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

Hyporeninemic Hypoaldosteronism

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

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.

Differential Diagnoses

Addison Disease
Metabolic Acidosis

Other Problems to Be Considered

Pseudohyperkalemia

Workup

Laboratory Studies

• The hallmark of diagnosis is the finding of hyperkalemia in the setting of mild-to-moderate chronic kidney disease.
  • First, exclude pseudohyperkalemia, which is seen with difficult venipunctures and in thrombocytosis. 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.
    
    Repeat serum potassium to confirm, with a better venipuncture, if possible.
    
    Obtain a complete blood count (CBC) with platelet count to screen for hyperkalemia caused by thrombocytosis or severe leukocytosis. The measurement of plasma potassium (P_K) can help to confirm the diagnosis of pseudohyperkalemia, if suspected.
  • 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 NH ^{₄ +}. 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 (U _Osm ) and plasma osmolality (P _Osm ) 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 U _K at the end of the CCT. Thus, U _K /(U _{O sm} /P _{O sm} ) is a crude estimate of U _K at that tubular site.
    • The ratio of the estimated tubular U _K to the P_K is known as the TTKG. Thus, TTKG = [U _K /(U _{O sm} /P _{O sm} )]/P _K . 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 in its tubular effect. This interpretation of the TTKG ratio assumes concentrated urine (U _Osm >P _Osm ) and a U_Na level of 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 longer turnaround time than routine studies do.
  • The results generally are not useful in guiding therapy; therefore, their use is limited to clinical research studies or to situations in which other endocrinopathies are being considered. In cases of clinical uncertainty, these studies certainly should 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. See Chronic Renal Failure
• 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

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 in patients with hyperkalemia and mild CKD is uncommon, because medical measures usually suffice.

Reduce or eliminate, if at all possible, medications that cause or may exacerbate potassium retention. The long-term approach is to utilize measures that increase net potassium excretion by the renal or intestinal routes:

• 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 may 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 (650 mg) 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 may also lead to 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 should not be given 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; note, however, 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 and therefore indicates the importance of tubular hyporesponsiveness to aldosterone 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.
  • Reports regarding the adverse effects of endogenous aldosterone on cardiac remodeling in patients with CHF raise serious concerns about 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 colon, thereby bypassing the impaired renal excretory mechanisms.
  • Kayexalate now is available in premixed doses in a sorbitol solution (to provide laxation, which is necessary for Kayexalate to be effective).
  • Effectiveness is variable; however, on average, Kayexalate removes 1 mEq of potassium for each gram ingested, at the cost of about 1 mEq of absorbed sodium. This sodium retention may be problematic for patients with CHF or impaired renal function
  • 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.
  • Kayexalate cannot be used in patients with ileostomy (absence of colon), ileus, or obstruction or in patients who have undergone recent intestinal surgery.

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 will 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

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

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.

Furosemide (Lasix)

Inhibits reabsorption of chloride, predominantly in the thick ascending limb of loop of Henle. The high efficacy of this drug is largely due to the large amount of sodium usually reabsorbed in this site.

Dosing

Adult

20-160 mg PO qd

Pediatric

1 mg/kg/dose PO

Interactions

Metformin decreases furosemide concentrations; furosemide interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides and furosemide (hearing loss of varying degrees may occur); concurrent administration with warfarin may enhance anticoagulant activity; may increase plasma lithium levels and toxicity when taken concurrently; nonsteroidals may reduce efficacy, leading to higher dose needs

Contraindications

Documented hypersensitivity; hepatic coma; anuria; state of severe electrolyte depletion

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor volume status and risk of volume depletion; perform frequent serum electrolyte, CO₂, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter; risk of hypokalemic hypochloremic metabolic alkalosis; risk of hypomagnesemia; may exacerbate gout; photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; diuretics are generally contraindicated in pregnancy

Mineralocorticoids

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

Fludrocortisone (Florinef)

Used as a third-line agent in patients for whom treatment with diuretics, sodium bicarbonate, and dietary measures has failed. Promotes increased reabsorption of sodium and loss of potassium from renal distal tubules.

