91-Year-Old Woman With Hyperkalemia.

A 91-year-old woman presented to the clinic with nighttime delirium and dysuria. The patient's medical history was provided by the patient and her daughter. Her medical history was significant for coronary artery disease, heart failure with preserved ejection fraction, hypertension, hyperlipidemia, obstructive sleep apnea, hypothyroidism, chronic kidney disease (CKD) stage 3b, chronic constipation, and depression. Her medications included levothyroxine, paroxetine, melatonin, cyanocobalamin, as-needed loratadine, and as-needed polyethylene glycol. Her daughter denied that the patient had regular over-the-counter medication use, including nonsteroidal anti-inflammatory drugs (NSAIDs). On physical examination, the patient was frail, afebrile, and bradycardic with a heart rate of 58 beats per minute. Her blood pressure was 142/58 mm Hg, and respiratory rate was 14, with an oxygen saturation of 95% on room air. She was confused, oriented to person only, but not in acute distress. Lower-extremity examination revealed 2+ bilateral edema up to the knees, which was around her baseline, with full strength bilaterally. Initial laboratory evaluation showed the following (reference ranges provided parenthetically): white blood cell 5.9x109/L (3.4-9.6x109/L), hemoglobin 12.0 g/dL (11.6 g/dL-15 g/dL), platelets 174 (157-371x109/L), potassium 5.9 mmol/L (3.6 mmol/L-5.2 mmol/L); sodium 135 mmol/L (135 mmol/L-145 mmol/L); chloride 110 mmol/L (98 mmol/L-107 mmol/L); bicarbonate 17 mmol/L (22 mmol/L-29 mmol/L); creatinine 1.21 mg/dL (0.59 mg/dL-1.04 mg/dL); estimated glomerular filtration rate (eGFR) 39 mL/min per body surface area (BSA) (>=60 mL/min per BSA); blood urea nitrogen 22 mg/dL (6 mg/dL-21 mg/dL); calcium 9.6 mg/dL (8.8 mg/dL-10.2 mg/dL); anion gap 8 (7-15). Urinalysis showed positive nitrite and microscopy was positive for white blood cells >100/high power field (hpf) (0-10/hpf). She was diagnosed with urinary tract infection (UTI).1.In addition to treating her UTI, what is the next appropriate step for managing her hyperkalemia?a)Repeat potassium levelb)Start oral sodium zirconium cyclosilicatec)Refer to emergency department and administer intravenous calcium gluconated)Admit to inpatient and initiate hemodialysise)Administer oral furosemide The most appropriate next step is to rule out pseudohyperkalemia, a common cause of hyperkalemia.1Smellie W.S.A. Spurious hyperkalaemia.BMJ. 2007; 334: 693-695Crossref PubMed Scopus (56) Google Scholar The most common cause for pseudohyperkalemia is mechanical trauma during venipuncture, resulting in potassium release from red blood cells. Repeated fist clenching during blood draws could also raise potassium concentration.2Gambino R. Sanfilippo M. Lazcano L. Pseudohyperkalaemia from finger flexion during venepuncture masks true hypokalaemia.Ann Clin Biochem. 2009; 46 (177-177)Crossref Scopus (7) Google Scholar Severe thrombocytosis or leukocytosis can also lead to falsely elevated potassium caused by increased cell fragility.3Meng Q.H. Wagar E.A. Pseudohyperkalemia: a new twist on an old phenomenon.Crit Rev Clin Lab Sci. 2015; 52: 45-55Crossref PubMed Scopus (39) Google Scholar Sodium zirconium cyclosilicate is an oral potassium binder that binds to the potassium in the gastrointestinal tract in exchange for hydrogen and sodium. Intravenous calcium gluconate and hemodialysis can be used in hyperkalemic emergency. Furosemide can be used to treat both acute and chronic hyperkalemia. Before initiating treatment, a confirmatory test is needed to rule out pseudohyperkalemia by repeating a potassium level. A repeat potassium level was confirmed to be elevated at 6.1 mmol/L. She was prescribed nitrofurantoin, and her delirium and dysuria resolved after treatment of her UTI.2.Which of the following is the next best step to assess hyperkalemia for this patient?a)Creatinine kinase (CK)b)Uric acid and phosphorusc)Haptoglobin and lactate dehydrogenase (LDH)d)Serum aldosteronee)Electrocardiogram (ECG) In a patient with confirmed hyperkalemia, the most important initial step is to identify clinical manifestations of hyperkalemia, which include muscle weakness or paralysis and cardiac conduction abnormalities or arrhythmias. A CK level is useful to detect any muscle breakdown: however, our patient does not have any signs or symptoms to suggest myopathy or rhabdomyolysis. Tumor lysis syndrome (TLS), characterized by hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia, is an oncologic emergency that needs to be recognized and treated in a timely manner. Our patient does not have any other presentations that are suspicious for an undiagnosed malignancy. Haptoglobin, LDH, reticulocytes, and peripheral blood smears are helpful to diagnose hemolysis, which can cause hyperkalemia. However, her