eMedicine Specialties > Nephrology > Acid-Base, Fluid, and Electrolyte Disorders

Hyporeninemic Hypoaldosteronism

Author: James H Sondheimer, MD, Director of Hemodialysis Unit, Harper Hospital; Associate Professor, Department of Internal Medicine, Division of Nephrology, Wayne State University School of Medicine
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Updated: Oct 7, 2009

Introduction

Background

The use of the term hyporeninemic hypoaldosteronism, strictly speaking, should be limited to those cases in which testing reveals the cause of hyperkalemia to be a deficiency of renin and aldosterone. Similarly, the term type IV renal tubular acidosis (RTA), or (more recently) hyperkalemic RTA or tubular hyperkalemia, should be employed for cases with normal renin and aldosterone production but impaired tubular responsiveness, usually caused by a distal tubular voltage defect. The term type IV RTA is in itself confusing because type III is rarely observed or discussed.

This article reviews some of the pathophysiologic aspects, the clinical picture, and the treatment strategies of hyporeninemic hypoaldosteronism from the standpoint of clinical presentation, evaluation, and treatment. These diagnoses often are less precise than they sound, and, in this article, the term type IV RTA is used in its broad sense as hyperkalemia due to some combination of derangements of renin or aldosterone production and/or of tubular responsiveness to aldosterone.

See Metabolic Acidosis for a detailed discussion of the regulation of acid-base balance.

Pathophysiology

The dietary potassium intake may exceed 120 mEq/d in patients in the United States and may be even higher elsewhere. Patients excrete 90% of this intake renally. Even with CKD, the kidneys usually can compensate and maintain potassium homeostasis, albeit with less ability to handle a surge of potassium intake. Potassium is filtered at the glomerulus and then reabsorbed in the proximal nephron. The main site of potassium excretion is located in the distal tubule, or, more precisely, the principal cells of the cortical collecting tubule (CCT). To achieve adequate potassium excretion, sodium delivery to that site must be adequate, aldosterone must be present to facilitate the sodium-potassium (Na-K) exchange, the principal cells must respond to aldosterone, and urine flow must be brisk enough to wash out the excreted potassium.^1,2

The degree of acidosis is variable and may be related to the underlying chronic renal disease. Note that unlike type I (ie, distal) RTA, in which the defect is in proton secretion with resulting high urine pH (>5.3), in type IV RTA, the defect is primarily with ammoniagenesis. This defect, albeit significant, still permits the elaboration of acidic (pH <5.3) urine. Hyperkalemia inhibits renal ammoniagenesis is several ways. Furthermore, hyperkalemia may produce acidosis by a shift of protons out from cells to the extracellular space, as homeostatic mechanisms attempt to buffer potassium by intracellular uptake.

The first step in the renin release cascade involves the juxtaglomerular apparatus of the nephron. Here, renin is released, allowing angiotensin I to be cleaved from angiotensinogen; this is the rate-limiting step in the cascade. Angiotensin I, in turn, is broken down by angiotensin converting enzyme (ACE) into angiotensin II. Angiotensin II is a cofactor, along with potassium, in aldosterone synthesis by the adrenal gland.

Renal tubular damage may cause inadequate renin production and release; adrenal dysfunction may lead to inadequate aldosterone production; and the principal cells of the CCT may not respond normally to aldosterone. In true cases of hyporeninemic hypoaldosteronism, atrophy of the juxtaglomerular apparatus may be present; this may be more prevalent in diabetic patients. Any combination of these factors may cause the clinical picture commonly called hyporeninemic hypoaldosteronism or RTA type IV (see Background). Indeed, as demonstrated by Schambelan and colleagues, all 3 factors may be present together in some patients.³

Frequency

United States

Specifying incidence or prevalence of RTA type IV is difficult for several reasons: the condition (1) is often undetected, (2) may only manifest when the patient is challenged by dietary potassium excess, (3) is often iatrogenic (in the sense that an underlying proclivity is exposed by certain medications), and (4) improves with the removal of exacerbating agents. This condition involves a spectrum of symptom severity, and only the more severe cases provoke attention and therapy. In the broad perspective of an aging population with a high prevalence of diabetes and polypharmacy, the clinical picture of RTA type IV is not uncommon.

Mortality/Morbidity

Occasionally, a patient presents with hyperkalemia-induced cardiac arrhythmias, which may be fatal. Muscle weakness and dyspnea may also be presenting symptoms. More typically, the patient presents with hyperkalemia on routine chemistry testing. If untreated, the risk of a fatal arrhythmia exists, but this risk is not quantified. Sublethal hyperkalemia, per se, is usually asymptomatic, but chronic acidosis contributes to bone demineralization over the long term.

Race

In the United States, renal disease is more common in blacks, Native Americans, and Hispanics; therefore, RTA type IV would be expected to show a higher prevalence in those groups. Diabetes also is more common in these groups, further compounding the problem of hyperkalemia.

Sex

No sexual predilection exists; however, a sexual prevalence does exist among the underlying renal diseases (eg, more systemic lupus erythematosus [SLE] occurs in women, more lead nephropathy occurs in men).

Age

This condition generally develops in middle-aged or older patients but can occur in younger patients with such disorders as diabetes type I or sickle cell anemia.

