sign in sign up
<<
Home , Albuminuria, Anion gap, Arterial blood gas test, Hypervolemia, Renal tubular acidosis, Urine anion gap

Case Report | Relato de Caso

Diabetes mellitus and hyperkalemic renal tubular : case reports and literature review mellitus e acidose tubular renal hipercalêmica: relatos de caso e revisão da literatura

Authors Abstract Resumo Carlos Henrique Pires Ratto Tavares Bello 1 Hyporeninemic , 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 along ença cursa com hipercalemia assintomática 1 Hospital de Egas Moniz, with hyperchloraemic 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 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 () (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 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 secretion. (RTA) comprises • Type 2 RTA (proximal RTA) - im- relatively frequent forms of hyperchlo- paired proximal of remic metabolic acidosis. This medical filtered . 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 reabsorp- hyperchloremic metabolic acidosis, fluid tion (voltage-dependent distal and balance disorders (involv- Submitted on: 01/18/2017. RTA). Approved on: 03/20/2017. ing in particular), and absence of significant renal impairment. The glo- In RTA, impaired hydrogen ion secre- merular 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 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 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 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 = 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, = 3300mg/g), high secretion (heparin, congenital adrenal hyperplasia 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 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 showed

Case 1 a pH of 7.35; paO2 = 90mmHg; paCO2 = 42mmHg; HCO - = 23.2mmol/L; base deficit 2.6; = 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), pH (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 (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- , 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 . 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 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 acidosis. to investigate cases of hyperkalemia.7 The mechanisms associated with renin depression Since hyperkalemic RTA occurs in conjunction include (directly precluding the release of with impaired renal ammoniagenesis, indirect mark- renin); diabetic autonomic neuropathy (inhibiting the ers of renal ammonia excretion were developed: urine conversion of prorenin into renin, reducing adrenergic anion gap (UAG) and urine osmolal gap (UOG) response to postural changes, and inducing beta-adren- (Table 1). ergic receptor desensitization, thus affecting juxtaglo- In patients without functional tubular disorders, merular apparatus function); deficiency acidosis usually decreases the UAG and increases the (namely prostacyclin, whose deficiency leads to reduced UOG. However, these formulas have their limitations. renin secretion and decreased conversion of prorenin The calculation of the UAG is based on the principle into renin). Metabolic acidosis stems from impaired am- that the ammonia secreted via the kidneys is bound moniagenesis and is partly mediated by hyperkalemia.5 to chlorine. Increases in urine ammonia levels are fol- The diagnosis is based on the confirmation of hy- lowed by increases in urine chlorine levels, and conse- perkalemia (K+ greater than 5.2mmol/L) accompa- quently decreases in the UAG. The UAG is, therefore, nied by hyperchloremic metabolic acidosis (pH typi- a surrogate marker of urine ammonia. cally normal, bicarbonate at 17-20mmol/L, and anion However, the UAG is not very reliable in the pres- gap < 12mmol/L) in the absence of significant renal ence of urine Na+ levels below 25mmol/L (frequently function impairment (GFR > 30mL/min/1.73m2) or seen in cases of prerenal ), in- drugs that may induce hyperkalemia (non-steroid an- creased excretion of non-measured anions (ketoaci- ti-inflammatory drugs, renin-angiotensin-aldosterone dosis, bicarbonate , D-lactacidemia, poisoning system inhibitors, calcineurin inhibitors or potassium by toluene or paracetamol), and during the neonatal supplements). Urine pH is typically lower than 5.5, period (a stage in which non-measured anions are ex- reflecting the preservation of distal acidification ca- creted in large quantities).9 pacity shown when the of urine buffer In these situations, the UOG might be more reli- (NH4+) for excreted acid valences is decreased. able. The UOG is based on the fact that ammonia is The impact of hypoaldosteronism (absolute and/ an element in the anions not considered in the calcula- or relative) at a tubular level may be assessed indi- tion of . In the presence of metabolic rectly through the transtubular potassium gradient acidosis, urine ammonia increases as part of a com- (TTKG). The TTKG reflects the distal tubular potas- pensatory mechanism, thus increasing the UOG. The sium secretion ability (in the collecting duct)5 and is limitations of the UOG include situations in which calculated as follows: there is overexcretion of anions not bound to ammo- TTKG = (Urine Potassium x Serum Osmolality) nia (alcohols and ) and urinary tract infec- (Serum Potassium x Urine Osmolality) tions (by bacteria producing urease, which catalyzes + 9 the formation of NH4 ). In the presence of hyperkalemia, the TTKG is Additionally, renin and aldosterone levels are use- physiologically expected to reach values above 7, re- ful to differentiate the mechanism of the underlying flecting compensatory . In hyper- hypoaldosteronism (Table 2). kalemic RTA, the TTKG is lower than 7.6,8 TTKG The absence of aldosterone and renin nomograms ad- variations with therapy (for example, with fludrocor- justed for serum potassium limits the analytical apprecia- tisone) help differentiate between aldosterone defi- tion of these clinical scenarios, since the thresholds defin- ciency and resistance: ing what might be considered normal are unclear. Given

