AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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 those substances. 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 reach 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.

The degree of acidosis is variable and may be related to the underlying chronic renal disease. Note that, unlike distal (ie, type I) RTA where 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.¹

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, 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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:
• • 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) whose 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:
• • Inhibitors of renin release: Beta-blockers include beta1 selective blockers. Nonsteroidal anti-inflammatory agents, including cyclooxygenase-2 (COX-2) inhibitors.
  • 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. 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Pseudohyperkalemia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The hallmark of diagnosis is the finding of hyperkalemia in the setting of mild-to-moderate chronic kidney disease.
• • First, exclude pseudohyperkalemia. The measurement of plasma potassium (P_K) can help to confirm the diagnosis of pseudohyperkalemia, if suspected. Serum is prepared by allowing whole blood to clot in a red top tube. In cases of thrombocytosis, enough potassium is released in vitro by the platelets to materially affect the serum potassium. Plasma, on the other hand, is prepared in a manner to prevent clotting in vitro, so the platelets largely remain intact and, therefore, do not release their cytosolic potassium.
  • Obtain a CBC with platelet count to screen for hyperkalemia caused by thrombocytosis or severe leukocytosis.
  • If adrenal insufficiency is at all suspected, a random cortisol level should be obtained as a screening test. However, a Cortrosyn stimulation test is preferred because it is more sensitive and specific and does not add greatly to the cost and complexity of the workup.
• If the potassium is 6.0 mEq/L or higher, examine the patient with a 12-lead ECG for signs of hyperkalemia. If these signs are found, institute emergent treatment.
• Acidosis generally is mild, with serum bicarbonate levels in the range of 18-22 mEq/L. The bicarbonate level is useful to guide therapy, as discussed in Treatment.
• Because unusual accumulation of unmeasured anions (either of endogenous or exogenous origin) does not occur, the anion gap generally is in the reference range (varies by laboratory). However, some patients in whom the diagnosis of type IV RTA is considered have sufficiently advanced CKD to accumulate endogenous metabolic acids (such as phosphate and urate), leading to a mild elevation of the anion gap.
• Urinary electrolytes
• • This test is useful in a corroborative role. In a healthy patient, high potassium intake is followed by a high urinary potassium excretion rate; in the presence of hyperkalemia, low urinary K is prima facie evidence of inadequate renal potassium excretion. The urinary anion gap is determined by adding sodium and potassium and by subtracting chloride from the sum ([Na + K] – Cl). This value is usually negative, reflecting the unmeasured cation NH⁴⁺. However, in impaired ammoniagenesis, as observed in type IV RTA, positive values of 40 or more may be observed. This test has meaning only with adequate distal sodium delivery (ie, U_Na >20 mEq/L) and in the absence of unmeasured anions, such as ketone bodies and lactate.
  • The transtubular potassium gradient (TTKG) is a further refinement of the random urine potassium measurement. Most tubular potassium excretion takes places in the CCT. At that point, urine is usually iso-osmotic to serum.
  • Downstream from the CCT, under the influence of antidiuretic hormone (ADH), the urine becomes concentrated and potassium is neither reabsorbed nor secreted; therefore, the ratio of urinary osmolality (UOsm) and plasma osmolality (POsm) is used to estimate the degree of urinary concentration that is relative to the end of the CCT. The urine potassium divided by this ratio is an estimate of the tubular UK at the end of the CCT.
  • Consider the ratio of this adjusted UK to the P_K, known as the TTKG, at the end of the CCT; thus, TTKG = UK/P_K divided by UOsm/POsm. Under normal conditions in a healthy person, the TTKG is 8-9. With potassium loading and appropriate aldosterone release and action, it rises to over 11. A value of less than 5 in the setting of hyperkalemia usually means an aldosterone lack, either in its release or tubular effect. This interpretation of the TTKG ratio assumes concentrated urine (UOsm > POsm) and a U_Na level greater than 25, indicating adequate distal sodium delivery.
  • Note here that if sodium is avidly resorbed more proximally, then inadequate sodium may be delivered to the aldosterone-mediated Na-K exchange site, leading to hyperkalemia, despite the presence of normal or high levels of aldosterone. This situation may be seen in severe congestive heart failure (CHF) or liver failure.
• Measurement of renin and aldosterone has been excluded from routine studies for the following reasons:
• • These levels must be determined under standardized conditions of position and volume status.
  • The tests are costly and usually have a long turnaround time.
  • The results generally are not useful in guiding therapy; therefore, their use is limited to clinical studies or to situations where other endocrinopathies are being tested. In cases of clinical uncertainty, these studies certainly can be obtained.
  • If it is desired to confirm the lack of renin and aldosterone, diurese the patient to achieve mild volume depletion, and then obtain a morning standing blood sample to maximally stimulate the renin-aldosterone axis.
• If the patient is newly presenting, then order a complete workup for the underlying renal disease. Serologic studies for SLE, hepatitis, and HIV, as indicated, may be necessary in many patients.
• Urine pH, performed with a pH meter, confirms that the patient can produce acidified urine (pH <5.3). This distinguishes type IV RTA from type I (ie, distal RTA).

