, but whether bicarbonate or mannitol is beneficial is controversial. The figure below from a recent NEJM review gives a nice overview of the state of the literature.

Image citation

Regardless of what therapy is ultimately decided upon it’s important to keep in mind that each can lead to unique but potentially counterproductive complications.

Hypocalcemia – Bicarbonate containing solutions have some attractive features based on animal data suggesting that they reduce:
1) Tubular precipitation of Tamm–Horsfall protein–myoglobin complexes
2) Generation of injurious oxidation products
3) Afferent arteriole vasoconstriction induced by metmyoglobin.

Unfortunately, in addition to these theoretical benefits, alkalinization of the blood pH can lead to increased calcium complexing with albumin thus decreasing physiologically active ionized calcium. This complication can be particularly problematic (eg tetany) early in rhabdo when serum calcium is dropping due to movement into damaged muscle and precipitation from serum as calcium phosphate.

Non-Gap Acidosis – Normal saline is used as an intravascular volume expander to replace fluid as it moves into damaged muscle.

Large volumes of NS are sometimes required in rhabdo and can lead to “dilutional acidosis.” There are several proposed mechanisms behind this that are nicely discussed in one of Nate’s prior posts. If clinically significant, lowering of the serum pH and subsequently urine pH could potentiate all of the mechanisms bicarbonate therapy experimentally mitigates.

Osmotic Nephrosis – The use of diuretics is again, controversial (must mean something when that word keeps popping up!) but in volume replete patients mannitol has several sited benefits.

Its main effect is as an osmotic diuretic leading to increased urinary flow and the flushing of nephrotoxic agents through the tubules. It also acts as a free-radical scavenger and an intravascular osmotic agent reclaiming fluid from injured muscles. Unfortunately, when large quantities of mannitol (greater than 200g/day or accumulated doses of greater than 800g) are used they can lead to renal vasoconstriction and direct tubular toxicity. This brand of AKI is termed osmotic nephrosis and histologically appears as tubular cytoplasmic vacuolization.

Pseudohyponatremia – Mannitol has the additional potential complication of hypertonic hyponatremia.

As an effective serum osmole, mannitol raises serum osmolality and pulls free water into the intravascular space diluting the serum sodium concentration. The effect on serum osms can lead to significant serum hypertonicity resulting in seizures as the brain shrinks.

Graham Abra, MD

World Cup fever

Congratulations to the USA and England on going through to the second round of the World Cup today. As an Irishman, I will confess to a modicum of schadenfreude at the humiliating exit of France yesterday, but we won't dwell on that... Unlike high-contact sports such as Rugby or American football, it seems possible to play soccer to a high level after a renal transplant. Ivan Klasnic, a Croatian who plays for Bolton in the English Premiership and the Croatian National team, is one such example. He developed ESRD in January 2007 and received his first transplant from his mother later that month, but unfortunately this was lost to rejection 5 days post-transplant. However, a second transplant from his father 7 weeks later was successful. He was back playing for FC Nantes one year after first becoming ill, wearing a protective belt over the transplant site. He went on to play a starring role in the Croatian National team in Euro 2008, the first transplant patient ever to do so, scoring in both the group stages against Poland and the quarter-finals against Turkey.

It hasn't all been plain-sailing though - England's controversy-prone John Terry allegedly punched him in the transplant during a match last year... a crime only marginally worse than a deliberate handball in the closing minutes of a crucial world cup qualifier, but maybe I'm biased...

Of snakes and men

As mentioned in a previous post, there is not much salt available in the Amazon and as a result, the inhabitants (human and otherwise) have developed very active renin/angiotensin systems in order to retain whatever salt they can find. Nature being what it is, some predators have evolved to take advantage of this.

Bothrops Jaracara, or the Brazilian Pit Viper, is a poisonous snake that lives in this region. Along with anticoagulants, in the 1960s it was discovered that its venom contains "bradykinin potentiating peptides" that inhibit the angiotensin converting enzyme. In this salt-deprived environment, a bite from this snake would rapidly lead to hypotension and syncope. Captopril, the first commercially available ACE inhibitor, was derived from these peptides in the 1970s. Thus, something which provided a competitive advantage to a viper in the Amazon has become a mainstay in the treatment of hypertension and renal disease today. Similar peptides have been found in the venom of another snake, Agkistrodon Halys Blomhoffii, which is native to Japan and China.

