What are you smoking?

I recently saw an interesting case series published in CJASN where they reported four cases of oliguric AKI  associated with synthetic cannabinoids use. Renal biopsy revealed acute tubular injury in three of them and calcium oxalate crystals  in two.

Interestingly, around the same period of time I was rotating in nephrology consult service and had an elderly patient with history of paraplegia and neurogenic bladder (on intermittent self-catheterization), who was brought to the ER with altered mental status for which he was intubated for airway protection. On presentation, he was found to have acute kidney injury (Cr 6.0). His renal function continued to deteriorate with no specific etiology for his renal failure, so he had a renal biopsy which showed evidence of an active tubulointerstitial nephritis with marked tubular injury and calcium oxalate crystals present within the tubular lumina. Remarkable findings in his history included the recent use of cannabinoids. He never had history of renal stones. His home medication includes: methadone, oxycodone, nortriptyline and pregabalin. Admission labs showed normal osmolar gap and negative toxicology analysis. Urine microscopy showed muddy brown casts with no identifiable crystals.  Abdominal ultrasound did not reveal any renal calculi. Renal replacement therapy was started for uremic symptoms and he continued to require replacement therapy after his discharge.

The use of these synthetic cannabinoid preparations has increased significantly in the United States over the past few years, and the incidence of acute kidney injury (AKI) from use of these agents  is underestimated. CDC investigators have identified 16 patients (15 males; median age, 18.5 years) from 6 states who presented to emergency departments in 2012 with acute kidney injury after smoking a synthetic cannabinoid product.  Six patients had acute tubular injury and three had acute interstitial nephritis. Even though we can relate tubular injury and interstitial nephritis to the use of cannabinoids  , presence of calcium oxalate crystals was perplexing. In the case series reported in CJASN, they mentioned the presence of calcium oxalate crystals in two patients, but the mechanism of development of these crystals was not fully elucidated . We are hypothesizing that synthetic cannabinoids could be the potential cause for calcium oxalate deposition in this patient (after all causes of secondary hyperoxaluria were excluded). One possible explanation is that synthetic cannabinoids contain additional compounds which are plant in origin and these may be oxalogenic

Synthetic cannabinoids use should be in our differential diagnosis for unexplained AKI in young adult population as it can cause either ATN or AIN or both. A high index of suspicion is required as they may not be detected on routine urine drug screens.

Posted by Mahmoud Kamel

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