Renin-antiotensin-aldosterone system.
This article reviews some of the pathophysiologic aspects and the clinical picture of, as well as treatment strategies for, hyporeninemic hypoaldosteronism, a condition in which hyperkalemia results from a deficiency of renin and aldosterone.[1]
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. (For a detailed discussion of the regulation of acid-base balance, see Metabolic Acidosis.)
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 mL/min). At times, however, 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. Strictly speaking, the term hyporeninemic hypoaldosteronism should be limited to cases in which testing reveals the cause of hyperkalemia to be, as stated above, a deficiency of renin and aldosterone.
Similarly, the term type IV renal tubular acidosis (RTA)—or 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. 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 or of tubular responsiveness to aldosterone.
The underlying renal disease and any associated illnesses (eg, systemic lupus erythematosus [SLE] or 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.
First, exclude pseudohyperkalemia, which is seen with difficult venipunctures and in thrombocytosis. Repeat the serum potassium determination 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. Measurement of plasma potassium (PK) can help to confirm the diagnosis of pseudohyperkalemia, if this is suspected.
If adrenal insufficiency is at all suspected, a random cortisol level should be obtained as a screening test. However, a cosyntropin 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, obtain a 12-lead electrocardiogram (ECG) to look for signs of hyperkalemia. If these signs are found, institute emergency treatment.
Acidosis generally is mild, with serum bicarbonate levels in the range of 18-22 mEq/L. The bicarbonate level is useful for guiding therapy (see 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 (which varies from one laboratory to another).
If the patient is presenting for the first time, order a complete workup for the underlying renal disease. Serologic studies for systemic lupus erythematosus (SLE), hepatitis, and human immunodeficiency virus (HIV), as indicated, may be necessary in many patients. (See Chronic Renal Failure.)
Urine pH measurement, 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.
Assessment of urinary electrolytes 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 potassium is prima facie evidence of inadequate renal potassium excretion.
If the patient has severe hyperkalemia or electrocardiographic (ECG) abnormalities are present, emergency measures for hyperkalemia are necessary (see Hyperkalemia).
Drug therapy for hyperkalemia may itself have adverse effects; in particular, patients must be adequately monitored for overtreatment with resulting hypokalemia, congestive heart failure (CHF), or metabolic alkalosis (depending on the agent[s] used).
Pharmacologic treatments include the following:
Recommend a dietary review, preferably by a renal dietitian, to uncover sources of dietary potassium excess.
In the United States, patients’ dietary potassium intake may exceed 120 mEq/day, and elsewhere, it may be even higher. Patients excrete 90% of this intake renally. Even with CKD, the kidneys usually can compensate and maintain potassium homeostasis, albeit at the cost of reduced 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.[2, 3]
The degree of acidosis varies and may be related to the underlying CKD. Whereas in type I (ie, distal) RTA, the defect is in proton secretion with resulting high urine pH (>5.3), in type IV RTA, the primary defect is in ammoniagenesis. This defect, albeit significant, still permits elaboration of acidic (pH < 5.3) urine. Hyperkalemia inhibits renal ammoniagenesis in several ways. Furthermore, it may produce acidosis by shifting protons from cells out 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 into angiotensin II by angiotensin-converting enzyme (ACE). 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 hyporeninemic hypoaldosteronism, atrophy of the juxtaglomerular apparatus may be present; this may be more prevalent in diabetics. Any combination of these factors may cause hyporeninemic hypoaldosteronism or RTA type IV. Indeed, as shown by Schambelan et al, all 3 factors may be present in some patients.[4]
As a rule, renal interstitial disorders are more likely to produce a picture of type IV RTA than glomerular diseases are. Interstitial diseases produce more tubular damage, cause more renin production impairment (eg, in the 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:
Diabetic nephropathy, though 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.[5]
Patients with HIV disease are at risk for 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.
