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

Renal Grand Rounds - Case of the month

A young woman with h/o polysubstance abuse and seizures was admitted to hospital with status epilepticus. She was treated with a propofol infusion at 5mg/kg/hr which was maintained due to perceived continuing seizure activity. On hospital day 5, she developed an acute metabolic deterioration – rhabdomyolysis : CPK 100,000, AG metabolic acidosis (HCO3 18) and non-oliguric AKI. Her EKG also became abnormal (RBBB). The diagnosis was propofol infusion syndrome.

What is propofol Infusion Syndrome (PRIS)? 

Like many syndromes, PRIS is a conglomeration of clinical and biochemical manifestations.  Based on  83 case reports from 1992-2007, PRIS is characterized by:

1) Metabolic acidosis, (pH less than 7.30 or HCO3 less than 19)

2) Rhabdomyolysis (CPK more than 10K)

3) Renal failure

4) Cardiac dysfunction (Brugada-like EKG pattern, asystole, PEA, sustained VTs, heart failure, or bradycardia) 

5) Hypertriglyceridemia (TG more than 400)

6) Hyperkalemia

7) Hypotension (or use of vasopressor agent)

8) Hepatic transaminitis

9) Hypoxia (PO2 less than 60mmHg). 

The first 5 manifestations are the most common. While there is no requirement for the number of clinical manifestations a patient must exhibit to meet diagnosis for PRIS, a prospective study showed that most patients exhibit at least 3 defining manifestations within 3 days of propofol use.  In the same study, the incidence of PRIS was found to be a low 1% --similar to other estimates.  However, PRIS is associated with high mortality, up to 30% in some studies. Moreover, because many of these manifestations are common, the presence of any of them could be attributed to another etiology, thus delaying diagnosis of PRIS.  For instance, in the case vignette, the initial rise of CK was attributed to seizure rather than PRIS.

Pathophysiology of PRIS

Inhibition of electron flow along the mitochondrial electron transport chain/ impairs oxygen utilization. Propofol or its metabolites inhibits fatty-acid oxidation leading to buildup of toxic fatty acid intermediates. As described in this nice review.

Risks of PRIS?

Critical illness (especially, CNS illness); Use of propofol dosage more than 4 mg/kg/hr —the usual adult maintenance dose is 0.3 to 3mg/kg/hr; duration of Propofol use greater than 24hr; exogenous cathecholamines and corticosteroids; poor intake of carbohydrate, see this reference.

Management of PRIS

Early recognition/diagnosis; Cessation of propofol infusion; Cardiopulmonary support; Hemodialysis (strongly advocated by expert opinion and outcome of case series).  However, there are no known RCT of use of renal replacement therapy in the treatment of PRIS.  Nonetheless, in case series, survivors of PRIS are more likely to have received HD/CVVH.  Therefore, prolonged use of HD/CVVH is worth considering by renal consult service.  Because propofol is lipophilic and has volume of distribution of 20-40L, it is poorly cleared by HD/CVVH, prolonged RRT is likely needed for PRIS management.

The patient in the case was treated with CVVH overnight, and then transitioned to intermittent HD.  At the time of her discharge, she was off HD with her Cr back to baseline.

See this previous post by Nate on PRIS.

Posted by Opeyemi Olabisi

FDA, Statin and Transplantation - A conundrum

We are facing a conundrum in post-transplant lipid management after the recent warning from the FDA, which updated the label of simvastatin. This drug is now contraindicated in patients taking cyclosporine due to the potential for liver dysfunction and myopathy.


Just to remind you, statins are metabolized by the hepatic cytochrome P450 3A4, similarly to calcineurin inhibitors and mTOR inhibitors. In the presence of these immunosuppressive agents, statin levels are raised and risk of myopathy is increased. This danger has always existed, however, the FDA has taken a harder stance lately with creating a “contraindication”. Moreover, simvastatin doses greater than 20 mg/day are also not recommended anymore in patients receiving amlodipine, which is the vast majority of transplant recipients (this is new since prior literature solely reported non-dihydropyridine CCB like diltiazem and verapamil as important interactions). Nonetheless, there is nothing listed when simvastatin is co-administered with tacrolimus, sirolimus and/or everolimus. However, the potential for a similar drug-interaction and adverse events exists. So what do we do?


First, let’s do a brief review of dyslipidemia post-transplantation. Elevated cholesterol levels are very prevalent in transplant recipients reaching above 80% of kidney recipients in some reports. Immunosuppressive drugs play a major role, with all the following classes glucocorticoids, calcineurin inhibitors (cyclosporine greater than tacrolimus) and mTOR inhibitors having deleterious effects. Among them, the effect of mTOR inhibitors is different since it causes predominantly elevated hypertriglycerides due to blockade of insulin-stimulated lipoprotein lipase.


The importance of dyslipidemia in the transplant population is related to the most common cause of death with a functioning allograft - cardiovascular disease (~40%). Similar to the dialysis data, statin trials in transplantation are limited to one prospective randomized trial (ALERT) with fluvastatin in kidney transplant recipients that showed lower cholesterol levels in the treatment arm compared to placebo, however there was only a non-significant trend towards reduction of composite cardiovascular events. Nonetheless, secondary outcomes of this trial, observational, long-term follow ups and post-hoc analyses have suggested some beneficial effects.


Most of our transplant patients are taking tacrolimus which is extensively metabolized by the cytochrome P450 family enzymes in the liver and excreted into the bile. Therefore, what should we do? Should we stop completely using simvastatin?


I think there is no straight answer here, especially since we have been using statins for a long time in combination with tacrolimus, monitoring in those settings LFTs and symptoms of myalgia. But now with the formal contraindication with cyclosporine, physicians will get more careful in prescribing even the sister CNI with simvastatin. Insurers will likely change their policies facilitating the use of other statins as well. So which statins are safe to use?


Fluvastatin and Pravastatin (both generic) have minimal drug interaction with CNIs/amlodipine and should be considered for mild hypercholesterolemia, since both are weaker statins (see strength and interconversion table above that I simplified from the FDA version). Atorvastatin should be the chosen statin for moderate-severe hypercholesterolemia, since it has increased potency requiring a lower dose and has a favorable safety profile despite some metabolism by P450. Rosuvastatin, a novel potent statin, could also be the agent of choice since it is not metabolized by cytochrome P450, though preliminary results from the PLANET trials have reported a higher risk of proteinuria when higher doses were administered. Therefore, it is wise to wait until final results are published.

The debate is open and would love to hear how others would face this dilemma.

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