• Open Access

A Case of Hyporeninemic Hypoaldosteronism in the Dog


  • The patient reported in this manuscript was seen at the Animal Medical Center, New York, NY. The manuscript has not been previously presented.

Corresponding author: J. J. Kreissler, DVM, Miami Veterinary Specialists, 8601 Sunset Drive, Miami, FL 33143; e-mail: jkreissler@mvshospital.com.


angiotensin-converting enzyme


alanine transferase


angiotensin I


angiotensin II


blood urea nitrogen


creatine kinase


extracellular fluid

FENa, FEK, FECl, and FECa

fractional excretion of Na, K, Cl, and Ca


hyporeninemic hypoaldosteronism


ionized calcium


intracellular fluid


juxtaglomerular apparatus




sodium/potassium ratio


nonsteroidal anti-inflammatory drugs




plasma renin activity


parathyroid hormone


renin-angiotensin-aldosterone system




transtubular potassium gradient


urine protein:creatinine ratio

A 13-year-old female spayed Yorkshire Terrier, weighing 6.1 kg, was referred to the Internal Medicine Service of the Animal Medical Center for hypercalcemia and hyperkalemia. Active medical problems included mild stable azotemia of 11 months duration (International Renal Interest Society Stage II, http://www.iris-kidney.com) and collapsing trachea. The owner also reported a lifelong history of infrequent seizures. Medical treatments at presentation included hydrocodone (0.625 mg PO), aminophylline (50 mg PO), aluminum hydroxidea (2.5 mL PO q12h), PetTinicb (2.5 mL PO q12h), and lactated Ringer's solution (150 mL SC q24h). The dog was receiving a home-cooked diet consisting of ground turkey, rice, and various vegetables. The diet was not prescribed by a veterinarian for a specific medical indication. The dog was obese, with a body condition score of 8 of 9, and had a persistent honking cough during examination, which precluded thoracic auscultation. The remainder of the physical examination was unremarkable. During this initial evaluation, blood was drawn for serum biochemistry, including venous blood gas and plasma electrolyte concentrations, and ACTH stimulation test. The dog was discharged without adjustments in management plan pending review of the laboratory results.

Serum biochemistry abnormalities (all reference ranges are for adult dogs) included increased alanine transferase (ALT) activity (75 U/L; reference range, 5–60 U/L), increased creatine kinase (CK, 232 U/L; reference range, 10–200 U/L), increased urea nitrogen concentration (blood urea nitrogen [BUN], 71 mg/dL; reference range, 7–27 mg/dL), increased creatinine concentration (2.0 mg/dL; reference range, 0.4–1.8 mg/dL), hypercalcemia (tCa, 12.7 mg/dL; reference range, 8.2–12.4 mg/dL), hyperkalemia (K, 7.5 mEq/L; reference range, 4.0–5.6 mEq/L), and decreased sodium/potassium ratio (Na/K, 19.9; reference range, 27–40).

Evaluation of venous blood gases and plasma electrolyte concentrations indicated normal plasma ionized calcium (iCa) concentration (4.8 mEq/L; reference range, 4.8–5.3 mEq/L) and pH (7.41; reference range, 7.35–7.45). Hyperkalemia (K, 5.94 mEq/L; reference range, 3.50–5.30 mEq/L) also was present.c

Hypocortisolism was excluded because adequate serum cortisol concentrations were present at baseline and in response to ACTH stimulation (baseline, 8.6 μg/dL; reference range, 2.0–6.0 μg/dL; post-ACTH, 31.1 μg/dL; reference range, 6–22 μg/dL).

Re-evaluation was performed 6 weeks later and the owner reported no new problems. Blood was obtained for serum biochemistry and parathyroid hormone (PTH) concentration. A voided urine sample was obtained for urinalysis, urine protein:creatinine ratio (UPC), and fractional electrolyte excretion. A cervical ultrasound examination was declined by the owner.

Serum biochemistry abnormalities included increased ALT activity (84 U/L), increased urea nitrogen concentration (BUN, 73 mg/dL), increased creatinine concentration (2.2 mg/dL), hyperglycemia (142 mg/dL; reference range, 60–125 mg/dL), hypercalcemia (tCa, 14.9 mg/dL), increased bicarbonate (28 mEq/L; reference range, 17–24 mEq/L), hyperkalemia (K, 6.3 mEq/L), and decreased Na/K (23.5). PTA concentration was increased (22.7 pmol/L; reference range, 2–13 pmol/L) with a concurrent slight increase in iCa concentration (1.47 mmol/L; reference range, 1.25–1.45 mmol/L). Urinalysis disclosed isosthenuria with proteinuria and an inactive sediment. The UPC was 7.3 (reference range, <1.0). Evaluation of fractional electrolyte excretion indicated excessive excretion of sodium (FENa, 4.5%; reference range, 0.11–0.51%), potassium (FEK, 25.9%; reference range, 3.4–15.2%), chloride (FECl, 5.22%; reference range, 0.06–0.56%), and calcium (FECa, 0.65%; reference range, 0.02–0.28%).1,2 The high fractional excretion of K suggested a nonrenal cause of hyperkalemia and the increased fractional excretion of sodium was consistent with euvolemia or volume expansion (and inconsistent with volume depletion).

