Could this be Refeeding Syndrome?

A young patient who was engaging in heavy weightlifting presented to the ED with proximal muscle weakness. The night before he had one hour of acute onset bilateral leg and hip flexor cramps with stiffness and "hardened" muscles and marked weakness that prevented him from standing or walking. This resolved spontaneously. After an intense workout the next morning he noted cramping and weakness in his legs and was unable to walk, therefore he presented to the ED. 

He had been taking a thyroid supplement for several months but had stopped about three weeks prior. He was also taking lisinopril for hypertension. He was currently using a steroid supplement containing designer steroids (10 mg androstenone and 10 mg androstan-one-azine) for several months. He also took vitamin B5 and niacin. He was eating a high protein diet mainly consisting of chicken and sauce (some sort of Teriyaki sauce) and some rice and very few vegetables for several months averaging 4000 to 8000 calories on most of the days of the week.

Two days before presentation he started eating "normally" again with high amounts of carbohydrates as a treat (cake and sweets).

In the ED: K 2.0 mmol/L, PO4 1.0 mg/dl, glucose 197 mg/dl, Mg 2.0 meq/L, CK 5070 U/L, TSH 0.01, low normal total T3, low total T4 and low free T4 but normal free T3. Urine electrolytes at the time of presentation were notable for a potassium of < 10 and an undetectable phosphorus level (Fractional excretion Phos < 5%). His ECG showed slight abnormalities but troponins were negative x 3.

Phosphate was repleted with 12 mmol NaPhosphate and normalized. Potassium was repleted with 40 meq KCl IV and 120 meq po until normal. His leg weakness resolved and the CK started to trend down.

The question is: what caused his profound electrolyte abnormalities? 

One possibility is refeeding syndrome as described in a previous post. The sudden surge of carbohydrates following a long period of high protein, low carb diet might have caused an increase in insulin driving potassium and phosphate into the cells. Hypomagnesemia was, however, not present in this patient. The time frame (within 4 days) would be consistent with refeeding syndrome. The rhabdomyolysis occurred as a consequence of hypokalemia and hypophosphatemia with a contribution from heavy exercise. He responded quite fast to potassium and phosphate supplementation and improved clinically within a day.

Patients with the following conditions have traditionally been at risk for refeeding syndrome: anorexia, chronic malnutrition (e.g. in patients with cancer), alcoholism, prolonged fasting, after a duodenal switch operation for obesity, hunger strikers and postoperative states. In these times of extreme dieting one should think outside the box and ask about special diets such as high protein diets. The kidney on the other side has been doing it's duty and preserved whatever electrolytes were still in the circulation by absolutely minimizing excretion of potassium and  and phosphate.
Posted by Florian Toegel

Πάντα ρεί - once more on the (right) fluids

Yet another manuscript evaluating fluids for IV replacement was published in JAMAthis week underscoring the importance and controversial nature of the topic. A large meta-analysis involving 10,868 patients from 38 trials showed that hydroxyethyl starch (HES) was associated with an increased risk of mortality and renal failure (RR 1.27; 95% CI 1.09 - 1.47). Of note, a recent large trial published in the NEJM in 2012 did not show an increased mortality but more patients who received resuscitation with HES were treated with renal-replacement therapy.

HES is mainly used by anesthesiologists and surgeons and has the potential advantage of decreasing the amount of total administered volume and sustaining intravascular volume for longer periods of time. The discussion about mortality and renal failure associated with HES has been going on for a long time, as has the discussion about the relative benefits of colloids vs. crystalloids. Despite the lack of strong evidence of superiority of HES over crystalloids, the clinical use has been increasing - even with the associated higher cost and safety concerns.

A major drawback for the supporters of HES was the realization that one of the leading authorities in the field and major proponent of HES, Joachim Boldt, has conducted one of the biggest cases of fraud in anesthesia with “false data published in at least 10 of the 91 articles examined, including, for instance, data on patient numbers/ study groups as well as data on the timing of measurements“. 80 articles have been retracted because the research was deemed unethical. A Cochrane review from 2012 did not find a significant difference in mortality even when the fraudulent studies were excluded. However, the current meta-analysis not only excluded the studies by Boldt, but also included 3 trials published in 2012 contributing more than half of the patients to the collective examined, thereby adding more weight to their analysis over prior ones. There was no difference in mortality when the Boldt papers were included in the analysis.

Side effects of HES mainly occur in the kidney but the exact pathophysiology of AKI associated with HES is unclear. Vacuolization as an injury pattern can be observed as discussed in an earlier post in this blog. In vitro HES showed a dose-dependent decreased viability of HK-2 cells (human immortalized proximal tubular cells) after incubation with HES130/0.4. A necropsy study suggested HES accumulation in the kidney might cause toxicity. 

What can we learn from this? Rigorous analysis and ongoing discussion and evaluation of data are of crucial importance in Medicine and scientific fraud, driven by motives such as recognition and money can cause data to shift to the wrong direction. There does not seem to be a major advantage of using HES over crystalloids and data on mortality and renal failure are tied between no difference and increased mortality/AKI in the HES group. From my perspective there seems to be no indication to use HES and this might be better for the kidney.

