1Department of Medicine, Hackensack Meridian School of Medicine Chief, Neptune, New Jersey, United States
2Department of Nephrology and Hypertension, Cleveland Clinic Lerner College of Medicine of Case
Western Reserve University, Glickman Urological & Kidney Institute Cleveland Clinic, Cleveland, Ohio, United States
Corresponding author details:
Sushil K. Mehandru, MD, Professor of Medicine
Hackensack Meridian School of Medicine Chief
Hypertension Jersey Shore University
New Jersey,United States
Copyright: © 2020 Mehandru S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 international License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Hyperkalemia is potentially a life-threatening electrolyte disorder. Recently published Mehandru Syndrome, reveals novel cases of Pseudohypoaldosteronism with new classification as PHA-M/Mehandru Syndrome, where patients with isolated hyperkalemia were successfully managed with low potassium diet. These case reports in the above mentioned syndrome were extension of the previously reported cases in August 2017 as the “Atypical Presentation of Gordon Syndrome and Its Management”. We report three additional cases in which Patiromer was administered to aid patients unable to adhere to our standard eight week low-potassium diet protocol. Patiromer protocol was established with the objective of lowering high serum potassium without inducing hypokalemia. In our case reports, two females (ages 56 and 68, respectively) and a male (age 64) presented with unexplained hyperkalemia (6.3 mEq/L, 5.5 mEq/L, and 5.8 mEq/L respectively). Similar to patients previously reported with Mehandru Syndrome, two of our three patients presented with normal to slightly-elevated blood pressures with no other reported complaints. There were no other suspected causes for hyperkalemia, such as diabetes mellitus or the use of NSAIDs, Beta Blockers, ACEIs, ARBs, potassium supplementation, potassium sparing diuretics, or unusually high potassium diets. The prevalence of individuals presenting with Mehandru Syndrome from just our solo practice urges us to disseminate our findings with the larger medical community, with the goal of discovering and helping treat thousands of undiagnosed or misdiagnosed, hyperkalemic individuals. There is a potential that our findings will help hyperkalemic individuals who have been misdiagnosed Type IV Renal Tubular Acidosis (RTA), and those who remain in the category of unknown etiology. Mehandru Syndrome appears to affect individuals with an average age of 53 years, irrespective of gender bias, and predominantly affecting those who are Caucasian.
Hyperkalemia; Hypertension; Mehandru Syndrome; Metabolic Acidosis;
Pseudohypoaldosteronism (PHA); Patiromer
Hyperkalemia a potentially life-threatening electrolyte disorder [1] in the absence of renal insufficiency or any other probable indicators, poses a challenge for the diagnosis and subsequent treatment. Mehandru Syndrome (PHA-M), reveals presence of isolated hyperkalemia in patients, corrected within eight weeks of diagnosis with strict adherence to a low potassium diet [2]. These cases were initially reported in August 2017 as “Atypical Presentation of Gordon Syndrome and Its Management”[3]. Potassium, the second-most abundant cation in the body, performs several important physiological functions, including cellular metabolism, glycogen and protein synthesis, and maintenance of the electrical action potential across cell membranes, especially in the myocardium [4,5]. Kidneys are responsible for potassium management in the body. Majority of hyperkalemia cases are seen in patients with reduced kidney function. Insulin and beta adrenergic receptor stimulation are important factors of potassium distribution between intra and extra cellular spaces. Excessive intake of potassium can cause hyperkalemia but usually in the setting of impaired renal function, isolated hyperkalemia may have been misdiagnosed as renal tubular acidosis type IV (RTA) and other diseases whereas this may not be the case as shown by our research. Hyperkalemia can result from interstitial renal disease that specifically affect the distal nephron; in this setting, the glomerular filtration rate is only mildly reduced, and circulating aldosterone levels are normal [6]. Pseudohypoaldosteronism (PHA) is an inherited disorder in which individuals have impaired response to Aldosterone [7]. There are several types of PHA with different presentations (Table 1).