Clinical

History

RTA type IV generally is asymptomatic unless severe hyperkalemia leads to muscle weakness or life-threatening arrhythmia (see Hyperkalemia for further discussion). Acidosis usually is mild and asymptomatic.

• The condition is usually discovered during routine laboratory evaluations.
• Because several commonly used drugs may unmask RTA type IV, hyperkalemia commonly is discovered during follow-up testing of a patient started on one of those agents. Patient history may include the following:
  • The above-mentioned drugs include medications affecting the renin-angiotensin-aldosterone axis (see Causes). Hyperkalemia with moderate doses of such agents may suggest a forme fruste of Type IV RTA. 
  • If the patient is newly discovered to have hyperkalemia and mild-to-moderate renal failure, focus the history on the causes of renal disease. In particular, consider long-term analgesic use, exposure to lead (industrial or from moonshine liquor), and obstructive symptoms.
  • Other illnesses (eg, diabetes, sickle cell anemia, SLE) would likely have become apparent earlier.
  • Other important historical data consist of dietary intake (including pica, fad diets, and use of salt substitutes) and current medication use (ie, over-the-counter [OTC] and prescription drugs).

Physical

• The underlying renal disease and/or associated illnesses (eg, SLE, sickle cell disease) dominate the physical findings.
• Except for arrhythmia and muscle weakness in severe cases, hyperkalemia produces no physical signs.
• Mild acidosis may be present, but associated physical signs (eg, Kussmaul respiration) usually are absent. However, some cases of symptomatic acidosis with dyspnea have been described.
• Patients demonstrate no signs of adrenal insufficiency, as glucocorticoid excretion is intact, by definition.
• Patients usually are hypertensive, in association with their underlying renal disease.
• The assessment of patient volume status is important because therapy commonly includes the use of diuretics.
• Adrenal insufficiency is part of the differential diagnosis and manifests with findings, including fever, orthostatic changes, hyperpigmentation, and signs of illnesses (eg, SLE), that, when resulting in treatment with long-term corticosteroids, can lead to secondary hypoadrenalism.

Causes

• As a rule, renal interstitial disorders are more likely to produce a picture of type IV RTA than glomerular diseases. Interstitial diseases produce more tubular damage, cause more renin production impairment (eg, in juxtaglomerular apparatus), and are more likely to compromise tubular potassium secretion in the distal nephron.
• The tubulointerstitial diseases commonly associated with RTA type IV include the following:
  • Sickle cell disease
  • Analgesic nephropathy
  • Lead nephropathy
  • Chronic pyelonephritis
  • Obstructive nephropathy
• Diabetic nephropathy, although primarily a glomerular disease, is an exception because it is associated with decreased renin production. Furthermore, patients with diabetes may have impaired extrarenal potassium homeostasis, caused by a lack of insulin, and autonomic neuropathy with resulting impaired beta2-mediated influx of potassium into cells.
• Patients with HIV disease are at risk for developing adrenal insufficiency, which may present as hyperkalemia.
  • At times, the adrenal defect may be selective for mineralocorticoid production. Furthermore, trimethoprim, a component of chemoprophylaxis regimens for patients with AIDS, may impair tubular potassium excretion.
• Many commonly used drugs affect renin release, aldosterone production, or tubular potassium excretory capacity. In these cases, some confusion exists in the literature regarding nomenclature. For example, if beta-blockade reduces renin release and leads to hyperkalemia in a given patient who is usually normokalemic, some authors would declare that patient to have hyporeninemic hypoaldosteronism, while others would limit that diagnosis to cases in which drug effects have been excluded. In addition, some drugs either contain potassium or impair extrarenal potassium homeostasis. The following are some of the commonly used drugs affecting potassium excretion and homeostasis^4,5 :
  • Inhibitors of renin release:
    • Beta blockers, including beta1 selective blockers
    • Nonsteroidal anti-inflammatory agents, including cyclooxygenase-2 (COX-2) inhibitors
  • Renin inhibitor: Aliskiren (Tekturna)⁶
  • Inhibitors of aldosterone production: ACE inhibitors block formation of angiotensin II (a cofactor in aldosterone production); this effect is similar to that of angiotensin II receptor blockers. Heparin interferes with adrenal gland aldosterone biosynthesis.
  • Inhibitors of tubular potassium excretion: Spironolactone and eplerenone are direct competitive inhibitors of aldosterone. Triamterene and amiloride inhibit the sodium channel necessary for potassium excretion. Triamterene has a mild effect on this channel. Calcineurin inhibitors, including cyclosporine A and tacrolimus, may interfere with the aldosterone receptor.
  • Potassium-containing drugs include penicillin (oral or IV).
  • Impaired potassium homeostasis: Nonselective beta blockers (and selective ones at higher doses) block beta2-mediated potassium influx into cells, which is part of moment-to-moment potassium regulation. Acute osmotic loads (eg, mannitol, radiocontrast) impair potassium homeostasis by causing osmotic efflux of water from cells, with convective drag of potassium. This effect is mostly seen in diabetics, who lack the homeostatic protections of insulin release and an intact autonomic system.
  • Some herbal products may be rich in potassium themselves or contain digitalis-like substances that may inhibit tubular potassium excretion.

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