I’ll Have A Gin and Tonic; Hold the Tonic

The gin and tonic is a classic cocktail, perfect with a sliver of lime on a hot summer day. But this simple-to-make drink also has a long-storied medical history that is credited with expanding and maintaining the British Empire for over a century. We’ll get to the kidney issues later.

This journey began in the 17th century, when it was noticed by Spanish invaders in South America that the bark of the cinchona tree had medicinal qualities for a variety of tropical febrile illnesses. The active ingredient from the tree was quinine, and the bark was brought back by the Spanish to Europe as both a remedy for and prevention of malaria.

From the early 1800s to 1940s, European nations such as England, Spain, France, and Germany were attempting to expand their colonies into tropical lands, and finding preventative measures against malaria were critical for survival. British leaders recognized the power of quinine powder, and due to their interest in conquering India, began importing the bark in massive quantities, supplying their soldiers in India with over 700 tons of cinchona bark annually.

The extracted quinine powder was effective, but very bitter, so it was soon made more palatable by mixing into drinks with soda and sugar. In 1858, the first commercial tonic water became available (patented by Erasmus Bond);  subsequently, Schweppes introduced “Indian Quinine Tonic,” turning a medical necessity into a commercial profitability. Mixing tonic with gin became a favorite balanced drink for soldiers in these tropical lands, and soon this tasty aperitif was widely adopted by the rest of the world. Sir Winston Churchill even credited the gin and tonic with saving “more Englishmen’s lives, and minds, than all the doctors in the Empire.”

Since the independence of India in 1947, the gin and tonic has not faded into obscurity. The drink even reached popularity as a “radioactive” party favorite, as it fluoresces with exposure to black light. Independent of its antimalarial actions, it was also found to be effective at relieving muscle cramps, and was widely adopted by nephrologists to treat this painful condition associated with hemodialysis treatments. During my research of this topic, I found one of the only randomized controlled trials using quinine for this indication. It was performed by my father, Frederick Whittier, MD, who compared its effectiveness to vitamin E. My dad et al found it to be equivalent to vitamin E, and due to the health risks that were being reported with quinine use, favored vitamin E for treatment of cramps in dialysis patients.

Unfortunately, although quinine is efficacious for cramps and is a potent antimalarial agent,  reports of quinine-associated fatalities from thrombotic thrombocytopenic purpura (TTP)-hemolytic uremic syndrome (HUS), renal failure, and torsades de pointes and other arrhythmias led the FDA to ban most forms of this drug in 2007. Now, 10 years later, only one form of quinine [Qualaquin, Mutual Pharmaceutical Co.] is approved in the US by prescription specifically for the treatment of malaria. This ban has dramatically reduced the use of quinine by prescription in the US, but it is still available in other countries. Specialty tonics are more common and frequently seen in “speakeasies” and other bars across the US, but how common is quinine-induced toxicity? What is the mechanism of injury? Is there enough quinine in tonic water to be of concern?

Page et al addresses these questions in a recent  AJKD publication. The authors define the hematologic and renal disturbances caused by quinine by detailing cases from the Oklahoma TTP-HUS registry of patients undergoing plasmapheresis who presented clinically with a thrombotic microangiopathy (TMA). All patients in this registry (n=509) had microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, and were referred for consideration of plasmapheresis. The investigators found that 19 of the 509 patients (4%) had quinine-induced TMA. Quinine pills were responsible for 18 of the cases, while one patient (highlighted here) presented after exposure to quinine in a vodka tonic drink.

Page et al found that quinine-induced TMA clinically presented more like HUS than TTP, as it had a renal predominance of organ injury and less severe thrombocytopenia. When 18 of the 19 patients were evaluated for quinine-dependent antibodies, they were universally present. As in many other drug-induced autoimmune syndromes, neutropenia was often present, and the level of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was always > 10%.  The renal failure was severe: anuria was common, all patients had Stage 3 acute kidney injury (AKI), > 90% required dialysis, 78% had residual chronic kidney disease (CKD), and 3 patients were left with end-stage renal disease (ESRD). Thus, nephrologists are more likely to see this disease first, often before hematologists, as the renal failure is so striking.

Outcomes of 19 Patients With Quinine-Induced TMA. Note: All patients except patient 12 survived the initial episode. a. Patients 9 and 13 received kidney transplants in 2006. The years of follow-up for their eGFRs are the years since their transplantation. b. Patient 12 died on hospital day 2 from complications of a subclavian central venous catheter insertion, planned for plasma exchange and dialysis, before a blood sample for quinine-dependent antibodies was obtained. The quinine cause was documented by the history of 2 previous episodes of sudden abdominal pain, nausea, and vomiting following ingestion of a quinine pill. She had stage 3 acute kidney injury documented by serum creatinine increase from 4.8 to 6.3 mg/dL during her 2 hospital days before her death. Table 2 from Page et al, AJKD © National Kidney Foundation.