At a re-evaluation 5 weeks later, the owner had removed squash and peas from the diet, and white rice was substituted for brown rice in an effort to reduce dietary K intake (K [mg] Content of Selected Foods per Common Measure, sorted alphabetically. USDA National Nutrient Database for Standard Reference, Release 23). Indirect systolic blood pressure measured between 140 and 150 mmHg without acclimation. Whole blood was collected into a chilled ethylenediaminetetraacetic acid tube, and then plasma was separated and frozen immediately for determination of plasma renin activity (PRA, this was performed by solid phase radioimmunoassay).d Blood was drawn for determination of serum aldosterone concentration at baseline and after ACTH stimulation. PRA and aldosterone concentration were undetectable at baseline, and aldosterone concentration was low after ACTH stimulation (117 pmol/L; reference range, 197–2103 pmol/L).

These results were consistent with a diagnosis of hyporeninemic hypoaldosteronism (HH). Fludrocortisone was initiated at 0.1 mg PO q24h. The owner failed to return for serial evaluation. The patient was euthanized 2 months later for recurrence of seizures.

This dog presented for 2 major problems, hypercalcemia and hyperkalemia. The hypercalcemia was determined to be mild. In the presence of renal dysfunction, the results of the total and iCa, phosphorus, and PTA concentrations are consistent with mild renal secondary hyperparathyroidism. The hyperkalemia was persistent and was moderate to severe.

K, a major intracellular cation in mammalian cells, functions as a solute to maintain cell volume and is necessary for the proper function of enzymes involved in nucleic acid, glycogen, and protein synthesis.1 The ratio of intracellular fluid (ICF) and extracellular fluid (ECF) K concentration is the primary determinant of the resting membrane potential.1 K concentration in the ECF must be maintained within a narrow range.1 Nearly all of ingested K is passively absorbed by the stomach and small intestine.1 Internal K balance is maintained by translocation of K between the ECF and ICF.1 Translocation of an acute K load from the ECF to ICF prevents life-threatening hyperkalemia during the time before the kidneys have excreted the K load via urine.1 External K balance primarily is maintained by matching urinary excretion with diet.1 Determinants of urinary K excretion include the electrochemical gradient between the tubular cells and tubular lumen, and tubular flow rate.1 Renal K excretion is increased by high sodium or K intake, aldosterone, alkalosis, and diuretics.1 Colonic K secretion is minor in the healthy individual, but can adapt to persistent increased or decreased plasma K concentration.1

Persistent hyperkalemia usually is because of inadequate urinary K excretion.1,2 Causes of hyperkalemia can be divided into 4 categories. Pseudohyperkalemia is an artifact caused by release of K from platelets and red blood cells during sample acquisition, storage, or processing. The magnitude of hyperkalemia typically is proportional to the degree of thrombocytosis, or hemolysis, and can be particularly severe as an heritable defect in certain breeds and diseases.3,4 In this patient, platelets were judged to be normal, but a platelet count was not obtained because of clumping. The venous blood gas was performed with a heparinized syringe and patient-side analyzer, eliminating cell lysis during clot formation and retraction as a cause for hyperkalemia. Additionally, neither anemia nor visible hemolysis was reported on a CBC or centrifuged plasma or serum samples. In the presence of normal renal function, increased K intake is unlikely to cause hyperkalemia unless iatrogenic.1 Dietary K intake could not be quantified in this patient, because the ingredients varied at the discretion of the owner. However, the adaptive response to K intake is maintained even in advanced chronic kidney disease by increasing K excretion per nephron and by increasing colonic K excretion.5 Translocation of K from the ICF to ECF is caused by acute mineral acidosis, insulin deficiency, drug administration, or cell lysis (eg, after reperfusion injury, rhabdomyolysis, or acute tumor lysis syndrome).1,5,6 The patient was not receiving drugs associated with K translocation (eg, nonspecific β-blockers, cardiac glycosides), and venous blood gas analysis indicated a normal pH. The mild hyperglycemia was not repeatable, and the absence of glucosuria further excluded diabetes mellitus. With the exception of very mildly increased CK activity on initial presentation, laboratory test results associated with muscle damage (eg, CK, AST) were normal on referral blood work and when repeated during subsequent evaluation. Furthermore, there was no clinical evidence for large-scale cell destruction in this patient. Decreased urinary K excretion is seen with urinary obstruction or rupture, oliguric or anuric kidney injury, chronic effusions, selected gastrointestinal diseases, and drug administration.1,6 These problems were not identified in this patient. An additional cause of decreased K excretion is hypoaldosteronism, as was demonstrated in this patient.5