PHA-M is reported by the author as Mehandru Syndrome [2], possessing some overlapping features of PHA classes I and II, and with significant differences in the presentation of disease and its management. Hyperkalemia, metabolic acidosis, and mild hypertension have been noted in PHA-M patients. Patients with Gordon Syndrome have suppressed renin consistent with a saltloaded state, but aldosterone levels are typically low given their hyperkalemia [8]. Contrary to Gordon Syndrome, our patients reported normal Renin and Aldosterone levels, normal plasma sodium, normal plasma volume, with absence of urine sodium wasting, hypercalciuria and renal stones [2]. Anatomical changes present in other types of PHA such as miliaria rubra in Renal PHA type I, multiple target organ in MTOD, short stature in Spitzer Weinstein syndrome, distal arthrogryposis in Gordon syndrome, and craniofacial dysmorphism in transient PHA type III. None of these anatomical deformities are found in Mehandru syndrome or PHA-M.
Initial therapy with Hydrochlorothiazide and a low sodium
diet failed to control serum potassium levels. The major difference
in presentation lies in the age of clinical onset. All patients with
PHA-M/Mehandru Syndrome were over the age of 45, with an
average age of 53 years. In 12 of our 15 patients, we successfully
lowered serum potassium to an optimal level over the span of two
months using a strict low-potassium diet protocol alone. Some of
the patients who struggled to maintain low potassium diet, the
administration of Patiromer was necessary in order to normalize
serum potassium levels. Overall, the Prognosis was found to be
excellent. Calcium and magnesium levels were monitored in all
patients, and were found to be within acceptable limits. PHA-M/
Mehandru protocol II was refined for optimal serum potassium
levels. Hypokalemia was not noted in any of our patients.
Patiromer was to be given to patient for a total of six doses. 8.4
gms Patiromer was prescribed to be taken three times a week for
the first week, twice a week for the second week, and once a week
dose for the third week. The labs were monitored weekly for the
first month and bi-monthly thereafter.
*Plasma renin activity nENaC: Epithelial sodium channel; GFR: Glomerular filtration rate; MLR: Mineralocorticoid receptor gene; PHA: Pseudohypoaldosteronism; RTA: Renal tubular acidosis
Table 1: Types of pseudohypoaldosteronism & their characteristics
Case 1
A 56-year-old Caucasian female was sent to the emergency room from the office of her cardiologist due to high serum potassium on her laboratory results, noting a serum potassium of 6.3 mEq/L. On examination, the patient was awake and alert, oriented × 3 with a blood pressure of 100/60 mmHg and a heart rate of 76 beats per minute. EKG showed slight widening of QRS complexes and flat P waves. She was afebrile and respirations were 18 per minute. The remainder of the physical exam was unremarkable. The patient’s laboratory workup showed normal GFR, Renin and Aldosterone levels, along with normal urine calcium, and the absence of renal stones. Trans-tubular potassium gradient (TTKG) was 3. The patient was immediately started on standard hyperkalemic protocol for management of severe hyperkalemia. She was observed in the hospital setting for 24 hours. She was followed up in our office, and serum potassium levels were found to be 5.3 mEq/L. By that time, patient was already on low sodium diet as initiated by the cardiologist. A trial of hydrochlorothiazide (HCTZ) and low potassium diet was started by our team. Despite the start of our low-potassium diet protocol, the patient’s serum potassium stayed between 5.1 mEq/L and 5.3 mEq/L. HCTZ and low potassium diet for eight weeks was unsuccessful in lowering potassium to below 5.0 mEq/L. Diagnosed with PHA-M/Mehandru syndrome and unable to adhere to low potassium diet, patient was introduced to our PHA-M/Mehandru Protocol II, and three weeks later, patient’s serum potassium normalized to 4.1 mEq/L. Upon completing our protocol, patient’s potassium has remained in the normal range (below 5.0 mEq/L), without any further pharmaceutical intervention, by solely adhering to a low potassium diet.
