Hello! Welcome to The Skeleton Key Group (SKG) world. We love analyzing and dissecting electrolyte abnormalities. We publish an electrolyte case every month on the Renal Fellow Network. We are honored to be invited to participate in this special Kidney News issue as part of a series on free open-access medical education (FOAMed).
The stem
A 42-year-old woman with a history of hypertension and diabetes mellitus was evaluated for hypokalemia and hypomagnesemia. She was diagnosed with invasive squamous cell carcinoma of the cervix for which she underwent radical hysterectomy and bilateral pelvic lymph node dissection, external beam radiotherapy with brachy-therapy, followed by cisplatin and 5-fluorouracil chemotherapy. She reported no nausea, vomiting, or diarrhea.
She was maintained on telmisartan 80 mg daily, amlodipine 5 mg daily, and metformin 500 mg 3 times a day.
Upon physical examination, her blood pressure (BP) was 120/70 mm Hg, heart rate 88/min, and respiratory rate 18/min with no note of difficulty breathing or desaturations. Her upper and lower limbs had a motor power of 5/5 with no sensory deficits. The rest of her physical exam was normal.
The labs
Her most recent glycosylated hemoglobin test was 6.5%. Albumin was normal. Baseline serum creatinine (Cr) during monthly pre-chemotherapy labs ranged from 0.6 to 1.0 mg/dL. This was her first episode of hypomagnesemia and hypokalemia.
Differential diagnoses of hypomagnesemia
The causes of hypomagnesemia can be divided into three distinct buckets (Figure 1).
Approach to hypomagnesemia
Citation: Kidney News 13, 8
EGFR, epidermal growth factor receptor. Adapted from Brenner and Rector's The Kidney (1).When trying to distinguish between kidney magnesium (Mg) wasting and extrarenal causes (i.e., skin or intestine) of Mg wasting, it is helpful to assess 24 h urinary Mg excretion or fractional excretion of Mg (FEMg).
More data
Spot urine Mg and Cr along with baseline serum Mg and Cr were obtained.
The formula for FEMg is as follows:
where 0.7 is used as a correction factor for the plasma Mg concentration to estimate the free, unbound Mg concentration. With the use of this formula, we calculate the FEMg of our patient:
The normal response of the kidney is to conserve Mg in the face of hypomagnesemia. Therefore, a urine Mg excretion rate of >24 mg/day in states of hypomagnesemia is considered abnormal (2). When this is not available, a FEMg >3%-4% in a patient with normal kidney function is indicative of inappropriate kidney Mg wasting (3).
Her FEMg value of 11.2% points to kidney wasting as the cause of her hypomagnesemia.
The answer
The use of cisplatin in our patient is the most likely cause of hypomagnesemia.
Cisplatin is a cytostatic, platinum compound used in the treatment of several carcinomas, sarcomas, and lymphomas. There are multiple mechanisms by which cisplatin manifests its nephrotoxicity. It can injure the glomerulus, blood vessels, and tubules—causing acute kidney injury and/or tubulopathies manifesting as hypomagnesemia, renal tubular acidosis, isolated proximal tubulopathy, Fanconi syndrome, or rarely, sodium wasting (4).
Cisplatin is freely filtered and actively secreted in the urine via two primary transporters: organic cation transporter 2 (OCT2) and human copper transport protein 1 (Ctr1), present on the basolateral sides of the proximal convoluted tubule and both proximal and distal tubules, respectively (5). Once inside the cell, cisplatin causes DNA damage, cytoplasmic and mitochondrial dysfunction, oxidative stress, inflammation, and apoptosis.
How is Mg reabsorbed in the kidney?
Figure 2 summarizes the distribution of Mg in the body (6).
Distribution of Mg in the body
Citation: Kidney News 13, 8
Infographic by Denisse Arellano, MD, Skeleton Key Group member.Mg reabsorption occurs paracellularly in the proximal tubule and thick ascending loop of Henle (TAL). Unlike most solutes, the majority (70%) of filtered Mg is reabsorbed in the TAL. The lumen-positive transepithelial voltage created by the activity of the Na+-K+-2Cl-(NKCC2) cotransporter and renal outer medullary K+(ROMK) channels at the apical side, and the kidney-specific Cl− (ClC-Kb) channel and Na+/K+-ATPase on the basolateral side of the TAL create a favorable gradient for paracellular reabsorption through claudins 16 and 19 (5, 7).