Imaging Studies

• For new patients with CKD, obtain an ultrasound to establish kidney size and to screen for obstruction.

Procedures

• In newly presenting patients with proteinuria, hematuria, or early stage CKD, a renal biopsy may be necessary for definitive diagnosis of the underlying renal disease.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

If the patient has severe hyperkalemia and/or ECG abnormalities are present, emergency measures for hyperkalemia are necessary (see Hyperkalemia). The need for dialysis for patients with hyperkalemia and mild CKD is unusual because medical measures usually suffice. Long-term measures attempt to reduce dietary potassium intake and to increase renal tubular potassium excretion.

• Diuretics, loop and/or thiazide
• • These agents are well known for their kaliuretic and chloruretic effects. While usually viewed as adverse effects, in RTA type IV these effects are exploited as a way to remove potassium and to treat the acidosis.
  • Diuretics are the first-line therapy for patients with signs of volume overload on examination.
  • Caution these patients to ignore the label that pharmacists often put on the diuretic bottle instructing them to take with a glass of orange juice.
  • The main adverse effects of diuretics are overdiuresis with volume depletion and alkalosis.
• Sodium bicarbonate (ie, NaHCO₃)
• This adjunctive agent is administered in 10-grain tablets.
• This agent usually corrects the acidosis and, by increasing distal delivery of bicarbonate anion, increases UK excretion.
• The consumption of NaHCO₃ may cause the patient to belch and also may cause the patient to develop volume overload.
• NaHCO₃ tablets may be used as a first-line agent in patients with more severe acidosis (eg, 14-16 mEq/L) or in volume-depleted patients who are unable to take diuretics.
• Fludrocortisone (ie, Florinef)
  • This is the third-line agent for patients with RTA type IV.
  • This synthetic corticosteroid is unique because its mineralocorticoid activity significantly exceeds its glucocorticoid activity.
  • Florinef is used as an aldosterone analogue; but, note that the dosage needed to achieve effective kaliuresis is generally 0.1-0.3 mg/d, which is higher than the dosage used as replacement in patients with adrenal insufficiency, indicating the importance of tubular aldosterone hyporesponsiveness in most patients with RTA type IV.
  • Also, note that Florinef has some glucocorticoid activity with the resultant metabolic and long-term side effects.
  • Florinef can exacerbate hypertension and fluid overload, and patients taking this drug need close follow-up care.
  • Recent reports regarding the adverse effects of endogenous aldosterone on cardiac remodeling in patients with CHF raise serious questions regarding the long-term use of Florinef, unless all other methods are exhausted.
• Sodium polystyrene sulfonate (ie, Kayexalate)
  • This agent is an exchange resin that is useful in achieving potassium removal via the gut, thereby bypassing the impaired renal excretory mechanisms.
  • Kayexalate now is available as premixed doses in a sorbitol solution to provide laxation and to exchange sodium for potassium in the lumen of the colon.
  • Effectiveness is variable; however, on average, it removes 1 mEq of potassium for each gram ingested, at the cost of about 1 mEq of absorbed sodium.
  • Compliance is an issue for long-term use because this agent is not very palatable.
  • If the patient develops constipation, this agent is ineffective.
  • Intestinal complications of oral or rectal use are well known.
  • Kayexalate clearly has a role in the long-term treatment of patients for whom the above kaliuretic approaches have failed, patients who are intolerant to them, or patients who are noncompliant with dietary restrictions.