Case 2
A 68-year-old Caucasian female was admitted to the hospital for hip fracture and was found to have serum potassium levels of 5.5 mEq/L. Laboratory data from her previous admissions showed elevated potassium levels of over 5.3 mEq/L for the past year, and CO2 was noted at 25. On examination, the patient was awake and alert, oriented × 3 with a blood pressure of 136/64 mmHg, and a heart rate of 82 beats per minute. She was afebrile and respirations were 18 per minute. The rest of the physical exam was unremarkable. Patient’s laboratory workup showed normal GFR, normal Renin and Aldosterone levels, along with normal urine calcium, and the absence of renal stones. Trans-tubular potassium gradient (TTKG) was 3. Patient was already on low sodium diet. Upon seeing no improvement after two months of a low-potassium diet and Hydrochlorothiazide (HCTZ), we initiated our PHA-M/Mehandru Protocol II. Three weeks after initiating the protocol, serum potassium normalized at 4.6 mEq/L. All follow up laboratory results have shown well-controlled serum potassium levels by solely adhering to low potassium diet after initial therapy with Patiromer.
Case 3
A 64-year-old Caucasian male presented to our office with hyperkalemia, serum potassium of 5.8 mEq/L, metabolic acidosis with CO2 15 mEq/L, and mild hypertension with a blood pressure of 138/86. On examination, the patient was awake and alert, oriented × 3 with heart rate of 76 beats per minute. He was afebrile and respirations were 17 per minute, and the rest of the physical exam was unremarkable. Laboratory workup showed normal GFR, Renin and Aldosterone levels, along with normal urine calcium, and absence of renal stones. Trans-tubular potassium gradient (TTKG) was 4. Patient was extensively counseled and initiated on a low-potassium diet. Despite his compliance with our lowpotassium dietary protocol, potassium remained over 5.1mEq/L after 8 weeks. We proceeded to initiate the PHA-M/Mehandru Protocol II, resulting in the normalization of the patient’s serum potassium at 4.5 mEq/L. Since the completion of our protocol, the patient has adhered to a low potassium diet and has successfully maintained serum potassium levels below 5.1 mEq/L.
The body of a typical 70-kg man contains about 3,500 mmol of potassium, 98% of which is in the intracellular space; the remaining 2% is in the extracellular space [6]. This large intracellular-to-extracellular gradient determines the cell voltage and explains why disorders in plasma potassium give rise to manifestations in excitable tissues such as the heart and the nervous system [6]. Hyperkalemia is the single most lethal electrolyte disruption with a narrow therapeutic index. According to Cleveland Clinic, a typical potassium level for an adult falls between 3.5 and 5.0 millimoles per liter (mmol/L). Hyperkalemia is defined as serum potassium levels exceeding 5.1 mEq/L; the disorder may be fatal when potassium level exceed 6.5 mEq/L (1) (Table 2).
Symptoms of high or low potassium levels do not always appear until it is sometimes too late. Changes in EKG and cardiac arrest are most commonly seen in hyperkalemic patients. The lack of an appropriate diagnosis, especially in the absence of kidney disease, makes treatment choices even harder. Most of the studies in literature focus on patients with hyperkalemia that have renal insufficiency or other concomitant diseases such as heart failure or diabetes mellitus, isolated hyperkalemia has not been described. It is also reported that decreased mineralocorticoid levels or activity due to disturbances in renin-angiotensinaldosterone system will impair renal potassium secretion [6]. Such disturbances can be the result of disease process or drugs (Figure 1) [6].
