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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT  
Year : 2020  |  Volume : 31  |  Issue : 5  |  Page : 1134-1139
Metabolic Acidosis, Hyperkalemia, and Renal Unresponsiveness to Aldosterone Syndrome: Response to Treatment with Low-Potassium Diet


1 Department of Medicine, Division of Nephrology, Jersey Shore University Medical Center, Hackensack-Meridian School of Medicine at Seton Hall University, Neptune, New Jersey, USA
2 Department of Nephrology and Hypertension, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA

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Date of Web Publication21-Nov-2020
 

   Abstract 


Gordon syndrome involves hyperkalemia, acidosis, and severe hypertension (HTN) with hypercalciuria, low renin and aldosterone levels. It is commonly observed in children and adolescents. Such patients respond successfully to sodium restriction and thiazide diuretics. In this article, we present three cases of metabolic acidosis, hyperkalemia, and renal unresponsiveness to aldosterone (MeHandRU Syndrome). All three patients did not have HTN or hypercalciuria and demonstrated normal renin and aldosterone levels. These patients did not respond to thiazide-type diuretic therapy and salt restriction. Two males (aged 55- and 62-year) and a female patient (aged 68-year) presented to the clinic with unexplained hyperkalemia (5.9 mEq/L, 5.9 mEq/L and 6.2 mEq/L, respectively). On physical examination, blood pressure (BP) was found to be normal (<140/90 mm Hg). Over the counter potassium supplement, nonsteroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, potassium sparing diuretic use, as well as hyporeninemic hypoaldosteronism states such as diabetes mellitus were excluded. Plasma renin and aldosterone levels were normal. All three patients had low transtubular potassium gradient, despite high serum potassium levels. None of the patients reported a family history of hyperkalemia or kidney failure. All failed to demonstrate a response to hydrochlorothiazide and salt restriction. After careful consideration, strict low potassium diet (<2 g/day) was initiated in consultation with the dietician. Diuretic therapy was discontinued while BP remained within normal range (<140/90 mm Hg). At eight weeks, all three patients demonstrated normalization of potassium and correction of acidosis. At follow-up of six months, all patients are maintaining a normal potassium level. We suggest that potassium restriction can be successful in patients presenting with MeHandRU syndrome.

How to cite this article:
Mehandru SK, Haroon A, Masud A, Shah J, Kaur S, Masud A, Hossain A, Asif A, Vachharajani TJ. Metabolic Acidosis, Hyperkalemia, and Renal Unresponsiveness to Aldosterone Syndrome: Response to Treatment with Low-Potassium Diet. Saudi J Kidney Dis Transpl 2020;31:1134-9

How to cite this URL:
Mehandru SK, Haroon A, Masud A, Shah J, Kaur S, Masud A, Hossain A, Asif A, Vachharajani TJ. Metabolic Acidosis, Hyperkalemia, and Renal Unresponsiveness to Aldosterone Syndrome: Response to Treatment with Low-Potassium Diet. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Dec 2];31:1134-9. Available from: https://www.sjkdt.org/text.asp?2020/31/5/1134/301183



   Introduction Top


Gordon syndrome is an autosomal dominant disease that usually presents in children and adolescents.[1] Classical presentation of Gordon syndrome includes hyperkalemia, severe hypertension (HTN), metabolic acidosis, low renin and aldosterone levels in the presence of normal renal function.[1] The treatment of Gordon syndrome has conventionally included aggressive salt restriction and low-dose thiazide diuretics.[1],[2] In this article, we report three cases of Metabolic Acidosis, Hyperkalemia and Renal Unresponsiveness to aldosterone (MeHandRU) syndrome that did not have HTN or hypercalciuria and did not respond to salt restriction and thiazide type diuretic therapy. Herein, we also report successful management of these cases with low-potassium diet.