The FEK was increased in this dog. An increase in FEK is common with chronic kidney disease, although spot measurement of electrolyte fractional excretion is poorly correlated with 24-hour electrolyte excretion.7 Calculation of the transtubular potassium gradient (TTKG) may help elucidate the cause of hyperkalemia. TTKG evaluates the effect of aldosterone on K excretion while correcting for the effect of free water absorption. The equation to calculate TTKG is (Urine [K] ÷ (Urine osm ÷ Plasma osm)) ÷ Serum [K]).1 In normal humans on a regular diet, TTKG is 8–9. The normal response to a K load would be an increase in aldosterone secretion leading to an increase in K secretion in the urine to excrete the excess K. In such cases, the TTKG should increase to >11.5 A result <5 in a hyperkalemic patient indicates inadequate aldosterone concentration or effect.5 In this case, urine and plasma osmolality were not measured, but estimated from the equations: urine osm = last 2 digits of urine specific gravity × 36 and by inline image. The TTKG was estimated at 2.4, supporting a diagnosis of hypoaldosteronism. The urinary FEK was increased (although not sufficiently) in this case despite hypoaldosteronism because hyperkalemia itself can directly affect K excretion independent of other factors such as aldosterone. K alone replicates all of the changes in the principal cells of the distal nephron that are induced by aldosterone.8 Without aldosterone, the kidney is less efficient at K excretion, and a higher plasma K concentration is needed to establish steady state, in which K excretion matches intake.8

The renin-angiotensin-aldosterone system (RAAS) exerts control over ECF volume via its effect on sodium balance. Pro-renin is an enzyme predominantly synthesized and stored in the juxtaglomerular cells localized in the afferent arterioles of the kidney. Cleavage of pro-renin to renin and subsequent secretion is stimulated by decreased renal perfusion pressure, β1-adrenergic receptor stimulation, and low chloride concentration of tubular fluid at the macula densa of the distal tubule. Renin secretion is inhibited by volume expansion and attendant increased tubular flow and chloride concentration at the macula densa, and via a negative feedback loop by angiotensin II (AT II). Renin converts angiotensinogen, an α-2 globulin synthesized by the liver, to angiotensin I (AT I). AT I is quickly converted to AT II by angiotensin-converting enzyme (ACE) present in vascular endothelium. Physiologic roles for AT II include increase in total peripheral resistance by vasoconstriction of the peripheral arterioles, direct effects on the renal tubules to increase sodium reabsorption, and stimulation of aldosterone release.9

Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex. Aldosterone release is stimulated by AT II and hyperkalemia, and inhibited by dopamine and atrial natriuretic factor, typically in response to volume depletion or expansion, respectively. The hormone exerts its action in the principal cells of the collecting duct and is the most important hormone affecting urinary K excretion.1 Although sodium balance is correlated with effective circulating volume, plasma sodium concentration generally is preserved during states of aldosterone deficiency or excess because of other compensatory adaptations in systemic hemodynamics and renal sodium excretion.10 However, cortisol plays a role in feedback inhibition of antidiuretic hormone release. Concurrent hypocortisolemia in primary adrenal insufficiency permits excessive antidiuretic hormone release in response to effective circulating volume depletion, which results in hyponatremia because of retention of free water in excess of solute.11 Functional hypoaldosteronism is associated with a primary decrease in adrenal synthesis, decreased activity of the RAAS, and aldosterone resistance.5 Causes for a primary decrease in adrenal synthesis of aldosterone in dogs include autoimmune destruction of the adrenal gland (Addison's disease),4 adrenal necrosis (eg, trilostane),12 bilateral adrenal malignancy,13 drug administration (mitotane), and bilateral adrenalectomy.4,6 Although aldosterone synthesis may transiently decrease after unilateral adrenalectomy of an aldosterone-secreting tumor as a result of reversible suppression of aldosterone production in the normal adrenal gland, this has not been documented in the dog.14–16 Low aldosterone concentrations at baseline and in response to ACTH stimulation, and low PRA, were documented in a dog with a deoxycorticosterone-secreting adrenocortical carcinoma that presented with clinical signs of mineralocorticoid excess.17 Unfractionated and low-molecular-weight heparin impairs aldosterone production by decreasing the number and affinity of ATII receptors in the zona glomerulosa.1,5 Congenital deficiencies of adrenal enzymes involved in aldosterone synthesis have been described in humans.5 Decreased activity of the RAAS is associated with drug administration (eg, cyclosporine, ACE inhibitors, nonsteroidal anti-inflammatory drugs [NSAIDs]). Additionally, acquired immunodeficiency syndrome, hypervolemia in chronic dialysis patients, and HH have been described as causes of decreased RAAS activity in humans.5 Aldosterone resistance invariably causes increased aldosterone concentrations and can be seen with use of drugs such as K-sparing diuretics, or acquired or genetic end-organ resistance (pseudohypoaldosteronism [PHA]). Acquired PHA typically is seen in association with tubulointerstitial diseases, whereas genetic forms of PHA in children are rare.5 A primary decrease in aldosterone synthesis or end-organ effect would be expected to impair sodium and water reabsorption. If this leads to a lower intravascular volume, PRA would be expected to increase in an attempt to stimulate increased aldosterone secretion.5