Normal kidney can secrete a large amount of potassium, making hyperkalemia uncommon in the absence of kidney disease. This large capacity may have evolved to handle the diet of Paleolithic humans, which contained 4 times as much potassium as contemporary diets [9-11]. With the onset of agriculture, dietary intake of potassium has progressively declined with an increase in sodium intake. A popular theory suggests this mismatch between the modern diet and the nutritional requirements encoded in the human genome during evolution may contribute to chronic diseases such as hypertension, stroke, kidney stones, and bone disease [12].
Mehandru Syndrome is a presumed sporadic genetic abnormality that causes electrolyte imbalance, mainly hyperkalemia without kidney disease, and is characterized by renal tubular unresponsiveness to the action of aldosterone. In all cases, patients presented with hyperkalemia, normal renin and aldosterone levels, normal to slightly-elevated blood pressure, demonstrated metabolic acidosis. None of the patients with Mehandru syndrome were on NSAIDs, ACE-I, ARBs, potassium supplements, potassium-sparing diuretics, or beta blockers. Additionally, there was no evidence of diabetes mellitus. In all cases, hyperkalemia did not respond to diuretic therapy Laboratory parameter Case 1 Case 2 Case 3 Serum Na (mEq/L) 141 140 139 K (mEq/L) 5.3 (4 weeks) 5.1 (8 weeks) 5.4 (4 weeks) 5.2 (8 weeks) 5.3 (4 weeks) 5.2 (8 weeks) K post Patiromer Therapy 4.1 (11 weeks) 4.6 (11 weeks) 4.5 (11 Weeks) Ca (mEq/L) 9.6 9.0 9.2 Urea (mg/dl) 13 18 18 Cr (mg/dl 0.98 0.72 0.79 GFR (ml/min) 64 60 70 Glucose (mg/dl) 94 96 98 Bicarb (mg/dl) 26 26 27 TTKG 3 3 4 Plasma Aldosterone 12 ng/dl 9 ng/dl 8 ng/dl Plasma Renin 1.9 ng/ml/h 1.7 ng/ml/h 2.1 ng/ml/h Urine calcium 240 mg/day 260 mg/day 160 mg/day Table 4: Laboratory parameters of patients after low potassium diet or a restricted sodium diet. In contrast, patients with Gordon Syndrome typically respond well to either salt restriction or low dose thiazide diuretics in normalizing hypertension and electrolyte disturbance. In patients with Gordon syndrome, low renin and aldosterone levels were reversed by salt-restriction [8] and/or HCTZ. All our current patients, up to this point, except the three reported cases responded optimally to dietary potassium restriction. in the three reported cases responded optimally to dietary potassium restriction.
The cases presented herein, did not respond to potassium restricted diet, and serum potassium continuously remained above 5.0 mEq/L. Thus, the patients required Veltassa (Patiromer) per our established protocol, leading to the successful lowering of serum potassium levels. Patiromer for oral suspension is a non-absorbed, sodium-free potassium binding polymer that exchanges calcium for potassium in the gastrointestinal (GI) tract, thereby increasing faecal potassium excretion and reducing serum potassium levels [13,14]. Plasma renin and aldosterone levels in all these patients were normal. Urine sodium and urine calcium levels were normal, and TTKG was 3 for the two of the three patients, third ones’ TTKG was 4. Patients diagnosed with Mehandru syndrome had no history of renal stones. Potassium exchange for calcium increases the calcium load in circulation, possibly leading to hypercalcemia. This was not noted in any of our patients. Hypocalcemia or hypomagnesemia were also absent in our patients during the course of therapy. Patiromer maintains normokalaemia successfully in patients without renal insufficiency. While hyperkalemia has been extensively reported in patients with renal disease, there is scarce research and data on the management of high potassium in patients in the absence of kidney disease. Overall, the diagnosis of PHA-M/Mehandru syndrome and subsequent employment of our therapy protocol has been successful in our patients without any adverse effects (Table 3 and 4).
Table 2: Major causes of hyperkalemia [9]
Table 3: Laboratory parameters of patients before low potassium diet
Table 4: Laboratory parameters of patients after low potassium diet