   Case Reports Top


Case 1

A 55-year-old Caucasian male with no past medical history was referred to the clinic for workup of isolated hyperkalemia with serum potassium level of 5.9 mEq/L (range 5.5–5.9) mEq/L in the past year's available laboratories. No electrocardiogram (EKG) changes were reported. Laboratory data showed serum sodium level of 141 mEq/L and CO2 of 18 mEq/L. He was reported to have hyperkalemia for the past several years with no history of potassium supplement intake or renal disease. The patient had no history of non-steroidal anti-inflammatory drug overdose, diabetes mellitus (DM), or hypoaldosteronism. He denied having polyuria, oliguria, hematuria, weakness, palpitation, headache, or dizziness. There was no family history of HTN, DM, hyperkalemia, or kidney disease. On examination, the patient was awake and alert, oriented ×3 with a blood pressure (BP) of 120/79 mm Hg and a heart rate of 80 beats/min. There was no peripheral or periorbital edema, abdominal tenderness, or swelling. Workup for hyperkalemia displayed low potassium excretion in the presence of markedly elevated serum potassium levels (5.9 mEq/L) [Table 1]. Transtubular potassium gradient (TTKG) was at 3. Plasma renin and aldosterone were normal. A diagnosis of MeHandRU syndrome was made based on patient's hyperkalemia, low potassium excretion, normal aldosterone and, normal glomerular filtration rate (GFR >60 mL/min). The patient was started on hydrochlorothiazide and low sodium diet by primary care provider without any improvement in serum potassium levels. During consultation with the nephrologist, patient's BP was 120/79 mm Hg (compared to 132/84 when hydrochlorothiazide 25 mg/day was initiated by the primary care) and patient complained of increased urinary frequency since the initiation of diuretic therapy and episodes of dizziness on standing. No orthostatic changes were present at the time of examination. The patient was started on a low potassium diet (<2 g/day) and diuretic therapy was discontinued. Four-and eight-week follow-up showed reductions in serum potassium level at 5.3 mEq/L and 4.6 mEq/L, respectively [Table 2], and CO2 of 26 [Table 2]. BP had been in the range of 130–135/78–86 mm Hg with no dizziness or urinary frequency.
Table 1: Laboratory parameters of patients before low potassium diet.

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Table 2: Laboratory parameters of patients after low-potassium diet.

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Case 2

A 62-year-old Caucasian male was referred to the clinic for workup of hyperkalemia with serum potassium level of 5.9 mEq/L (range 5.6–6.0 mEq/L in the past year's available labs). No EKG changes were reported. Laboratory data also showed serum sodium level of 140 mEq/L and CO2 of 21 mEq/L; TTKG was 3. There were no reports of polyuria, oliguria, hematuria, weakness, palpitation, headache, or dizziness. Patient's past medical history included coronary artery disease and hypercholesterolemia. There was no report of family history of HTN, DM, hyperkalemia or kidney failure. On examination, the patient was awake, alert, and oriented ×3 with a BP of 124/76 mm Hg and a heart rate of 75 beats/min. There was no peripheral or periorbital edema, abdominal tenderness or swelling. A diagnosis of MeHandRU syndrome was made based on hyperkalemia, low potassium excretion, normal aldosterone, normal GFR (60 mL/min), and no history of NSAID use, DM, or hypoaldosteronism. Calcium excretion was normal. The patient was already on a sodium-restricted diet with no improvement in serum potassium levels. Hydrochlorothiazide (25 mg/ day) and low-sodium diet had been a part of patient's medication regimen for a while without any improvement in serum potassium levels. Importantly, patient's BP prior to diuretic therapy had been in the range of 118–128/70–78 mm Hg. He was started on a low potassium diet (<2 g/day). At follow-up of four and eight weeks, serum potassium level was found to be 5.4 mEq/L and 4.1 mEq/L, respectively [Table 2]. Following a low potassium diet, serum sodium level of 138 mEq/L and CO2 of 26 was also noted [Table 2]. BP was found to be 132/88 mm Hg.