HH is common in humans, accounting for 50–75% of all cases of initially unexplained persistent, asymptomatic hyperkalemia.5 HH is found most commonly in older adults with mild to moderate renal insufficiency, diabetic nephropathy, or chronic tubulointerstitial disease.2 Chronic volume expansion and structural damage to the juxtaglomerular apparatus (JGA) are considered likely causes for HH in these syndromes.5 Common findings include asymptomatic hyperchloremic metabolic acidosis, hyperkalemia disproportionate to the level of glomerular filtration rate reduction, systemic hypertension, and congestive heart failure because of volume expansion.18 Similar metabolic derangements may be seen in patients with renal insufficiency who are taking certain medications, including NSAIDs or ACE inhibitors, or who have destruction of the renin-secreting cells in the macula densa.2,5 Comparative findings in this case include renal insufficiency and disproportionate hyperkalemia. Metabolic acidosis, diabetes mellitus, systemic hypertension, and congestive heart failure were not identified during evaluation of the dog of this case report, and the patient was not receiving medications that could contribute to the findings. The magnitude of proteinuria in this dog was substantial and the proteinuria was thought to be glomerular.19 Proteinuria may have been an indication of functional or structural damage to the JGA.5,20 Kidney biopsy specimens may have provided useful diagnostic information, but the owner declined renal biopsy specimens because of the risk of complications of percutaneous renal biopsy in small dogs, and postmortem samples were not made available.21 HH associated with functional or structural damage to the JGA has been reported in humans with diseases such as lupus nephritis,22 amyloidosis,23 monoclonal gammopathy,24 and acute glomerulonephritis.20,25 Reports of treatment of HH with concurrent proteinuria showed improvement or resolution with therapy targeted at the primary etiology.

Treatment for HH in humans varies with the underlying cause, but generally includes mineralocorticoid hormone replacement, and the dosage may be higher than usually needed for Addison's disease.5,26 Caution is appropriate in these cases because of volume expansion and subsequent effects on blood pressure, congestive heart failure, and renal insufficiency. An alternative approach may include dietary salt restriction and administration of a loop or thiazide-type diuretic to mitigate acidosis and hyperkalemia. Occasionally, a combination of these 2 approaches is used.5,26 In this case, mineralocorticoid replacement was prescribed, but response to treatment was not evaluated. Specific antiproteinuric treatment such as an ACE inhibitor was not used because it would further decrease aldosterone production and potentially exacerbate the hyperkalemia, although use of a protein-restricted diet was recommended.

Persistent hyperkalemia typically is associated with decreased K urinary excretion. Kaliuresis is proportional to K intake in order to maintain normokalemia. So, even in patients with moderate to advanced nonoliguric chronic kidney disease, some other factor usually is superimposed. Therefore, once predisposing causes are identified and the diagnosis is confirmed by measurement of plasma K concentration, clinical objectives are to ensure appropriate K intake, adequate urine output, and unimpaired aldosterone secretion and response. Many commonly used drugs can affect the production or effect of aldosterone, including ACE inhibitors, NSAIDs, K-sparing diuretics, and cyclosporine. In most cases, the hyperkalemia is asymptomatic, although dose modification or discontinuation of the offending drug may be indicated. When persistent hyperkalemia cannot be otherwise explained, assessment of serum aldosterone concentration at baseline and in response to ACTH stimulation, and PRA can help elucidate underlying RAAS dysfunction. Several congenital and acquired causes of hypoaldosteronism have been described in children and adults, but few clinical reports evaluating RAAS disorders are reported in the veterinary literature.


a Alternagel, Johnson & Johnson, New Brunswick, NJ

b Pet-Tinic, Pfizer Inc, New York, NY

c Siemens RapidLab 860, Munich, Germany

d Ani Lytics Inc, Gaithersburg, MD


The work was not supported by a grant or otherwise.