Thank you to commenter Trevedy who pointed me in the direction of an article on the origin of ACE inhibitors.

The bad habit of ACEI!!!!

Coming to the transplant clinic from 2 years of CKD clinic, prescribing ACEI/ARBs was a habit, a good one I guess. Does this hold truth in the transplant world, well... I am not sure anymore after I read this meta analysis in Transplantation last year. The reason simply is that kidney recipients are biologically different from CKD patients. Most of our kidney transplant patients are on calcineurin inhibitors (CNI) which induce afferent arteriolar vasoconstriction. Thus, the advantage of calcium channel blockers (CCB) over ACEI in this population is that it may promote vasodilation of afferent arterioles which may counteract CNI’s effect.

In this meta analysis of 60 trials, enrolling 3802 recipients:

· 29 trials (2262 patients) compared calcium channel blockers (CCB) with placebo or no treatment

· 10 trials (445 patients) compared angiotensin-converting enzyme inhibitors (ACEi) with placebo or no treatment

· 7 studies (405 patients) compared CCB with ACEi

CCB compared with placebo or no treatment (plus additional agents in either arm as required) reduced graft loss (risk ratio [RR] 0.75, 95% confidence intervals [CI] 0.57–0.99) and improved glomerular filtration rate (GFR; mean difference [MD] 4.5 mL/min, 95% CI 2.2–6.7).

Data on ACEi versus placebo or no treatment were inconclusive for GFR (MD -8.1 mL/min, 95% CI -18.6–2.4) and inconsistent for graft loss, precluding meta-analysis.

In direct comparison with CCB, ACEi decreased GFR (MD 11.5 mL/min, 95% CI 7.2–15.8), proteinuria (MD 0.28 g/day, 95% CI 0.10–0.47), hemoglobin (MD 11.5 g/L, 95% CI 7.2–15.8), and increased hyperkalemia (RR 3.7, 95% CI 1.9–7.7). Graft loss data were inconclusive (RR 7.4, 95% CI 0.4–140).

So according to this study there is no advantage of ACEI/ARBs over CCB, with more side effects from angiotensin inhibitors. Obviously, a good randomized trial is needed to resolve this issue.

These data suggest that CCB may be preferred as first-line agents for hypertensive kidney transplant recipients and the KDIGO guidelines consider ACEI/ARB as first line therapy for HTN in renal transplant patients only if their proteinuria is > 1gm/day. A good practice would be to hold them in acute illness as those patients are very sensitive to dehydration due to afferent arterioles vasoconstriction by CNI.

Board question: Transplant-1 answer

The vast majority of people answered correctly; the best answer is D.


Approximately 3-5% of patients with Alport's syndrome develop de novo anti-glomerular basement membrane (GBM) disease in the transplanted kidney. Alport’s syndrome is a genetic disorder that results from mutations in the genes encoding the alpha-3, alpha-4, or alpha-5 chains of type IV collagen. Following transplantation, recipients can become alloimmunized and develop antibodies to the normal chains of type IV collagen in the basement membrane of the donor kidney (hence, the linear pattern of staining noted on IF). Treatment is not standardized, but generally consists of plasmapharesis, +/- cyclophosphamide and steroids. Long-term allograft survival is poor and re-transplantation carries a high risk of anti-GBM recurrence. For the boards, remember the post-transplant association between Alport’s syndrome and de novo anti-GBM disease.

Link to NEJM review which contains above picture

Michael Lattanzio DO

No salt, no hypertension

Back in the early 1970s researchers traveled into the jungle in Northern Brazil to visit a group of Indians. The Yanamomo tribe had lived in isolation for thousands of years and had only been contacted in the 1950s. What made them a subject of interest was their diet; their staple food was a kind of large cooking banana, supplemented occasionally with game, fish, wild vegetables and insects. This diet contained almost no salt. At the time, it was regarded as normal that blood pressure rose gradually with age. However, the BP of the Yanamomo Indians remained remarkably stable throughout life, ranging from 107/66 in teenagers to 100/63 in those >50. The investigators went on to perform 24h urine collections on a number of the Indians – this was difficult – in their own words “the collections were complicated by the rather difficult conditions under which the work was conducted as well as the free and unfettered nature of the Yanomamo psyche, which found it difficult to take seriously the concept of a 24 hr urine”. Despite this they managed to acquire complete collections on 26 male subjects and took a series of collections on themselves as western controls.