The fine tuning of Mg handling in the kidney occurs in the distal convoluted tubule (DCT). Here, Mg is re-absorbed via the transcellular route through the cation channel, transient receptor potential melastatin member 6 (TRPM6) (8). Insulin and epidermal growth factor increase the expression of the TRPM6. Since no significant chemical gradient for Mg exists in this segment, the voltage-gated K channel (Kv1.1) is thought to provide the membrane potential needed for TRPM6 activity and Mg reabsorption in the distal collecting tubule. Its exit pathway in the basolateral side of the DCT is less clear but is thought to be via a Na+/Mg2+ exchanger (Figure 3).
Mg reabsorption in different segments of the nephron and a closer look at Mg handling in the DCT
Citation: Kidney News 13, 8
NCC, NaCl cotransporter. Adapted from Zeidel et al. (7).Back to our patient…
Increased intracellular concentrations of cisplatin in the DCT and TAL may activate a number of intracellular injury pathways and cause tubular injury manifesting as hypomagnesemia with or without acute kidney injury (9, 10).
What is the cause of the hypokalemia?
The prevalence of hypokalemia is increased sixfold among patients with cisplatin-induced hypomagnesemia (11). Potassium secretion through the ROMK predominates in the late distal tubular and cortical collecting ducts (CCDs). Intracellular Mg in the TAL, DCT, and CCD regulates the ROMK channel by blocking the channel's pore from the inside, thereby preventing K+ secretion. In states of hypomagnesemia, this blockage is lost, and potassium is more readily secreted into the lumen causing hypokalemia.
It is also thought that injury to the proximal tubule during cisplatin use may lead to increased delivery of sodium to the distal nephron, which then increases sodium-dependent potassium secretion (11). Impairment of the Mg-dependent Na+/K+-ATPase may also contribute to potassium wasting (12).
Management
Management of hypomagnesemia is guided by the severity of symptoms. Most patients are asymptomatic and can tolerate oral supplementation. Electrolyte abnormalities without kidney injury is not a reason to stop cisplatin chemotherapy, especially if the goal is cure from cancer.
Our patient was given Mg oxide 800 mg three times a day as well as potassium chloride 10 mEq twice daily. Electrolytes normalized within 1 week, and supplementation was continued for the duration of cisplatin therapy.
One of the main strategies to prevent cisplatin-induced nephrotoxicity is short-duration, low-volume outpatient hydration a few hours before and after cisplatin administration. There is a lack of consensus on which protocols to use, but usually intravenous (IV) saline incorporated with potassium chloride and Mg sulfate may be used to induce forced diuresis 2-3 h before to 2-3 h after cisplatin administration. This forced diuresis is thought to reduce urinary cisplatin concentrations and proximal tubule transit time, thereby decreasing risk for kidney tubular injury. Electrolyte supplementation is given to avoid diuresis-induced hypokalemia and hypomagnesemia. It has also been suggested that Mg supplementation may reduce kidney tubular damage (13).
Take-home points
Mg, sometimes called the forgotten ion, is the second-most abundant intracellular cation. It plays an important role in the structure of proteins and enzymatic reactions.
Cisplatin-induced hypomagnesemia occurs via direct tubular injury in the distal collecting tubule causing impaired Mg absorption and hypokalemia.
Thank you for reading this case. SKG is a team of 57 nephrology enthusiasts who work closely together and publish monthly educational cases. Special shout-out to our fellow editors: Chi Chu and Alex Meraz; our faculty advisors: Kartik Kalra, Sudha Mannemuddu, Michelle Lim, Dhwanil Patel, and Nasim Wiegley; our social media/podcast leaders: Sai Achi, Raad Chowdhury, and Narjes Alamri; and all our team members.
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The Skeleton Key Group: A MAGnificent Case of Electrolyte Deficiency
Citation: Kidney News 13, 8
F, female. Visual abstract by Dhwanil Patel, MD, SKG Faculty Member and Nephrologist, Overlook Medical Center, Summit, NJ.References
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Pabla N, et al. The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity. Am J Physiol Renal Physiol 2009; 296:F505–F511. doi: 10.1152/ajprenal.90545.2008
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