hemoglobin level was normal, which makes this unlikely. Aldosterone level and renin activity are appropriate diagnostic tests for chronic or stable hyperkalemia. However, in this case, the most important step is to determine if she has hyperkalemic emergency by ECG evaluation. ECG manifestations in hyperkalemia include peaked T-waves, widening of the QRS complex, PR interval prolongation, P-wave flattening or absence, or “sine-wave” appearance of the QRS complex.4Mattu A. Brady W.J. Robinson D.A. Electrocardiographic manifestations of hyperkalemia.Am J Emerg Med. 2000; 18: 721-729Abstract Full Text PDF PubMed Scopus (160) Google Scholar If any of these findings are present, the patient should be treated for hyperkalemic emergency. Asymptomatic patients with potassium level above 6.5 mmol/L, or with potassium level above 5.5 mmol/L with acute kidney injury (AKI) and concerns for tissue breakdown (eg, rhabdomyolysis, crush injury, TLS), or ongoing potassium absorption (eg, significant gastrointestinal bleed) also constitute hyperkalemic emergencies. These patients require inpatient monitoring. Rapid acting therapies for hyperkalemic emergencies include intravenous calcium to stabilize the cardiac cell membrane against undesirable depolarization, intravenous insulin with glucose, nebulized albuterol and correction of acidosis by promoting shifting of the potassium intracellularly. In addition, removal of the potassium should also be attempted by using gastrointestinal cation exchanger, loop diuretics with or without thiazide diuretics, or hemodialysis. Asymptomatic patients with mild to moderate hyperkalemia can be managed in the outpatient setting. Treatments include resolving the underlying causes such as replacing contributing medications; dietary potassium restriction; and temporizing measures, which include the use of diuretics and oral potassium binders. Common potassium binders include patiromer, sodium zirconium cyclosilicate, and sodium polystyrene sulfonate. An ECG was obtained and did not reveal any significant abnormalities. She denied any muscle weakness, paralysis, or palpitations. She had no historical or clinical features consistent with rhabdomyolysis as a potential etiology of hyperkalemia, and her creatinine was stable previously, which excluded AKI as a cause of her hyperkalemia. Urinalysis was normal with a urine pH of 5.0. On review of her medical record, she was noted to have incidental hyperkalemia when hospitalized for generalized weakness 2 years ago, which resolved with temporizing measures during that hospital stay. At that time, her angiotensin-converting enzyme inhibitor for heart failure treatment was stopped because of hyperkalemia, and her beta blocker was stopped because of bradycardia. In the office, in order to assess her acid-base status, a venous blood gas was obtained and showed pH 7.30 (7.32-7.43), pCO2 37 mm Hg (41 mm Hg-51 mm Hg), and pO2 27 mm Hg (not applicable).3.What is the next best step to evaluate hyperkalemia for this patient?a)24-hour urinary potassium excretionb)Transtubular potassium gradient (TTKG)c)24-hour urinary sodium excretiond)Repeat urinalysise)Morning cortisol, serum aldosterone and plasma renin activity Acidosis causes increased potassium release from cells and therefore needs to be evaluated. Her laboratory findings were consistent with normal anion gap metabolic acidosis (NAGMA). Common causes for NAGMA include profound diarrhea, pancreatic or intestinal fistula, administration of large quantity of chloride-containing fluids, and renal tubular acidosis (RTA). Type 4 RTA, or hyperkalemic RTA, is the most common form of RTA, of which hypoaldosteronism is a hallmark manifestation. Hypoaldosteronism could be acquired or inherited and most commonly presents as hyporeninemic hypoaldosteronism. Type 4 RTA is often asymptomatic and is associated with a mild metabolic acidosis. Type 1 RTA, also known as distal RTA, is characterized by impaired acid excretion in distal tubules, and patients often have elevated urine pH above 5.3. Acquired type 1 RTA is commonly associated with autoimmune diseases such as systemic lupus erythematosus, Sjögren syndrome, and rheumatoid arthritis. Type 2 RTA, also known as proximal RTA, is characterized by defects in bicarbonate reabsorption in proximal tubules, and its acquired form is commonly associated with monoclonal gammopathies, medications such as carbonic anhydrase inhibitors (eg, acetazolamide and topiramate), and Fanconi syndrome. In type 1 and type 2 RTA, the serum potassium level is typically low to normal. Type 3 RTA is a rare form with overlaps between distal and proximal RTA. A 24-hour urine potassium excretion has limited utility in patients with persistent stable hyperkalemia, as potassium excretion matches potassium intake via multiple regulatory mechanisms.5Welling P.A. Regulation of renal potassium secretion: molecular mechanisms.Semin Nephrol. 