Case 3

A 68-year-old otherwise healthy Caucasian female was referred from primary care clinic to nephrology for workup of hyperkalemia with serum potassium level of 6.2 mEq/L (range 5.8–6.0 mEq/L in the past six month available labs). TTKG was 4. No EKG changes were reported. Along with hyperkalemia, laboratory data also showed serum sodium level of 140 mEq/L and CO2 of 23 mEq/L. The patient did not report any polyuria, oliguria, hematuria, weakness, palpitation, headache or dizziness. There was no family history of HTN, DM, hyperkalemia, or kidney failure. On examination, the patient was awake, alert, and oriented × 3 with a BP of 138/60 mm Hg and a heart rate of 70 beats/min. There was no peripheral or periorbital edema, abdominal tenderness or swelling. Workup for hyper-kalemia displayed low potassium excretion in the presence of markedly elevated serum potassium levels of 6. 2 mEq/L 9 [Table 1]. There was no hypercalciuria. There was no history of NSAID use, over-the-counter supplements or DM. The patient was already on a sodium-restricted diet but no improvement in serum potassium level was noted. Her medication regimen included hydrochlorothiazide (25 mg/day). The diagnosis of MeHandRU syndrome was made. She was subsequently started on a low potassium diet (<2 g/day). Because of the normal BP prior to the initiation of hydrochlorothiazide and no improvement in hyperkalemia, diuretic therapy was discontinued. Four- and eight-week follow-up showed a serum potassium level of 4.2 mEq/L and 4.1 mEq/L, respectively [Table 2]. Following a low potassium diet, serum sodium level of 141 mEq/L and CO2 of 27 was also noted [Table 2].


   Discussion Top


Gordon syndrome is a genetic electrolyte abnormality, characterized by renal tubular unresponsiveness or resistance to the action of aldosterone.[1],[3] The molecular basis for most individuals with Gordon syndrome has been linked to the loss-of-function mutations in WNK1 and WNK4 or KLHL3 and CUL3 mutations.[4],[5],[6],[7],[8] It presents with severe HTN, hyperkalemia, and metabolic acidosis in the setting of low renin and low aldosterone.[1],[3],[9] Gordon syndrome responds well to sodium restriction and hydrochlorothiazide therapy. The three cases featured here presented with hyperkalemia (without an obvious etiology) with normal renin and aldosterone levels. However, they did not have HTN and demonstrated only mild acidosis (20–23 mEq/L). None of the patients were on nonsteroidal anti-inflammatory drugs, angiotensin-convertingenzyme inhibitors, potassium sparing diuretics or beta-blockers. There was no evidence of diabetes. Hyperkalemia did not respond to diuretic therapy or sodium restriction. All responded well to potassium restriction diet in consultation with renal dietician with normalization of serum potassium. All discontinued their diuretic therapy due to the lack of an indication and in at least one patient due to the presence of dizziness (perhaps brought on by volume depletion).

Why might one observe normalization of acidosis (albeit mild acidosis) with low potassium diet? We postulate that reduction in serum potassium due to low potassium diet might have pushed hydrogen back into the cells resulting in correction of acidosis. Indeed, our patient number 3 demonstrated the highest increase in serum bicarbonate to 27 mEq/L with potassium reduction to 4.1 mEq/L. That said, we acknowledge that the exact mechanism of serum bicarbonate increase observed in our cases is not known. It is important to mention that TTKG remained essentially unchanged after low potassium diet at 3, 3, and 4 for case number 1, 2, and 3, respectively. At 6-month follow-up visit all patients are maintaining normal potassium levels.