Dosing

Adult

0.05-0.2 mg/d PO divided bid

Pediatric

0.05-0.1 mg/d PO

Interactions

Antagonizes effects of anticholinergics; decreases effects of rifampin, hydantoins, barbiturates, and vaccines; decreases salicylate levels; concomitant use with midodrine results in hypernatremia or increase in IOP and glaucoma

Contraindications

Documented hypersensitivity; systemic fungal infections; uncontrolled hypertension; uncontrolled CHF

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Taper dose gradually when therapy is discontinued; caution in Addison disease, potassium loss, and sodium retention

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.

Sodium polystyrene sulfonate (Kayexalate)

Exchanges sodium for potassium and binds in the gut, primarily in the large intestine. Also decreases total body potassium. Onset of action after PO administration ranges from 2-12 hours and is longer when administered rectally.

Dosing

Adult

15-30 g PO in 70% sorbitol suspension q6h; repeat prn until desired effects
30-60 g PR in 70% sorbitol suspension as retention enema q6h; repeat q6h or prn

Pediatric

1 g/kg PO in sorbitol q6h
1 g/kg PR in sorbitol as retention enema q2-6h

Interactions

Systemic alkalosis may occur if administered concurrently with magnesium hydroxide, calcium carbonate, aluminum carbonate, similar antacids, and similar laxatives; may decrease effects of levothyroxine

Contraindications

Documented hypersensitivity; hypernatremia; acute abdominal pathology; ileus; obstruction

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May lead to decompensation when administering to patients who can be adversely affected by a small increase in sodium loads (eg, severe hypertension, severe CHF, marked edema); constipation, with the possibility of fecal impaction (PO related to obstruction, PR related to perforation), may occur; treat constipation with 10-20 mL of 70% sorbitol q2h or as necessary to produce at least 1-2 watery stools qd

Alkalinizing agents

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

Sodium bicarbonate (Neut)

Used IV in emergency treatment of hyperkalemia. Used PO in patients with metabolic acidosis and hyperkalemia.

Dosing

Adult

650-1300 mg PO tid/qid, titrate to serum bicarbonate level of 18-24 mEq/L
1 mEq/kg IV for hyperkalemic emergencies

Pediatric

325 mg PO tid or prn
1 mEq/kg IV for hyperkalemia

Interactions

Urinary alkalinization induced by increased sodium bicarbonate concentrations may cause decreased levels of lithium, tetracyclines, chlorpropamide, methotrexate, cefpodoxime, itraconazole, ketoconazole, and salicylates; increases levels of amphetamines, pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine

Contraindications

Documented hypersensitivity; alkalosis, hypernatremia, hypocalcemia; severe pulmonary edema; unknown abdominal pain

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Only used to treat documented metabolic acidosis and hyperkalemia-induced cardiac arrest; can cause alkalosis, decreased plasma potassium, hypocalcemia (may cause tetany), and hypernatremia; caution in electrolyte imbalances (eg, patients with CHF, cirrhosis, edema, corticosteroid use, or renal failure); when administering, avoid extravasation because this agent can cause tissue necrosis; PO use may cause belching

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.

Hydrochlorothiazide (HydroDIURIL, Esidrix)

Inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium, water, potassium, and hydrogen ions.

Dosing

Adult

25-100 mg PO qd

Pediatric

1-4 mg/kg/d PO divided bid

Interactions

May decrease effects of anticoagulants, antigout agents, and sulfonylureas; may increase toxicity of ACE inhibitors, allopurinol, anesthetics, antineoplastics, calcium salts, loop diuretics, lithium, diazoxide, digitalis, amphotericin B, and nondepolarizing muscle relaxants; glucocorticoids and carbamazepine increase risk of hyponatremia; cholestyramine may decrease effects of thiazides; coadministration with beta-blockers may enhance hypoglycemia and hypertriglyceridemia; coadministration with ketanserin may lead to prolonged QT interval and increased risk of ventricular arrhythmias

Contraindications

Documented hypersensitivity; anuria; renal decompensation

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor for metabolic alkalosis, hypercalcemia, and volume depletion; photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; caution in renal disease, hepatic disease, gout, diabetes mellitus, and erythematosus; diuretics are generally contraindicated in pregnancy

Follow-up

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

Medicolegal Pitfalls

• Failure to adhere to monitoring guidelines after starting medications that have a risk of exacerbating RTA type IV is a pitfall, because although hyperkalemia is treatable, it may be lethal if undetected. (Early detection of renal disease may help in identifying those patients who are 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

1. Hoskote SS, Joshi SR, Ghosh AK. Disorders of potassium homeostasis: pathophysiology and management. J Assoc Physicians India. Sep 2008;56:685-93. [Medline].