Surgical Care

If the patient presents with hyperkalemia as a complication of urinary tract obstruction, institute appropriate urologic measures.

Consultations

• Consult a dietitian for assistance in teaching the patient about a potassium-restricted diet.
• Consultation with a urologist may be necessary if urinary tract obstruction is discovered.
• Because many cardiac medications (eg, ACE inhibitors, angiotensin receptor blockers [ARBs], beta-blockers, aldosterone inhibitors) produce hyperkalemia, a cardiologic consultation may be indicated to design a cardiac regimen that is compatible with the patient's intolerance of these medication classes.

Diet

Recommend a dietary review, preferably by a renal dietitian, to uncover sources of dietary potassium excess. Salt substitutes commonly are overlooked, which often contain large amounts of potassium chloride (KCl). Dietary teaching also is an important part of long-term therapy.

• Two-gram potassium restriction, including complete avoidance of KCl-containing salt substitutes.
• Sodium intake is variable because most patients are hypertensive and/or retain salt from CKD, but some patients waste salt.
• Counsel patients against the use of OTC nonsteroidal agents.
• Caution patients on the use of herbal remedies and dietary supplements unless known to be safe.

Activity

Although no published data exist regarding whether to limit patient activity with this condition, a theoretical concern exists that these patients might be ill equipped to handle the transient hyperkalemia that strenuous exercise produces; accordingly, instruct the patient to approach strenuous exercise with caution and only if stable control of potassium is demonstrated.

MEDICATION

Section 7 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Loop diuretics

Diuretics increase sodium and potassium loss in the urine. The latter usually is considered an adverse effect but is the desired effect in treating patients with RTA type IV.

Drug Category: Mineralocorticoids

Provide pharmacologic amounts of mineralocorticoid activity, so the patient can overcome tubular resistance to physiologic amounts of aldosterone.

Drug Category: Ion-exchange resins

By increasing gut excretion of potassium, these agents bypass renal impairment of potassium excretion. Difficult to take on a regular basis, limiting its use in long-term therapy.

Drug Category: Alkalinizing agents

Provide bicarbonate anion to replete patients with metabolic acidosis. Alkalinizes urine, enhancing kaliuresis.

Drug Category: Thiazide diuretics

Useful in the treatment of RTA type IV because of kaliuretic effects. Less likely to produce marked volume depletion than loop diuretics and may be better antihypertensive agents.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Prior to discharge, ensure that the patient's potassium level is stable in an acceptable range using a regimen suitable for outpatient use. Generally, a stable potassium level below 5.5 mEq/L is acceptable, provided that the patient is compliant with diet, medications, and follow-up care. For those patients who may be less compliant, tighter control may be targeted to provide some margin of safety.
• Ensure that the patient received dietary counseling.
• Schedule timely outpatient follow-up care and laboratory testing.

Further Outpatient Care

• Outpatient care consists of monitoring the response to therapy, with particular attention to blood pressure, volume status, and electrolytes.
• If the RTA type IV was exacerbated by a drug that was discontinued, further therapy directed toward lowering potassium may no longer be needed and may even be harmful by causing hypokalemia and alkalosis.

Deterrence/Prevention

• Because the tendency of many clinically important classes of medications is to produce an RTA type IV picture, preventing this condition by eliminating the patient's use of those agents is impossible. Rather, enable early detection by conducting laboratory screenings of patients at risk, after starting medicines in those classes.