Quinine has been known to cause a multitude of hematologic abnormalities. Immune-mediated thrombocytopenia, autoimmune hemolytic anemia, TTP, and HUS have all been described. In the last decade, investigators have performed elegant experiments to determine the molecular basis for quinine-induced TMA. Similar to peanut-related anaphylaxis, an initial exposure to quinine leading to sensitization and antibody production is necessary. A repeat exposure is then enough to massively bind antigen to antibodies, which can then activate the glycoprotein (GP) IIb/IIIa receptor leading to platelet aggregation. Clinically, this action is the exact opposite of GP IIb/IIIa platelet inhibitors such as clopidogrel (used after acute coronary syndrome). Instead of inhibiting the GP IIb/IIIa receptor to prevent further coronary thrombosis and platelet aggregation (as seen with clopidogrel), quinine antibodies create the reverse end-organ effect. This antithesis-causing activation of GP IIb/IIIa receptor is one mechanism, but not the only one. Additionally, the quinine induced antibodies can also interact directly with endothelial cells, as well as neutrophils, which can lead to neutrophil adhesion to endothelial cells, causing direct vascular injury.

Could one sip of tonic be enough to cause a TMA? Quinine in tonic water is limited by the FDA to a dose of 83 mg/L, but the daily therapeutic dose of quinine for malaria prevention is up to 1000 mg. By the proposed immune mechanisms, only a miniscule amount would be needed to trigger the TMA if a prior exposure occurred, and therefore, a simple sip of tonic could be enough to cause a patient to have severe AKI requiring dialysis.

Currently, when a patient presents with AKI, MAHA, and TMA, TTP appropriately needs to be ruled out. After excluding TTP by confirming adequate ADAMTS-13 levels, the differential diagnosis of TMA becomes more challenging, weighing the clinical and laboratory data. Narrowing the differential diagnosis occurs by excluding other causes of TMA, such as bloody diarrhea with shiga toxin, direct endothelial toxins (avastin, calcineurin inhibitors), drug-induced immune-mediated TMA (oxaliplatin, gemcitabine, sulfasoxazole), pregnancy-related conditions (HELLP syndrome), malignant hypertension, infections, malignancies, scleroderma, and other autoimmune conditions. What often happens when these other causes are not apparent is that we are left to consider whether the TMA diagnosis is that of an “atypical” or complement-mediated HUS (complement-HUS).  Unfortunately, this diagnosis remains one of exclusion, as some cases of complement-HUS exist even when genetic/complement analyses and serum levels of C3 are normal.

Left with no other obvious cause, therapy is often initiated with eculizumab, which has established benefit of stabilizing or improving GFR over time in patients with complement-HUS, even in severe cases of AKI, allowing some patients to recover enough renal function to come off of dialysis.  Once a patient embarks on eculizumab therapy, there is also the conundrum of when, if ever, it can be stopped. In addition, consideration should be given to the enormous cost of the medication (over half a million US dollars for the first year of therapy). This detailed study by Page et al is instrumental in reminding us to rule out one other clinical diagnosis before embarking on expensive, potentially lifelong therapy, for complement-HUS: quinine-induced TMA.

Annual frequency of quinine-induced thrombotic microangiopathy (TMA) and acquired thrombotic thrombocytopenic purpura (TTP) among patients enrolled in the Oklahoma TTP−Hemolytic Uremic Syndrome (TTP-HUS) Registry, 1995 to 2015. The first patients with quinine-induced TMA were diagnosed in 1995. Because serum was collected for measurement of ADAMTS13 activity beginning November 13, 1995, the 1 patient with TTP diagnosed in 1995 is not included in this graph. Only patients with TTP who were identified by ADAMTS13 activity < 10% during a complete year are included in this graph. Quinine-induced TMA and acquired TTP are mutually exclusive syndromes with distinct causes. Quinine-induced TMA is caused by an acute immune-mediated systemic reaction to quinine. Acquired TTP is caused by a severe deficiency of ADAMTS13 activity caused by autoantibody inhibition. ADAMTS13 activity is not severely deficient in patients with quinine-induced TMA. Figure 2 from Page et al, AJKD © National Kidney Foundation.

Before accepting a diagnosis of complement-mediated HUS and committing a patient to eculizumab, a careful history of quinine or tonic exposure should be sought. If such a history exists, consideration should be made for evaluation of quinine-induced antibodies which can be done through the Blood Center of Wisconsin. If quinine antibodies are present, the patient should probably not receive eculizumab and should be counseled to avoid all future quinine exposure. For the acute treatment after an exposure, the role of plasmapheresis is currently not recommended by the American Society of Apheresis; however, given that this is an antibody-driven disease, clarification of this requires further study.

As I finish this blog post on my porch one evening, sipping a gin and tonic, my thoughts are swirling like the ice in my drink: malaria, the British Empire, my father, and finally how far science has come to describe many of the TMA syndromes at the molecular level. Before I prescribe eculizumab for the next patient I see with presumed complement-mediated HUS, I will certainly now make sure to take a detailed history for quinine and tonic exposure. If I’m sending blood to a specialty lab to evaluate for the complement dysregulation of HUS, I can easily include another order for quinine antibodies. Even though this reaction to quinine is rare, I pour my drink out onto the lawn, wishing I had a black light to see if the grass fluoresces. For my next drink, I think I’ll make a gin gimlet instead.  Now, I’m sure I won’t get a TMA, and I won’t get scurvy either.

Post prepared by William L. Whittier, AJKDBlog Contributor. Follow him @TWhittier_RUSH.

 To view the Page et al article (subscription required), please visit AJKD.org.

Title: Quinine-Induced Thrombotic Microangiopathy: A Report of 19 Patients
Authors: E.E. Page, D.J. Little, S.K. Vesely, and J.N. George
DOI: 10.1053/j.ajkd.2017.05.023

 

 

1 Comment on I’ll Have A Gin and Tonic; Hold the Tonic

  1. Nice post.

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