2013; 33: 215-228Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Therefore, 24-hour urine potassium excretion is more useful in monitoring compliance in patients treated with potassium supplementation (such as potassium citrate for treatment of hypocitraturia) and to evaluate for renal potassium wasting. Transtubular potassium gradient (TTKG), an index based on serum and urine potassium and osmolality, was developed in 1986 to evaluate for appropriate renal compensation to aberrant potassium levels,6West M. Bendz O. Chen C. et al.Development of a test to evaluate the transtubular potassium concentration gradient in the cortical collecting duct in vivo.Miner Electrolyte Metab. 1986; 12: 226-233Google Scholar with supporting evidence limited to case series. However, in an updated publication, the TTKG test was invalidated.7Kamel K.S. Halperin M.L. Intrarenal urea recycling leads to a higher rate of renal excretion of potassium: an hypothesis with clinical implications.Curr Opin Nephrol Hypertens. 2011; 20: 547-554Crossref PubMed Scopus (38) Google Scholar A 24-hour urinary sodium excretion is most used to estimate dietary sodium intake to assess compliance with a low-sodium intake diet and would not be an appropriate test to order here. Repeat urinalysis would be of low yield in evaluating her hyperkalemia. Obtaining an aldosterone level and renin activity would help with the diagnosis of type 4 RTA. Primary adrenal insufficiency is also associated with type 4 RTA and should be evaluated for as well. Further laboratory testing (aldosterone <4.0 ng/dL [<=21 ng/dL], renin activity <0.6 ng/mL per hour [0.6-3.0 ng/mL per hour]) confirmed hyporeninemic hypoaldosteronism. Her morning cortisol level was normal at 9.7 μg/dL (4.8 μg/dL-20 μg/dL). Thyroid stimulating hormone level was normal. She was diagnosed with type 4 RTA.4.Which of the following conditions is most likely associated with hyporeninemic hypoaldosteronism in this patient?a)Primary adrenal insufficiencyb)CKDc)Severe illnessd)Medicationse)Inherited disorders All these conditions could be related to type 4 RTA. Primary adrenal insufficiency can cause a type 4 RTA through a lack of aldosterone and cortisol production; however, this condition is associated with an elevated renin level. In addition, our patient does not have other presentations of primary adrenal insufficiency such as hyponatremia, hyperpigmentation, weight loss, nausea, vomiting, abdominal pain, or hypotension. CKD is the most pertinent for our patient and is specifically related to hyporeninemic hypoaldosteronism caused by decreased renal production of renin. She did not have a severe illness. Medications such as direct renin inhibitors, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers could lead to type 4 RTA by reducing renin activity, inhibiting the conversion of angiotensin I to angiotensin II, and blocking angiotensin II receptors, respectively. Heparin could cause type 4 RTA by inhibiting production of aldosterone from the adrenal zona glomerulosa cells. NSAIDs could also lead to type 4 RTA by causing hyporeninemia. Calcineurin inhibitors could cause type 4 RTA by rendering decreased aldosterone secretion and sensitivity.8Kamel K.S. Ethier J.H. Quaggin S. et al.Studies to determine the basis for hyperkalemia in recipients of a renal transplant who are treated with cyclosporine.J Am Soc Nephrol. 1992; 2: 1279-1284Crossref PubMed Google Scholar Some antibiotics, such as trimethoprim and pentamidine, can cause type 4 RTA through aldosterone resistance,9Velazquez H. Perazella M.A. Wright F.S. Ellison D.H. Renal mechanism of trimethoprim-induced hyperkalemia.Ann Intern Med. 1993; 119: 296-301Crossref PubMed Scopus (185) Google Scholar but this is also associated with hyperreninemia. Diabetes mellitus is also commonly related to hyporeninemic hypoaldosteronism. Inherited disorders, such as congenital isolated hypoaldosteronism and pseudohypoaldosteronism type 1 and type 2 (Gordon syndrome),10Soriano J.R. Renal tubular acidosis: the clinical entity.J Am Soc Nephrol. 