483 Braz. J. Nephrol. (J. Bras. Nefrol.) 2017;39(4):481-485 Diabetes Mellitus and renal tubular acidosis

Table 1 reference values (RV) for urine anion and urine osmolal gap in physiological situations without acidosis (column showing normal values), in clinical situations with metabolic acidosis without hyperkalemic RTA (column showing acidosis RV), and values expected for hyperkalemic RTA (column showing ATR ↑K+). uNa - urine sodium; UK - urine potassium; uCl - urine chlorine; uOsm urine osmolality Formula Normal values Acidosis RV ATR ↑ K+ (uNa+ + uK+) - (uCl-) 20-90mEq/L < 0mEq/L > 0mEq/L Measured uOsm - Urine osmolal gap 80-100mOsm/kg > 100mOsm/kg < 100mOsm/kg calculated uOsm

+ Table 2 typical workup changes in the subtypes In moderate de novo (K 6.5-7.4mmol/L) or severe of hyperkalemic RTA hyperkalemia (K+ ≥ 7.5mmol/L), patients are man- Renin Aldosterone aged in a level 2 unit to have electrocardiograms do- Hyporeninemic ne and undergo electrocardiographic follow-up and N/↓ N/↓ hypoaldosteronism more detailed tests (confirmation of hyperkalemia Isolated congenital through serum and urine ionograms and additional ↑ N/↓ hypoaldosteronism tests for renal function, , TSH, Pseudohypoaldosteronism ↑ ↑ serum and urine osmolality, and arterial blood gas. (aldosterone resistance) If needed, other tests for aldosterone, renin, cor- tisol, digoxin levels, (tumor lysis), CK, and Table 3 summary of workup findings typically seen in hyperkalemic renal tubular (rhabdomyolysis) should be carried out. acidosis. HH - hyporeninemic The treatment of more severe cases requires the cor- hypoaldosteronism; PHA - rection of the underlying cause of the disease, the Pseudohypoaldosteronism; GFR - stabilization of the myocardial membrane (calcium glomerular filtration rate; TTKG - gluconate) and the introduction of measures to de- transtubular potassium gradient; UAG crease potassium circulating levels by promoting the - urine anion gap; UOG - urine osmolal intracellular entry of K+ (insulin, dextrose solution, gap HH PHA bicarbonate (in the event of acidosis) and salbutamol) + K+ > 5.1mmol/L and/or K loss (ion-exchange resins, furosemide, and pH > 7.3 hemodialysis).10 + HCO3- 17-21 mmol/L In cases of mild hyperkalemia (K 5.2-6.5mmol/L) TFG 30-90 ml/min/1.73m2 without electrocardiographic repercussions, outpa- GTTK < 7 tient treatment with regular follow-up may be pro- HAU > 0 mEq/L posed. The choice of therapeutic strategy depends on HOU < 100 mOsm/L the underlying cause of the disease: Aldosterona N/↓ ↑ Renina ativa N/↓ ↑ Drug-induced hyperkalemia: suspend the drug, if possible. If the drug causing hyperkalemia is in- the lack of accurate dynamic data, with the exception of dispensable (cyclosporine in transplant patients, for the TTKG, the reference values for renin and aldosterone instance), ion-exchange resins (sodium/calcium poly- (ignoring the possible fact that they resided in the upper styrene sulfonate 1-3 times a day), (loop or or lower limit of normality and equally neglecting their thiazides), low-potassium diets may be used, and in variations with baseline values) are assumed to provide cases of extreme necessity, fludrocortisone.11 enough evidence for the differentiation between aldoste- Hyporeninemic hypoaldosteronism: although the rone deficiency and resistance as the cause of hyperkale- underlying cause is aldosterone deficiency, the treatment mia. Table 3 summarizes the workup findings related to does not consist necessarily of fludrocortisone. Since hyperkalemic renal tubular acidosis. affected patients often suffer with high blood pressure, Treatment options are limited and aim to normal- CKD, coronary artery disease (CAD), and ize potassium levels and acidosis. Different strategies (HF), the fluid overload induced by mineralocorticoids have been described depending on the severity of might be potentially deleterious and counterproduc- workup findings and underlying etiology: tive for these patients. To make matters worse, in these

