CASE REPORT | RELATO DE CASO Diabetes mellitus and hyperkalemic renal tubular acidosis: case reports and literature review Diabetes mellitus e acidose tubular renal hipercalêmica: relatos de caso e revisão da literatura Authors ABSTRACT RESUMO Carlos Henrique Pires Ratto Tavares Bello 1 Hyporeninemic hypoaldosteronism, de- Apesar de comum, o hipoaldosteronismo hi- João Sequeira Duarte 1 spite being common, remains an underdi- poreninêmico continua a ser uma entidade Carlos Vasconcelos 1 agnosed entity that is more prevalent in sub-diagnosticada, com maior prevalência patients with diabetes mellitus. It presents em pacientes com diabetes mellitus. A do- with asymptomatic hyperkalemia along ença cursa com hipercalemia assintomática 1 Hospital de Egas Moniz, with hyperchloraemic metabolic acidosis acompanhada de acidose metabólica hiper- Centro Hospitalar de Lisboa without significant renal function impair- clorêmica sem disfunção renal significativa. Ocidental, Lisboa, Portugal. ment. The underlying pathophysiological O mecanismo fisiopatológico subjacente mechanism is not fully understood, but não é entendido em sua totalidade, mas it is postulated that either aldosterone postula-se que a deficiência de aldosterona deficiency (hyporeninemic hypoaldoste- (hipoaldosteronismo hiporeninêmico) e/ou ronism) and/or target organ aldosterone a resistência à aldosterona no órgão-alvo resistance (pseudohypoaldosteronism) (pseudo-hipoaldosteronismo) possam ser may be responsible. Diagnosis is based on responsáveis. O diagnóstico é fundamentado laboratory parameters. Treatment strat- em parâmetros laboratoriais. A estratégia te- egy varies according to the underlying rapêutica varia de acordo com o mecanismo pathophysiological mechanism and etiol- fisiopatológico subjacente e a etiologia, mas ogy and aims to normalize serum potas- seu objetivo é normalizar o potássio sérico. sium. Two clínical cases are reported and O presente artigo relata dois casos e analisa the relevant literature is revisited. a literatura relevante sobre o assunto. Keywords: acidosis; acidosis, renal tubu- Palavras-chave: acidose; acidose tubular lar; diabetes mellitus; hyperkalemia; hy- renal; diabetes mellitus; hiperpotassemia; poaldosteronism. hipoaldosteronismo. INTRODUCTION • Type 1 RTA (distal RTA) - impaired distal hydrogen ion secretion. Renal tubular acidosis (RTA) comprises • Type 2 RTA (proximal RTA) - im- relatively frequent forms of hyperchlo- paired proximal reabsorption of remic metabolic acidosis. This medical filtered bicarbonate. condition is underdiagnosed and poorly • Hyperkalemic RTA - aldosterone understood due to the complexity of the deficiency or resistance (Type 4 involved pathophysiological mechanisms. RTA or hypoaldosteronism); or It is characterized by the occurrence of impaired distal sodium reabsorp- hyperchloremic metabolic acidosis, fluid tion (voltage-dependent distal and electrolyte balance disorders (involv- Submitted on: 01/18/2017. RTA). Approved on: 03/20/2017. ing potassium in particular), and absence of significant renal impairment. The glo- In RTA, impaired hydrogen ion secre- merular filtration rate (GFR) of affected Correspondence to: tion and/or bicarbonate reabsorption at a Carlos Henrique Pires Ratto individuals is relatively preserved, while Tavares Bello. tubular level are the bases for the onset of E-mail: bello.carlos04@gmail. tubular impairment is the main element acidosis.1 Potassium serum levels vary de- com responsible for the observed alterations. pending on the subtype of RTA, but high DOI: 10.5935/0101-2800.20170086 Renal tubular acidosis is divided into potassium levels are observed only in hy- three forms of involvement: perkalemic (or Type 4) RTA. 481 Diabetes Mellitus and renal tubular acidosis Though relatively common, hyperkalemic RTA is potassium gradient (TTKG) was decreased - 3.93. an underdiagnosed condition. It has been estimated Renin levels were within reference values (renin = 2.4 to affect 3.8% of hospitalized individuals with hyper- uU/mL, reference values (RV) 1.1-16.5; and aldoste- kalemia.2 The clinical manifestations of the disease rone = 6.9 ng/dL, RV 1-16). An electrocardiogram are mild, and usually revolve around various degrees did not reveal de novo relevant alterations and, given of hyperkalemia and hyperchloremic metabolic aci- that he was clinically stable and probably had hypoal- dosis without significant glomerular filtration rate dosteronism, treatment with calcium polystyrene sul- drops. Hyperkalemia secondary to renal involve- fonate twice a day, oral fluids, furosemide 40mg/day, ment requires a GRF below 15mL/min/1.73m2.3 and low-potassium diet was initiated. Hyperkalemia and metabolic acidosis are usually The patient was assessed a week later after having mild (potassium < 6.5mmol/L and bicarbonate > significantly improved his workup - K+ = 5.8mmol/L 17mmol/L), although exacerbation may occur in the - and HCO3 = 20mmol/L. Two years after the initial event of acute kidney injury and/or undesired drug in- assessment the patient was taking an ion exchange teractions.2 The consequences of Type-4 RTA beyond resin twice a day and furosemide 40 mg/day; his po- the electrophysiological risks introduced by hyperka- tassium levels were under control (K+ = 5.6mmol/L lemia are largely unknown. and creatinine = 1.6mg/dL), but the TTKG was still Hypoaldosteronism and distal tubular volt- altered. age defects have been described as the pathophysi- ological mechanisms causing hyperkalemic RTA.3,4 CASE 2 Hypoaldosteronism may stem from decreases in the A 56-year-old male patient diagnosed with DM type stimulus to release aldosterone (hyporeninemic hy- 2 for six years had stage 3aA3 CKD (estimated GFR poaldosteronism), reduced aldosterone synthesis and = 47mL/min/1.73m2, albuminuria = 3300mg/g), high secretion (heparin, congenital adrenal hyperplasia blood pressure, dyslipidemia, a toxic thyroid adeno- or hypoplasia, adrenoleukodystrophy) and/or al- ma, and peripheral artery disease. He was initially dosterone resistance in the target organ (pseudohy- taking insulin glargine once a day (20 units bedtime), poaldosteronism).5 Several studies enrolling diabetic pentoxifylline, clopidogrel, and perindopril. individuals showed they had lower-than-expected al- He was referred to an endocrinologist on ac- dosterone and renin levels, particularly in subgroups count of having primary hyperthyroidism. Workup with diabetic nephropathy and neuropathy. findings indicated the patient had hyperkalemia (K+ 6.1mmol/L), a creatinine level of 1.8mg/dL (GFR = 42; CLINICAL CASES usually 47mL/min/1.73m2); the blood gas test showed CASE 1 a pH of 7.35; paO2 = 90mmHg; paCO2 = 42mmHg; HCO - = 23.2mmol/L; base deficit 2.6; anion gap = A 58-year-old male patient diagnosed with type 2 3 DM for three years had high blood pressure, dys- 10. Perindopril was discontinued and a week later the lipidemia, coronary artery disease (underwent an- patient came in for additional tests, which revealed + gioplasty and bypass surgery), stage 3bA2 chronic he still had hyperkalemia (K 6.21mmol/L), urine pH kidney disease (CKD) (estimated GFR of 40mL/min = 5.5, TTKG = 0.5 and renin and aldosterone levels and occasional albuminuria of 160mg/g), and periph- within the reference range (renin = 2.8 uU/mL, RV = eral artery disease. The patient was taking linagliptin, 1.1-16; aldosterone = 2.2 ng/dL, RV 1-16). isosorbide mononitrate, bisoprolol, acetylsalicylic The therapeutic strategy then prescribed to the pa- acid, allopurinol, and rosuvastatin. He was referred tient included a low potassium diet, chlorthalidone, to an endocrinologist on account of having DM type and calcium polystyrene sulfonate until his workup 2 and CKD. His blood pressure was 136/90 mmHg was normalized. The ACE inhibitor was not reintro- and he was euvolemic, without signs of peripheral duced. Eighteen months after the initial assessment edema. His workup showed HbA1c at 6.8%, creati- the patient had his potassium serum level under con- + nine at 1.8mg/dL (estimated GFR by the CKD-EPI of trol (K 4.73mmol/L) and stable renal function (GFR 2 41mL/min/1.73m2), potassium at 6.5mmol/L, and a 50mL/min/1.73m ). urine pH of 5.5. The arterial blood gas test revealed - DISCUSSION that he had metabolic acidosis - pH 7.36; HCO3 = 18mmol/L; base deficit = 7.2; paCO2 = 32mmHg; paO2 Hyporeninemic hypoaldosteronism (HH) is the most = 100mmHg; and anion gap = 9). His transtubular frequent cause of hyperkalemic RTA.6 It typically Braz. J. Nephrol. (J. Bras. Nefrol.) 2017;39(4):481-485 482 Diabetes Mellitus and renal tubular acidosis appears on the sixth or seventh decade of life and is • Aldosterone deficiency: early normalization (2- more prevalent in females.7 Most patients have dia- 4h) of the TTKG after physiological doses of betes mellitus and mild to moderate involvement of fludrocortisone (0.1mg/day). the glomerular filtration rate - 30-90mL/min/1.73m2). • Aldosterone resistance: late normalization (> HH occurs in conjunction with asymptomatic chron- 24h) of the TTKG after supraphysiological ic hyperkalemia, and with hyperchloremic metabolic doses of fludrocortisone (> 0.1mg/day). acidosis in about 50% of the cases.2 Renin deficit and primary adrenal disorders related to the synthesis of Some authors claimed that the TTKG formula is aldosterone lie on the basis of the workup alterations. based on incorrect assumptions and challenged its va- Hyperkalemia is the finding responsible for generat- lidity. Therefore, additional measures must be taken ing and sustaining metabolic