2002; 13: 2160-2170Crossref PubMed Scopus (353) Google Scholar could lead to type 4 RTA but are more often seen in younger patients. The patient was diagnosed with type 4 RTA related to CKD. She was estimated to have stage 3b CKD by creatinine measurement. Estimation of GFR using creatinine is the primary approach to assess renal function. However, as creatinine is a metabolite from muscle breakdown and the digestion of dietary protein, the estimation is less accurate in certain cases, such as patients with high or low muscle mass, amputees, and patients with severe chronic diseases. Our patient was frail on examination and most likely had low muscle mass, and her eGFR may be overestimated with creatinine-based equation. In this patient population, cystatin C might be more accurate in estimating renal function.5.What is the best next step for management in this patient?a)Obtain genetic testing before treatmentb)Start hydrochlorothiazidec)Start torsemided)Start fludrocortisonee)Start sodium zirconium cyclosilicate For younger patients with type 4 RTA, genetic testing for inherited disorders is a reasonable next step. However, our patient presented after the age of 90 years, so given the unlikelihood of an inherited disorder, no genetic testing was pursued. Thiazide diuretics such as hydrochlorothiazide are reasonable options to treat hyperkalemia by promoting potassium secretion. However, thiazide diuretics could cause hyponatremia, and our patient has a borderline sodium level of 135 mmol/L; also, her concurrent use of a selective serotonin reuptake inhibitor also increases the risk for hyponatremia. Therefore, hydrochlorothiazide is less desirable in our patient. Oral loop diuretics would both lower the potassium level and potentially improve symptoms from heart failure and hypertension. They are therefore preferred in this setting, and are usually adequate to normalize mild hyperkalemia.11Gross P. Pistrosch F. Hyperkalaemia: again.Nephrol Dial Transplant. 2004; 19: 2163-2166Crossref Scopus (15) Google Scholar Fludrocortisone, a potent mineralocorticoid, is effective for patients with hyporeninemic hypoaldosteronism, and the dose required for potassium level normalization in patients with RTA is typically higher than the dose used in primary adrenal insufficiency.12Dobbin S. Petrie J. Lean M. McKay G. Fludrocortisone therapy for persistent hyperkalaemia.Diabetic Med. 2017; 34: 1005-1008Crossref Scopus (4) Google Scholar In patients without hypertension, edema, or heart failure, fludrocortisone could be considered; however, in our patient with these comorbidities, fludrocortisone is less desired because of the concern for worsening pre-existing conditions. Oral potassium binders are a reasonable choice; however, the side effects include constipation, rendering this treatment less ideal in our patient with chronic constipation. The cost of the newer binders (patiromer and sodium zirconium cyclosilicate) is significantly higher, and financial concerns need to be considered before starting therapy. In addition, dietary potassium restriction is helpful in patients with CKD to prevent hyperkalemia. She was started on torsemide 10 mg daily for hyperkalemia in the setting of her other comorbidities and was recommended to start on a low-potassium diet. Her potassium level had normalized to 4.5 mmol/L at her 2-month follow-up. Hyperkalemia is a common electrolyte abnormality, and the etiology includes increased potassium release and reduced potassium excretion. Common causes of increased potassium release from cells include pseudohyperkalemia, other cell or tissue breakdown (tumor lysis syndrome, rhabdomyolysis, gastrointestinal bleed, absorption of hematoma), metabolic acidosis, insulin deficiency, the use of beta blockers, and exercise. Common causes of impaired potassium excretion include hypoaldosteronism, medications, acute kidney injury, and CKD. Urinary tract obstruction could disrupt potassium homeostasis and should not be overlooked, for which ultrasound of the kidneys and bladder would be helpful. Hypoaldosteronism, or type 4 RTA, is a condition that could lead to persistent hyperkalemia and a mild hyperchloremic metabolic acidosis with a normal anion gap. The etiologies of hypoaldosteronism include both acquired and inherited disorders that affect aldosterone synthesis and secretion or its function at the tissue level. Based on the laboratory findings, this patient was diagnosed with hyporeninemic hypoaldosteronism: the most common acquired cause of hypoaldosteronism. Review of her medications did not show any potential pharmacologic causes. Diabetes and CKD are commonly related to hyporeninemic hypoaldosteronism. Although further testing for type 4 RTA was deferred in this patient because of her age and the favorable response to oral loop diuretic therapy, it would be reasonable to pursue further work-up for other causes of hypoaldosteronism, particularly for hereditary causes in younger patients. In conclusion, this case summarizes the outpatient work-up pathway for longstanding hyperkalemia and the diagnosis and treatment of type 4 RTA. In patients with chronic hyperkalemia, the diagnosis of type 4 RTA should be considered, and the diagnosis primarily relies on laboratory testing. Careful review of the medication list and medical comorbidities is important for a comprehensive evaluation of the underlying causes of type 4 RTA. The authors report no competing interests.