Braz. J. Nephrol. (J. Bras. Nefrol.) 2017;39(4):481-485 484 Diabetes Mellitus and renal tubular acidosis situations treatment with renin-angiotensin-aldosterone hyperkalemia and hyperchloremic metabolic acidosis, system (RAAS) inhibitors (which improve the prognosis in the presence of relatively preserved renal function of patients with CKD, HF, and CAD) is often suspended (GFR) and no specific associated symptoms. Risk de- due to its hyperkalemic effects. Therefore, patients are rives principally from the order of magnitude of hy- not only exposed to neurohormonal stimuli that gener- perkalemia. It is more prevalent in individuals with ate, perpetuate, and aggravate the injuries to the target diabetes with mild to moderate renal impairment organ (activating the RAAS), but also to a “toxic” over- (CKD stages 2-3). Diagnosis is achieved with the load of aldosterone. Thus, treatment with fludrocorti- aid of transtubular potassium gradient (TTKG) and sone is typically reserved for cases refractory to serum aldosterone and renin levels. The purpose of therapy (loop or thiazides), low potassium diets, and treatment is to normalize potassium levels, and may ion-exchange resins. The dose of fludrocortisone need- include a low-potassium diet, fludrocortisone, ion-ex- ed is usually supraphysiological (0.2 to 1mg/day), and change resins, and even hemodialysis. Given the lack possibly reflects some degree of associated aldosterone of specific studies and the fact that this is an under- resistance.12 diagnosed condition, many questions still persist con- Aldosterone resistance: fludrocortisone therapy is cerning the long-term consequences (with or without recommended in doses of 0.2 to 1mg/day. An interest- therapy) and the ideal treatment for the disease. ing exception is Gordon’s Syndrome (pseudohypoal- dosteronism type 2), in which hyperkalemia stems References from WNK4 (with no lysine kinase 4) functional im- 1. Rodríguez Soriano J. Renal tubular acidosis: the clinical en- pairment or WNK1 functional gain. The described tity. J Am Soc Nephrol 2002;13:2160-70. DOI: http://dx.doi. org/10.1097/01.ASN.0000023430.92674.E5 + - alterations cause functional gains in the Na -Cl co- 2. Haas CS, Pohlenz I, Lindner U, Muck PM, Arand J, Suefke S, transporter in the decreasing et al. Renal tubular acidosis type IV in hyperkalaemic patients- - -a fairy tale or reality? Clin Endocrinol (Oxf) 2013;78:706-11. Cl in the distal , in addition to decreasing DOI: http://dx.doi.org/10.1111/j.1365-2265.2012.04446.x the supply of Na+ to the collecting duct, producing a 3. Karet FE. Mechanisms in hyperkalemic renal tubular acido- sis. J Am Soc Nephrol 2009;20:251-4. DOI: http://dx.doi. lower electric gradient in these segments of the neph- org/10.1681/ASN.2008020166 ron and, consequently, lower distal tubular secretion 4. Lehnhardt A, Kemper MJ. Pathogenesis, diagnosis and ma- of K+. Treatment includes the use of thiazides.12 nagement of hyperkalemia. Pediatr