2. Karet FE. Mechanisms in hyperkalemic renal tubular acidosis. J Am Soc Nephrol. Feb 2009;20(2):251-4. [Medline].

3. 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].

4. Düsing R, Sellers F. ACE inhibitors, angiotensin receptor blockers and direct renin inhibitors in combination: a review of their role after the ONTARGET trial. Curr Med Res Opin. Sep 2009;25(9):2287-301. [Medline].

5. Estacio RO. Renin-angiotensin-aldosterone system blockade in diabetes: role of direct renin inhibitors. Postgrad Med. May 2009;121(3):33-44. [Medline]. [Full Text].

6. Doulton TW, Macgregor GA. Combination renin-angiotensin system blockade with the renin inhibitor aliskiren in hypertension. J Renin Angiotensin Aldosterone Syst. Jul 17 2009;[Medline].

7. 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].

8. 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].

9. 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].

10. DeFronzo RA. Hyperkalemia and hyporeninemic hypoaldosteronism. Kidney Int. Jan 1980;17(1):118-34. [Medline].

11. 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].

12. 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].

13. Knochel JP. The syndrome of hyporeninemic hypoaldosteronism. Annu Rev Med. 1979;30:145-53. [Medline].

14. Michelis MF. Hyperkalemia in the elderly. Am J Kidney Dis. Oct 1990;16(4):296-9. [Medline].

15. Oster JR, Singer I, Fishman LM. Heparin-induced aldosterone suppression and hyperkalemia. Am J Med. Jun 1995;98(6):575-86. [Medline].

16. Perazella MA, Mahnensmith RL. Hyperkalemia in the elderly: drugs exacerbate impaired potassium homeostasis. J Gen Intern Med. Oct 1997;12(10):646-56. [Medline].

17. Tan SY, Burton M. Hyporeninemic hypoaldosteronism. An overlooked cause of hyperkalemia. Arch Intern Med. Jan 1981;141(1):30-3. [Medline].

18. Williams GH. Hyporeninemic hypoaldosteronism. N Engl J Med. Apr 17 1986;314(16):1041-2. [Medline].

Keywords

hyporeninemic hypoaldosteronism, aldosterone, renin, angiotensin renin, aldosterone angiotensin, renal tubular acidosis, distal renal tubular acidosis, hyperkalemia, hyperkalemic renal tubular acidosis, tubular hyperkalemia, cortical collecting tubule

Contributor Information and Disclosures

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
James H Sondheimer, MD is a member of the following medical societies: American College of Physicians and American Society of Nephrology
Disclosure: Nothing to disclose.

Medical Editor

Donald A Feinfeld, MD, FACP, FASN, Consulting Staff, Division of Nephrology & Hypertension, Beth Israel Medical Center
Donald A Feinfeld, MD, FACP, FASN is a member of the following medical societies: American Academy of Clinical Toxicology, American Society of Hypertension, American Society of Nephrology, and National Kidney Foundation
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Christie P Thomas, MBBS, FRCP, FASN, FAHA, Professor, Department of Internal Medicine, Division of Nephrology; Medical Director, Kidney and Kidney/Pancreas Transplant Program, University of Iowa Hospitals and Clinics
Christie P Thomas, MBBS, FRCP, FASN, FAHA is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Heart Association, American Society of Nephrology, American Society of Transplantation, American Thoracic Society, International Society of Nephrology, and Royal College of Physicians
Disclosure: Genzyme Grant/research funds Other

CME Editor

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association
Disclosure: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Amgen Honoraria Speaking and teaching; Ortho Biotech Honoraria Speaking and teaching

Chief Editor

Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System
Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology
Disclosure: Nothing to disclose.

The author would like to thank Dr. Jaideep Hingorani for his many helpful comments and suggestions.

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