The results were remarkable.

• The mean 24 hr sodium excretion was 1mEq/24hrs in the Indians compared to 152 mEq/24hrs in the controls.
  
• Potassium excretion was 152 v 38 mEq/24hrs and Chloride was 14 v 102 mEq/24hrs.
• Urinary aldosterone excretion was 75 v 3 ug/24 hrs.
• The plasma renin activity was also significantly higher in the Indians.
  

The high potassium/low sodium diet that they were consuming resulted in appropriate hyperaldosteronism in the absence of hypertension. It is likely that this diet is similar to the one our ancestors in Africa were accustomed to. Perhaps the low level of aldosterone that we regard as normal in the west is actually an adaptation to the extremely high level of salt in the western diet – certainly, these Indians prove that we can survive comfortably on less than 1% of our usual salt consumption. It is interesting to note the extremely high urinary anion gap in the Indians – mean 130. What was the anion excreted with the potassium? In all likelihood this was bicarbonate. The potassium in bananas exists in the form of potassium citrate and this would need to be excreted along with the potassium to maintain normal acid-base balance. Unfortunately we do not have any record of the acid base status of the subjects so that is a subject for conjecture. Other studies of isolated tribes who were contacted in the last 70 years have shown a gradual rise in BP in the years after contact. This may be due to increasing quantities of salt in their diets as they are “civilized”.

Here is a previous post from Matt on dietary salt reduction.

Ultrasound guided vas-cath placement

Much of the clinical year of the renal fellow is spent in the hospital rounding on patients admitted with access malfunction, catheter related infections or are in the ICU's with acute kidney injury. Many of these patients will require temporary dialysis access that in many cases will be life saving. Nate has already nicely discussed the debate between when to choose the femoral vs. the internal jugular vein in a previous post. These lines have the potential to pose many difficulties as patients with renal failure can have difficult and limited access sites. A difficult line can be avoided with appropriate training and imaging. We are fortunate to have an ultrasound readily available in our dialysis unit for vas-cath placement, but many hospitals do not.

An interesting article was published in the Feb 2010 CJASN by Prabhu et al in which 110 patients were randomized into two groups. One group had ultrasound guided femoral catheter placement and one group did not. The results, not surprisingly, showed that patients who had ultrasound guided vas-cath placement had a higher overall success rate (98.2% vs. 80%), better first attempt success rate (85.5% vs. 54.5%) and had few complications (5.5% vs. 18.2%). Furthermore, of the 11 patient who did not have a successful catheter placed without ultrasound guidance, 10 of these had success with use of the ultrasound in the exact same leg. This article also reviewed 3 other studies comparing ultrasound vs. standard landmark techniques. These studies show similar results.

Another interesting article was published in AJKD in 2009 by Barsuk et al from Nothwestern University. This study looked at the use of an ultrasound compatible central line simulator (like on the picture above) and deliberate practice before actually placing lines on patients. Again two groups were assessed in an unblinded fashion.

• Simulator Group- 12 first-year fellows were trained with the simulator and tested before and 2 weeks after the intervention with a 27 item clinical skills examinations checklist (available from the supplementary data).
• Traditional Group- 6 graduating second-year fellows were tested using the simulator once during the last 2 months of their fellowship.
  

Results from this study also showed benefit using the central line simulator. Interestingly, only one of the six graduating fellows met the minimum passing score. The simulator group improved dramatically from a score of 29.5% to a score of 88.6%. The course was highly rated by the attendees. It would be interesting to see if complications rates went down after the intervention. Also, I wonder if the higher scores would hold up over time. If I took the same test in a 2 week interval, I'm pretty sure I would score much higher on the second attempt. Especially after attending a 2 hour course.

I hope that more nephrology programs begin instituting programs like the simulator course. Likewise, ultrasound guided vas-cath placement needs to become standard practice. This can only help patient care and improve the competency of the graduating fellows. That being said, how many times do nephrologists in private practice put in temporary catheters? As the interventional radiology field continues to grow, this is surely decreasing.