Welcome to the 23rd case of the Skeleton Key Group, a team of 50-odd nephrology fellows who work together to build a monthly education package for the Renal Fellow Network. The cases are actual cases (without patient identifying information) that intrigued the treating fellow.
Written by: Ankita Ashoka
A. The Stem
A 55-year-old woman presented to the emergency room for lab abnormalities found at her outpatient appointment. She has coronary artery disease, heart failure with reduced ejection fraction (EF 37%), diffuse systemic sclerosis, and chronic kidney disease stage G3aA2 presumed due to type 2 diabetes.
Three months ago, she presented with acute hypoxic respiratory failure secondary to acute decompensated heart failure. Her volume status was optimized and she was eventually discharged with a dry weight of 88 kg. Her creatinine was 2.2 mg/dL at discharge (baseline SCr: 1.3 mg/dL). She was sent home on 60 mg torsemide daily. She was followed closely by cardiology and nephrology in the outpatient setting for titration of diuretics, and her Cr returned to baseline.
One month later she was seen in clinic, due to hypervolemia and weight increase to 91 kg, she was instructed to take torsemide 80 mg BID and metolazone 2.5 mg daily. Over the next month, she began to develop orthostasis with BP ranging from 80-100/40-50s. Given her hypotension and improving lower extremity edema, her metolazone was discontinued. Repeat labs obtained the day metolazone was discontinued were critically abnormal.
Her home medications include aspirin 81 mg daily, clopidogrel 75 mg daily, torsemide 80 mg BID, atorvastatin 40 mg daily, insulin detemir 45 units daily, insulin lispro correction dose pre meals, allopurinol 100 mg daily, calcium carbonate 500mg TID, mycophenolic acid 360 mg BID, omeprazole 20 mg daily, and pregabalin 150 mg daily. She had no history of NSAID use.
Personal & Social History: She does not report smoking, alcohol, or illegal drug use.
Vitals on arrival at the ED: Temp: 37 °C HR: 100 bpm RR: 13/ min BP: 102/46 mm Hg SpO2: 97% on room air. Weight: 90 kg
On examination, she was alert and oriented, her oral mucosa moist, with normal skin turgor. Cardiac examination was remarkable for tachycardia and trace lower extremity edema. Pulmonary examination was unremarkable.
B. The Labs
Her initial labs are listed below:
Baseline serum creatinine: 1.3 mg/dL; Albumin 4 g/dL; uric acid 15.3 mg/dL
She received one liter of lactated Ringer’s in the emergency room.
C. Differential Diagnosis
To summarize, we have a patient with acute kidney injury, hypokalemia, hypomagnesemia, hypocalcemia, and hyperuricemia. With so many abnormalities, understanding how these electrolytes are handled by the kidney can help us narrow down the etiology!
The discussion on potassium, calcium, magnesium handling in the kidney, and relationship of hypomagnesemia with hypokalemia, has been discussed in previous skeleton key group cases. Is her hyperuricemia a clue to the possible etiology?
Let’s quickly review how uric acid is handled by the kidney (Figure 1). There are 2 transport processes to think about: tubular reabsorption and tubular secretion of uric acid.
Urate reabsorption: 90 – 95% of filtered urate is reabsorbed at the proximal tubule. Monovalent anions such as lactate, butyrate, nicotinate, and salicylate are exchanged with urate through urate transporter (URAT) 1 or organic anion transporter (OAT) 10 transporters on the apical surface of proximal tubular cells. OAT4 is another apical transporter that assists with urate reabsorption through exchange of divalent anions. Urate subsequently is reabsorbed via glucose transporter (GLUT) 9 present on the basolateral surface.
Urate Secretion: A different set of transporters handle urate secretion at the proximal tubule. Secretion of urate from the interstitium into the cell across the basolateral membrane is driven by OAT1 and OAT3 anion exchangers. This is driven by increased intraluminal alpha-ketoglutarate concentrations. Urate is then secreted at the apical membrane by the apical transporters ABCG2, MRP4, NPT1,and NPT4.
Figure 1: Uric acid handling in the proximal tubule. alpha-2KG: alpha-ketoglutarate.
Uric acid levels can be high in multiple states including chronic diuretic use, tumor lysis syndrome, or in periods of poor urinary filtration such as chronic kidney disease, or high dietary intake. Because she was on both a thiazide and a loop, this begs the question whether one or both of these medications could explain the remainder of her electrolyte abnormalities.
C. What electrolyte disturbances occur with the use of loop and thiazide diuretics?
Loop and thiazide diuretics affect urate handling in the kidney by either increasing reabsorption or reducing secretion. Diuretic induced volume contraction causes increased hydrogen ion secretion in the proximal tubule via the apically located sodium hydrogen exchanger (NHE3). This creates a favorable pH gradient for urate uptake via OAT 4, enhancing uric acid reabsorption. Some studies have also suggested the direct stimulation of OAT 4 by hydrochlorothiazide and torsemide.
Thiazides and loops also compete with urate at OAT 1 and OAT 3 on the basolateral membrane, thereby lowering urate excretion. Inhibition of voltage driven NPT 4 transporter at the apical surface is another postulated mechanism.