Kulkarni reported on a diabetic patient aged 66 years who was found to have type IV RTA following a kidney transplant.[6] A study by Lin et al noted the development of type IV RTA in association with the use of calcineurin inhibitors (cyclosporine A and tacrolimus) in patients who underwent solid organ transplantation. Reduction of the drug dosage, the addition of low-dose fludrocortisone, or the temporary replacement of calcineurin inhibitor with sirolimus was reported to improve the RTA-related prognosis.[7] In another study, Schmoyer et al reported that a patient who underwent orthotopic liver transplantation developed tacrolimus-induced type IV renal tubular acidosis (RTA).[8]
Type IV RTA can in rare cases be seen in patients with systemic lupus erythematosus (SLE) as a result of SLE-associated renal disease.[9, 10]
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 such a patient to have hyporeninemic hypoaldosteronism, whereas 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 that affect potassium excretion and homeostasis[11, 12] :
A study by Tseng et al suggested that in infants who, despite having no identifiable risk factors, develop type IV RTA as a complication of urinary tract infection, mutation of the NR3C2 gene may be a contributing factor.[14]
Specifying the incidence or prevalence of RTA type IV is difficult for the following reasons:
RTA type IV involves a broad spectrum of symptom severity, and only the more severe cases provoke attention and therapy. In an aging population with a high prevalence of diabetes and polypharmacy, the clinical picture of RTA type IV is not uncommon.
A recent retrospective report[15] from Germany showed an incidence of type IV RTA of 3.8% of hospital admissions in a single center.
RTA type IV 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. True RTA type IV and its drug-induced counterpart are increasing problems among elderly patients and are aggravated by polypharmacy.
No sexual predilection exists; however, sex-related differences in frequency have been documented for the underlying renal diseases (eg, more systemic lupus erythematosus [SLE] occurs in women, and more lead nephropathy occurs in men).
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.
RTA type IV can almost always be treated through some combination of addition or elimination of eliminating medications and implementation of dietary restraint. The underlying renal disease, however, often progresses towards eventual end-stage renal disease (ESRD). Note that the 2 classes of agents with proven benefit in delaying progression of renal disease (ie, ACE inhibitors and ARBs) also are common causes of hyperkalemia, which may limit their utility in delaying the progression of CKD in some patients.
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.
Renal tubular acidosis (RTA) type IV generally is asymptomatic unless severe hyperkalemia leads to muscle weakness or life-threatening arrhythmia (see Hyperkalemia).[16] 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. These drugs include medications affecting the renin-angiotensin-aldosterone axis (see Causes). Hyperkalemia with moderate doses of such agents may suggest a forme fruste of RTA type IV.
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, and systemic lupus erythematosus [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 use of medications (ie, over-the-counter [OTC] and prescription drugs).
The underlying renal disease and any associated illnesses (eg, SLE or 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, because glucocorticoid excretion is intact by definition. Patients usually are hypertensive, in association with their underlying renal disease. 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 (such as fever, orthostatic changes, hyperpigmentation, and signs of illnesses [eg, SLE]) that, when resulting in treatment with long-term corticosteroids, can lead to secondary hypoadrenalism.
The hallmark of diagnosis is the finding of hyperkalemia in the setting of mild-to-moderate chronic kidney disease. The condition is usually discovered during routine laboratory evaluations.
For new patients with chronic kidney disease (CKD), perform ultrasonography to establish kidney size and to screen for obstruction. 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.
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 by the platelets in vitro to affect serum potassium materially. Plasma, on the other hand, is prepared in a manner that prevents clotting in vitro; thus, the platelets largely remain intact and do not release their cytosolic potassium.
Repeat the serum potassium determination 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. Measurement of plasma potassium (PK) can help confirm the diagnosis of pseudohyperkalemia, if this is suspected.
If adrenal insufficiency is at all suspected, a random cortisol level should be obtained as a screening test. However, a cosyntropin 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, obtain a 12-lead electrocardiogram (ECG) to look for signs of hyperkalemia. If these signs are found, institute emergency treatment.