There are some differences between Gordon syndrome and our cohort [Table 3]. Gordon syndrome typically presents with severe HTN. In contrast, our patients had normal BP. The diuretic therapy did cause a reduction of BP in all three patients, however, none of our patients met the indication for diuretic therapy once hyperkalemia did not improve with hydrochlorothiazide. Diuretic therapy brings on its own complications particularly in the elderly placing them at a particular risk for falls. At least, one patient complained of dizziness that disappeared after the discontinuation of hydrochlorothiazide. Gordon syndrome is also associated with hypercalciuria and renal stones.[7] This finding was not observed in our patients. In fact, calcium excretion was found to be normal in all of our patients. Finally, augmented sodium reabsorption in the distal tubule of the kidney has been linked to the development of HTN, which explains the low renin and aldosterone due to slight volume expansion.[5] However, our patients did not have HTN and had normal renin and aldosterone levels.
Table 3: Typical features of Gordon and Metabolic acidosis, Hyperkalemia and Renal Unresponsiveness syndromes.

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   Conclusion Top


We present three cases of MeHandRU syndrome with metabolic acidosis, hyperkalemia, normotensive, normal calcium excretion and normal renin and aldosterone levels. These patients did not respond to hydrochlorothiazide therapy and sodium restriction. Instead, management with low potassium diet resulted in normalization of serum potassium and correction of acidosis. We propose that MeHandRU syndrome be considered in the differential diagnosis of patients presenting with unexplained hyperkalemia and acidosis. Our cases have unusual clinical characteristics and as yet undefined genetic abnormalities. Further genetic mutations need to be defined to understand the changes at molecular level.


   Declaration of Patient Consent Top


The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflict of interest: None declared.



 
   References Top

1.
Gordon RD, Geddes RA, Pawsey CG, O’Halloran MW. Hypertension and severe hyperkalaemia associated with suppression of renin and aldos-terone and completely reversed by dietary sodium restriction. Australas Ann Med 1970;19:287-94.  Back to cited text no. 1
    
2.
Mayan H, Vered I, Mouallem M, Tzadok- Witkon M, Pauzner R, Farfel Z. Pseudohypoaldosteronism type II: Marked sensitivity to thiazides, hyper-calciuria, normomagnesemia, and low bone mineral density. J Clin Endocrinol Metab 2002;87: 3248-54.  Back to cited text no. 2
    
3.
Achard JM, Disse-Nicodeme S, Fiquet-Kempf B, Jeunemaitre X. Phenotypic and genetic hetero-geneity of familial hyperkalaemic hypertension (Gordon syndrome). Clin Exp Pharmacol Physiol 2001;28:1048-52.  Back to cited text no. 3
    
4.
Armanini D, Kuhnle U, Strasser T, et al. Aldosterone-receptor deficiency in pseudohypoaldosteronism. N Engl J Med 1985;313: 1178-81.  Back to cited text no. 4
    
5.
Louis-Dit-Picard H, Barc J, Trujillano D, et al. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat Genet 2012;44:456-60, S1- 3.  Back to cited text no. 5
    
6.
Ohta A, Schumacher FR, Mehellou Y, et al. The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: Disease-causing mutations in KLHL3 and WNK4 disrupt interaction. Biochem J 2013;451:111- 22.  Back to cited text no. 6
    
7.
Stratton JD, McNicholas TA, Farrington K. Recurrent calcium stones in Gordons syndrome. BJU Int 1998;82:925-25.  Back to cited text no. 7
    
8.
Tsuji S, Yamashita M, Unishi G, et al. A young child with pseudohypoaldosteronism type II by a mutation of Cullin 3. BMC Nephrol 2013;14:166.  Back to cited text no. 8
    
9.
O’Shaughnessy KM. Gordon Syndrome: A continuing story. Pediatr Nephrol 2015;30: 1903-8.  Back to cited text no. 9
    

Top
Correspondence Address:
Sushil K Mehandru
Department of Medicine, Division of Nephrology, Jersey Shore University Medical Center, Hackensack-Meridian School of Medicine at Seton Hall University, Neptune, New Jersey
USA
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DOI: 10.4103/1319-2442.301183

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