Loop diuretics cause volume contraction which activates the renin-angiotensin- aldosterone system and increases aldosterone. Enhanced secretion of aldosterone and increased delivery of Na+ create a favorable electrochemical gradient for Na+ reabsorption (via epithelial sodium channels, ENaC) and K+ secretion (via ROMK channels). The effects of aldosterone on potassium are further discussed in our previous post. Thiazide diuretics stimulate K+ secretion indirectly by lowering intraluminal Ca+ in the distal tubule. Ca+ normally inhibits ENaC channels. Decreased Ca+ activates ENaC, and contributes to the favorable gradient needed for K+ secretion. As detailed below, loops increase the distal delivery of luminal calcium. This could explain why thiazides potentially cause more urinary potassium loss compared to loop diuretics.
Majority of the filtered magnesium is reabsorbed in the loop of Henle. Loop diuretics compete with the chloride site on the Na – K – 2Cl (NKCC2) transporter site in the thick ascending loop of Henle. This inhibits the sodium chloride reabsorption and back leak of potassium into the lumen abolishing lumen electropositivity. Absence of lumen electropositivity inhibits paracellular reabsorption of magnesium thereby increasing urinary magnesium excretion.
In the distal tubule, thiazide diuretics inhibit the electroneutral Na-Cl cotransporter (NCC) which reduces the movement of luminal sodium and chloride into the cell. This in turn causes loss of favourable electrochemical gradient responsible for transcellular movement of magnesium via Transient Receptor Potential Cation Channel Subfamily M Member 6 (TRPM6). Another hypothesis is reduced kidney expression of TRPM6 gene when treated with thiazides chronically.
Hypocalcemia & Hypercalcemia
The mechanism of hypocalcemia in loop diuretics is similar to the mechanism of action of hypomagnesemia. Lack of intraluminal positive potential from blockade of NKCC2 transporter inhibits paracellular reabsorption of calcium.
While loop diuretics cause hypocalcemia, thiazide diuretics cause hypercalcemia. Volume contraction from thiazide diuretics leads to increased proximal sodium and water reabsorption, and therefore passive absorption of calcium in the proximal tubule. Other proposed mechanisms include increased expression of TRPV5 calcium transporter on the apical surface of the distal nephrons. Lack of sodium entry via NCC hyperpolarizes the cell which reportedly activates the calcium entry and increases calcium efflux through sodium/calcium exchanger on the basolateral surface.
In summary, electrolyte abnormalities seen from diuretics use are listed below (Table 1)
Table 1: Electrolyte abnormalities seen with loops and thiazides diuretics
D. More Data
Urine Microscopy – Bland urine sediment; Urine sodium – creatinine ratio: 94 mmol/g creat; Urine potassium – creatinine ratio: 29 mmol/g creat
After her potassium was normalized with IV and PO supplementation, her serum calcium remained low at 7.2 mg/dL with a serum phosphorus of 3.4 mg/dL. Labs at this time were significant for:
Intact PTH: 293 pg/ml (15 – 65)
25 OH Vitamin D: 27.3 ng/ml (>20)
Taking a step back, is there a relationship of calcium and magnesium to each other and to intact PTH (Figure 2.)?
Much like calcium, magnesium regulates the release of PTH. Low magnesium levels stimulate the release of PTH, which acts on the distal tubule, resulting in transcellular reabsorption of magnesium via activation of signalling pathways. However, very low Mg levels (below 0.5 mM or ~1.3mg/dl) paradoxically inhibit the release of PTH which is mediated by disinhibition of Gα-subunits thereby mimicking activation of calcium sensing receptor. So in the setting of hypocalcemia, if you have concurrent hypomagnesemia, your intact PTH may be inappropriately low. High magnesium levels on the other hand will bind the calcium-sensing receptor tricking the body into thinking there is enough calcium and suppress PTH release.
Figure 2. The relationship between magnesium and PTH
E. Final Diagnosis & Management
Given the timing of AKI and electrolyte changes with her medications, it was suspected all of her lab abnormalities were due to the loop and thiazide diuretics. AKI was thought to be prerenal from overdiuresis. The diuretics were held and she was given one liter of lactated Ringer’s solution after which her creatinine improved initially to 2.4 mg/dL. IV potassium chloride was given to raise her potassium to 3.5 mmol/L. IV magnesium sulfate was given slowly to correct hypomagnesemia, then IV calcium gluconate was given thereafter. Given improvement in labs, she was discharged home after two days on a lower diuretic dose, instructions to monitor daily weights, watch for symptoms including shortness of breath and worsening lower extremity swelling. Follow up labs and a nephrology appointment were set up for two days after discharge. Lab trends on discharge are seen in Figure 3.
Albumin: 3.1 gm/dl uric acid: 10.8 mg/dl
Figure 3. Electrolytes trend prior to discharge
F. Take Home Points:
- Loop and thiazide diuretics cause hyperuricemia by increased reabsorption and decreased secretion in the proximal tubule.
- Electrolyte changes from loop and thiazide diuretics are similar: hypomagnesemia, hypokalemia, hyperuricemia; but loop diuretics can lead to hypocalcemia and thiazide diuretics can lead to hypercalcemia.
- Low and high magnesium can suppress PTH secretion.