Acidosis generally is mild, with serum bicarbonate levels in the range of 18-22 mEq/L. The bicarbonate level is useful for guiding therapy (see 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 (which varies from one laboratory to another). However, some patients in whom the diagnosis of type IV RTA is considered have CKD that is sufficiently advanced to result in the accumulation of endogenous metabolic acids (eg, phosphate and urate), leading to a mild elevation of the anion gap.
If the patient is presenting for the first time, order a complete workup for the underlying renal disease. Serologic studies for systemic lupus erythematosus (SLE), hepatitis, and HIV, as indicated, may be necessary in many patients. (See Chronic Renal Failure.)
Urine pH measurement, 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.
Assessment of urinary electrolytes 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 potassium is prima facie evidence of inadequate renal potassium excretion.
The urinary anion gap is determined by adding sodium and potassium and then 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, urinary sodium [UNa] >20 mEq/L) and in the absence of unmeasured anions (eg, ketone bodies and lactate).
The transtubular potassium gradient (TTKG) is a further refinement of the random urine potassium (UK) measurement. Most tubular potassium excretion takes places in the cortical collecting tubule (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) to plasma osmolality (POsm) is used to estimate the degree of urinary concentration relative to the end of the CCT. Dividing UK by this ratio yields an estimate of the tubular UK at the end of the CCT. Thus, UK/(UOsm/POsm) is a crude estimate of UK at that tubular site.
The ratio of estimated tubular UK to PK constitutes the TTKG:
TTKG = [UK/(UOsm/POsm)]/PK
Under normal conditions in a healthy person, the TTKG is 8-9. With potassium loading and appropriate aldosterone release and action, it rises to exceed 11. A value lower than 5 in the setting of hyperkalemia usually means an aldosterone deficiency, either in its release or in its tubular effect. This interpretation of the TTKG assumes concentrated urine (UOsm >POsm) and a UNa level higher than 25 mEq/L, indicating adequate distal sodium delivery.
Note that if sodium is avidly resorbed more proximally, inadequate amounts of 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:
If confirmation of a lack of renin and aldosterone is desired, perform diuresis to achieve mild volume depletion and then obtain a morning standing blood sample to maximally stimulate the renin-aldosterone axis.
If the patient has severe hyperkalemia or electrocardiographic (ECG) abnormalities are present, emergency measures for hyperkalemia are necessary (see Hyperkalemia). The need for dialysis in patients with hyperkalemia and mild chronic kidney disease (CKD) is uncommon, because medical measures usually suffice.
Drug therapy for hyperkalemia may itself have adverse effects; in particular, patients must be adequately monitored for overtreatment with resulting hypokalemia, congestive heart failure (CHF), or metabolic alkalosis (depending on the agent[s] used).
Because many clinically important classes of medications have a tendency to produce a picture reflecting renal tubular acidosis (RTA) type IV, 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.
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.
If the patient presents with hyperkalemia as a complication of urinary tract obstruction, institute appropriate urologic measures.
Reduce or, if at all possible, eliminate 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.
Loop and thiazide diuretics are well known for their ability to promote kaliuresis and chloruresis. Although these effects are usually viewed as adverse ones, in RTA type IV they are exploited as a way of removing potassium and treating 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 the diuretic with a glass of orange juice. The main adverse effects of diuretics are overdiuresis with volume depletion and alkalosis.
Sodium bicarbonate (ie, NaHCO3) is administered in 10-grain (650-mg) tablets. This adjunctive agent usually corrects the acidosis and, by increasing distal delivery of bicarbonate anion, increases urinary potassium excretion. 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. Consumption of NaHCO3 may cause the patient to belch and may also lead to volume overload.
Fludrocortisone is the third-line agent for patients with RTA type IV. This synthetic corticosteroid is unique in that its mineralocorticoid activity significantly exceeds its glucocorticoid activity.
Fludrocortisone is used as an aldosterone analogue; however, the dosage needed to achieve effective kaliuresis is generally 0.1-0.3 mg/day, which is higher than the dosage used as replacement in patients with adrenal insufficiency. This underscores the importance of tubular hyporesponsiveness to aldosterone in most patients with RTA type IV.