Nephrol 2011;26:377-84. DOI: http://dx.doi.org/10.1007/s00467-010-1699-3 The two case reports are typical accounts of hy- 5. Arai K, Chrousos GP. Aldosterone Deficiency and Resistance. poreninemic hypoaldosteronism. The patients had In: De Groot LJ, Chrousos G, Dungan K, eds. Endotext [Inter- net]. South Dartmouth: MDText.com, Inc.; 2000 [citado 2017 no clinical manifestations, and their workup showed Out 27]. Disponível em: https://www.ncbi.nlm.nih.gov/books/ mild to moderate hyperkalemia, moderate renal im- NBK279079/ 6. Choi MJ, Ziyadeh FN. The utility of the transtubular potas- pairment, and hyperchloremic metabolic acidosis. sium gradient in the evaluation of hyperkalemia. J Am Soc Differences were found in TTKG values, as numbers Nephrol 2008;19:424-6. DOI: http://dx.doi.org/10.1681/ closer to what should be expected in cases of hyper- ASN.2007091017 7. Kamel KS, Halperin ML. Intrarenal urea recycling leads to kalemia (> 7) were found in the first case, revealing a a higher rate of renal excretion of potassium: an hypothe- likely relationship with higher aldosterone levels. sis with clinical implications. Curr Opin Nephrol Hyper- tens 2011;20:547-54. DOI: http://dx.doi.org/10.1097/ However, in both cases aldosterone and renin levels MNH.0b013e328349b8f9 were unexpectedly normal in the presence of hyperkale- 8. West ML, Marsden PA, Richardson RM, Zettle RM, Halperin ML. New clinical approach to evaluate disorders of potassium mia and unable to sustain ion . Hypertension excretion. Miner Electrolyte Metab 1986;12:234-8. and the need to take multiple drugs to manage blood pres- 9. DeFronzo RA. Hyperkalemia and hyporeninemic hypoaldos- teronism. Kidney Int 1980;17:118-34. DOI: http://dx.doi. sure, the presence of diabetes mellitus type 2 and the ab- org/10.1038/ki.1980.14 sence of typical clinical signs make corticoadrenal insuf- 10. Kovesdy CP. Management of Hyperkalemia: An Update for ficiency an unlikely diagnostic possibility. Treatment with the Internist. Am J Med 2015;128:1281-7. DOI: 10.1016/j. amjmed.2015.05.040 DOI: http://dx.doi.org/10.1016/j.amj- diuretics and ion-exchange resins effectively controlled med.2015.05.040 hyperkalemia, thus allowing the resolution of metabolic 11. Sousa AG, Cabral JV, El-Feghaly WB, de Sousa LS, Nunes AB. Hyporeninemic hypoaldosteronism and diabetes mellitus: Pa- acidosis and the attainment of a state of workup stability. thophysiology assumptions, clinical aspects and implications for management. World J Diabetes 2016;7:101-11. DOI: http:// dx.doi.org/10.4239/wjd.v7.i5.101 onclusion C 12. Young WF Jr. Etiology, diagnosis, and treatment of hypoal- dosteronism (type 4 RTA). Uptodate [citado 2017 Out 27]. Hyporeninemic hypoaldosteronism is a frequent un- Disponível em: https://www.uptodate.com/contents/etiology- derdiagnosed medical condition. It manifests with -diagnosis-and-treatment-of-hypoaldosteronism-type-4-rta

485 Braz. J. Nephrol. (J. Bras. Nefrol.) 2017;39(4):481-485