Prognosis

• RTA type IV can almost always be treated through some combination of adding and eliminating medications and implementing dietary restraint. The underlying renal disease, however, often progresses towards eventual end-stage renal disease (ESRD). Note that the 2 classes of agents (ie, ACE inhibitors, ARBs) with proven benefit in delaying progression of renal disease also are common causes of hyperkalemia, which may limit their utility in delaying the progression of CKD in some patients.

Patient Education

• Educate patients about the risk of sudden catastrophic events from hyperkalemia and the importance of compliance with medications, diet, and follow-up procedures.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to adhere to monitoring guidelines after starting medications that have a risk of exacerbating RTA type IV because hyperkalemia is treatable but may be lethal if undetected (early detection of renal disease may help in identifying those patients at greatest risk)
• Drug therapy of hyperkalemia may itself have adverse effects; in particular, patients must be adequately monitored for overtreatment with resulting hypokalemia, CHF, or metabolic alkalosis (depending on the agent[s] used).

Special Concerns

• True RTA type IV and its drug-induced counterpart are increasing problems among elderly patients and are aggravated by polypharmacy.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Schambelan M, Sebastian A, Biglieri EG. Prevalence, pathogenesis, and functional significance of aldosterone deficiency in hyperkalemic patients with chronic renal insufficiency. Kidney Int. Jan 1980;17(1):89-101. [Medline].
2. Batlle DC, Hizon M, Cohen E, Gutterman C, Gupta R. The use of the urinary anion gap in the diagnosis of hyperchloremic metabolic acidosis. N Engl J Med. Mar 10 1988;318(10):594-9. [Medline].
3. Bomann JS, Peckler BF. Type IV renal tubular acidosis presenting as dyspnea in two older patients taking angiotensin-converting enzyme inhibitors. Ann Emerg Med. Jan 2002;39(1):73-6. [Medline].
4. Caramelo C, Bello E, Ruiz E, Rovira A, Gazapo RM, Alcazar JM, et al. Hyperkalemia in patients infected with the human immunodeficiency virus: involvement of a systemic mechanism. Kidney Int. Jul 1999;56(1):198-205. [Medline].
5. DeFronzo RA. Hyperkalemia and hyporeninemic hypoaldosteronism. Kidney Int. Jan 1980;17(1):118-34. [Medline].
6. Ethier JH, Kamel KS, Magner PO, Lemann J Jr, Halperin ML. The transtubular potassium concentration in patients with hypokalemia and hyperkalemia. Am J Kidney Dis. Apr 1990;15(4):309-15. [Medline].
7. Heering PJ, Kurschat C, Vo DT, Klein-Vehne N, Fehsel K, Ivens K. Aldosterone resistance in kidney transplantation is in part induced by a down-regulation of mineralocorticoid receptor expression. Clin Transplant. Apr 2004;18(2):186-92. [Medline].
8. Knochel JP. The syndrome of hyporeninemic hypoaldosteronism. Annu Rev Med. 1979;30:145-53. [Medline].
9. Michelis MF. Hyperkalemia in the elderly. Am J Kidney Dis. Oct 1990;16(4):296-9. [Medline].
10. Oster JR, Singer I, Fishman LM. Heparin-induced aldosterone suppression and hyperkalemia. Am J Med. Jun 1995;98(6):575-86. [Medline].
11. Perazella MA, Mahnensmith RL. Hyperkalemia in the elderly: drugs exacerbate impaired potassium homeostasis. J Gen Intern Med. Oct 1997;12(10):646-56. [Medline].
12. Tan SY, Burton M. Hyporeninemic hypoaldosteronism. An overlooked cause of hyperkalemia. Arch Intern Med. Jan 1981;141(1):30-3. [Medline].
13. Williams GH. Hyporeninemic hypoaldosteronism. N Engl J Med. Apr 17 1986;314(16):1041-2. [Medline].

Article Last Updated: Sep 21, 2007