Fludrocortisone can exacerbate hypertension and fluid overload, and patients taking this drug need close follow-up care. It should also be kept in mind that fludrocortisone has some glucocorticoid activity, with the resultant metabolic and long-term side effects.
Reports regarding the adverse effects of endogenous aldosterone on cardiac remodeling in patients with CHF raise serious concerns about the long-term use of fludrocortisone, suggesting that it should be avoided unless all other methods are exhausted.
Sodium polystyrene sulfonate is an exchange resin that is useful in achieving potassium removal via the colon, thereby bypassing the impaired renal excretory mechanisms. It now is available in premixed doses in a sorbitol solution (to provide the necessary laxation ).
Sodium polystyrene sulfonate is of variable effectiveness in this setting; however, on average, it removes 1 mEq of potassium for each 1 g 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 sodium polystyrene sulfonate is not very palatable. If the patient develops constipation, this agent is ineffective. Intestinal complications of oral or rectal use are well known.
Sodium polystyrene sulfonate clearly has a role in the long-term treatment of patients for whom other kaliuretic approaches have failed, patients who are intolerant to these approaches, or patients who are noncompliant with dietary restrictions. It cannot be used in patients with ileostomy (absence of colon), ileus, or obstruction or in patients who have recently undergone intestinal surgery.
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, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], beta blockers, and 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.
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.
Although there are no published data regarding whether to impose activity restrictions on patients with RTA type IV, there is a theoretical concern that these patients might be ill equipped to handle the transient hyperkalemia that strenuous exercise produces. Accordingly, instruct patients to approach strenuous exercise with caution and to proceed with it only if stable control of potassium is demonstrated.
Before discharge, ensure that the patient’s potassium level has stabilized within an acceptable range on 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. Educate patients about the risk of sudden catastrophic events from hyperkalemia and the importance of compliance with medications, diet, and follow-up procedures. Schedule timely outpatient follow-up care and laboratory testing.
Outpatient care consists of monitoring the response to therapy, with particular attention paid to blood pressure, volume status, and electrolytes.
If 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 cause harm by giving rise to hypokalemia and alkalosis.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Medications employed in the management of renal tubular acidosis (RTA) type IV include loop and thiazide diuretics, mineralocorticoids, ion-exchange resins, and alkalinizing agents.
Clinical Context: Furosemide inhibits reabsorption of chloride, predominantly in the thick ascending limb of the loop of Henle. The high efficacy of this drug is largely due to the large amount of sodium usually reabsorbed in this site.
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.
Clinical Context: Fludrocortisone is used as a third-line agent in patients for whom treatment with diuretics, sodium bicarbonate, and dietary measures has failed. It promotes increased reabsorption of sodium and loss of potassium from renal distal tubules.
These agents provide pharmacologic amounts of mineralocorticoid activity, so that the patient can overcome tubular resistance to physiologic amounts of aldosterone.
Clinical Context: Sodium polystyrene sulfonate exchanges sodium for potassium and binds in the gut, primarily in the large intestine; it also decreases total body potassium. The time to onset of action ranges from 2-12 hours after oral administration and is longer after rectal administration.
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.
Clinical Context: Sodium bicarbonate is administered intravenously (IV) for emergency treatment of hyperkalemia. It is given orally to patients with metabolic acidosis and hyperkalemia.
Alkalinizing agents provide bicarbonate anion for repletion of patients with metabolic acidosis. They alkalinize the urine, enhancing kaliuresis.
Clinical Context: Hydrochlorothiazide inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium, water, potassium, and hydrogen ions.
Clinical Context: Chlorothiazide inhibits the reabsorption of sodium in distal tubules, causing increased excretion of sodium and water as well as of potassium and hydrogen ions.
Thiazide diuretics are useful in the treatment of RTA type IV by virtue of their kaliuretic effects. They are less likely to produce marked volume depletion than loop diuretics are, and they may be better antihypertensive agents.
Renin-antiotensin-aldosterone system.