Posted by Florian Toegel

Spare the Chloride

Fluid therapy is essential in ICUs and not surprisingly there is still much controversy about which fluid to use, how much and when. Nephrologists often roll their eyes at other subspecialty's preferences, e.g. surgeon's preferences for Ringers, citing the risk of hyperkalemia in renal failure patients given Ringers. I learned that normal saline is the preferred agent unless there is a special consideration such as acidemia necessitating alternatives. Now chloride, the partner of sodium that gets considerably less attention most of the time, enters the stage.

Yunos et al in JAMA suggest that too much of chloride increases acute kidney injury (AKI) episodes in tertiary ICUs and increases the need for renal replacement therapy (RRT) but does not affect mortality.

The physiological rationale for the detrimental effect of chloride on the kidney is described as vasoconstriction mediated by chloride in dog experiments and a possible role of tubuloglomerular feedback mediated vasoconstriction as well as decrease in GFR caused by increased distal chloride delivery. Furthermore they cite thromboxane mediated vasoconstriction caused by chloride and enhanced responsiveness to vasoconstrictor agents as possible physiological sequelae of chloride administration.

The authors of the JAMA article conducted a prospective, open-label sequential pilot study of patients admitted consecutively to the ICU. Initially patients were treated with chloride-rich IV fluids (0.9% saline, 4% succinylated gelatin solution or 4% albumin solution) and after that initial control period a chloride-restricted strategy was implemented with lactate (Hartmann solution), a balanced solution (Plasma-lyte 148) or chloride-poor 20% albumin as preferred agents.

The results were a lower increase in serum creatinine levels and fewer episodes of RRT in the chloride-restricted group but no differences in mortality, hospital or ICU length of stay or need for RRT after discharge.

How does this study affect our choice of ICU fluids? Certainly, these results are hypothesis generating and important but need to be viewed as preliminary given the design of the study. An accompanying editorialby Waikar mentions the Hawthorne effect as potential major concern. Clearly these important preliminary data need follow up in a controlled prospective trial. 

Posted by Florian Toegel

The Good the Bad and the Ugly - Uric Acid and the Kidney

At some point during evolution humans lost the enzyme uricase and during the long and tedious process of getting to the modern age and this was initially a good thing. Uric acid accumulation as a result of uricase loss is thought to have been protective in situations of hypotension in low salt environments, conferred increased intelligence and reduced oxidant stress (although some authors consider this highly speculative). The Nephrologist often has a role in managing gout, since uric acid is mainly excreted by the kidney.

So now that we do not have a shortage of salt anymore and our diet is rich in purines we get to see the drawbacks of evolution. This comes in the unpleasant form of gout. Most of the time, gout is caused by under-excretion of uric acid by the kidney and only in the minority of cases (~10%) by overproduction. Renal uric acid handling is complicated and about a decade ago a transporter with specific apical urate-anion exchange activity was described.

Gout can be triggered by a number of gluttonous habits:

• Alcohol - causes increased urate synthesis and increased lactate production which increases urate reabsorption
• Foods high in purines increase uric acid levels.
• Lead causes increased uric acid levels by impairing urate excretion, which is associated with the development of gout (termed “saturnine gout”). This was much more common in older days when lead ingestion was high.
• Dietary fructose acutely raises serum uric acid levels.

Therefore gout was considered a "true nobleman's disease" in earlier centuries and artists such as William Hogart used to portray them in their works.

Now some people are worse off because they have to take medications that cause hyperuricemia. Amongst them are transplant patients depending on immunosuppressants and diuretics, for example a heart transplant patient whom I recently saw in clinic.

Cyclosporine: Decreased GFR and possibly tubular damage contribute to cyclosporine induced uric acid retention. Tacrolimus does not offer any advantage over cyclosporine. A study in children with transplants concluded that cyclosporine induced tubular reabsorption of uric acid.

Diuretics:HCTZ is a common trigger of gout attacks but all other diuretics also do. Rising serum uric acid with diuretic use occurs with low doses and increases dose-dependently. Volume depletion stimulates a marked increase in proximal tubular reabsorption of urate. The mechanisms involved in the regulation of urate reabsorption by extracellular volume status are however unclear. Furosemide can induce hyperlacticacidemia sufficient to suppress tubular excretion of urate. Diuretics have also been shown to interfere directly with uric acid handling by the kidney. Loop diuretics and thiazides have been shown to directly inhibit NPT4-mediated urate secretion and furosemide can inhibit urate uptake by URAT1.

Management is aimed at lowering serum uric acid levels with Allopurinol or Febuxostat. Febuxostat is an alternative to allopurinol in patients with allopurinol intolerance or hypersensitivity.  In my (limited) experience uricosuric drugs such as Probenecid are rarely used in practice anymore and the teaching is that they actually can trigger acute gout attacks by initially decreasing excretion. Pegloticase, a pegylated recombinant porcine-like uricase, can be given in severe cases when Allopurinol or Febuxostat are not effective. The drug needs to be given IV but thanks to its long half-life only every 2-4 weeks.

Posted by Florian Toegel