Hyporeninemic Hypoaldosteronism 

In chronic kidney disease (CKD), the kidney retains a remarkable ability to compensate for nephron loss by increasing single nephron excretion of various substances. This situation is particularly important in the renal adaptation to potassium handling. In fact, when compensation is intact, hyperkalemia is uncommon until renal function (glomerular filtration rate [GFR]) decays to an advanced stage (ie, GFR or creatinine clearance ≤ 15 cc/min); however, at times, tubular adaptation is impaired, and hyperkalemia is observed much earlier in the course of CKD.

This picture of hyperkalemia, often with mild acidosis, in the setting of mild-to-moderate CKD (stages 2-4) is quite common in clinical practice. Several pathophysiologic mechanisms are involved. However, the diagnostic workup does not always establish the precise mechanism, and, unfortunately, much confusion has arisen from the nomenclature employed.

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.

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.