Hyporeninemic Hypoaldosteronism

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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.

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 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.

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 (P_K) 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. ^{[1, 2]}

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. ^[3]

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:

Sickle cell disease

Analgesic nephropathy

Lead nephropathy

Chronic pyelonephritis

Obstructive nephropathy

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. ^[4]

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. ^[5]  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. ^[6]  In another study, Schmoyer et al reported that a patient who underwent orthotopic liver transplantation developed tacrolimus-induced type IV renal tubular acidosis (RTA). ^[7]

Type IV RTA can in rare cases be seen in patients with systemic lupus erythematosus (SLE) as a result of SLE-associated renal disease. ^{[8, 9]}

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 ^{[10, 11]} :

Inhibitors of renin release – These include beta blockers, including beta₁ selective blockers, and nonsteroidal anti-inflammatory agents (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors

Renin inhibitors (eg, aliskiren) ^[12]

Inhibitors of aldosterone production – ACE inhibitors block formation of angiotensin II (a cofactor in aldosterone production), an effect similar to that of angiotensin II receptor blockers (ARBs); 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, with triamterene exerting a mild effect on this channel; calcineurin inhibitors, including cyclosporine A and tacrolimus, may interfere with the aldosterone receptor

Potassium-containing drugs (eg, oral or intravenous [IV] penicillin)

Drugs that impair 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, from mannitol or radiocontrast material) impair potassium homeostasis by causing osmotic efflux of water from cells, with convective drag of potassium—an effect mostly seen in diabetics, who lack the homeostatic protections of insulin release and an intact autonomic system

Certain herbal products – Some herbal formulations are rich in potassium themselves or contain digitalislike substances that may inhibit tubular potassium excretion

Specifying the incidence or prevalence of RTA type IV is difficult for the following reasons:

The condition is often undetected

It may manifest only when the patient is challenged by dietary potassium excess

It is often iatrogenic (in the sense that an underlying proclivity is exposed by certain medications)

It improves with the removal of exacerbating agents

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 ^[13] 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.

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

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

Schambelan M, Sebastian A, Biglieri EG. Prevalence, pathogenesis, and functional significance of aldosterone deficiency in hyperkalemic patients with chronic renal insufficiency. Kidney Int. 1980 Jan. 17(1):89-101. [Medline].

Sousa AG, Cabral JV, El-Feghaly WB, de Sousa LS, Nunes AB. Hyporeninemic hypoaldosteronism and diabetes mellitus: Pathophysiology assumptions, clinical aspects and implications for management. World J Diabetes. 2016 Mar 10. 7 (5):101-11. [Medline]. [Full Text].

Kulkarni M. Type 4 renal tubular acidosis in a kidney transplant recipient. Biomed J. 2016 Feb. 39 (1):85-6. [Medline].

Lin W, Mou L, Tu H, et al. Clinical analysis of hyperkalemic renal tubular acidosis caused by calcineurin inhibitors in solid organ transplant recipients. J Clin Pharm Ther. 2017 Feb. 42 (1):122-4. [Medline].

Schmoyer C, Mishra S, Fulco F. Tacrolimus-Induced Type IV Renal Tubular Acidosis following Liver Transplantation. Case Reports Hepatol. 2017. 2017:9312481. [Medline]. [Full Text].

Sanchez-Marcos C, Hoffman V, Prieto-Gonzalez S, Hernandez-Rodriguez J, Espinosa G. Renal tubular acidosis type IV as a complication of lupus nephritis. Lupus. 2016 Mar. 25 (3):307-9. [Medline].

Porteous H, Morgan N, Lanfranco J, Garcia-Buitrago M, Young L, Lenz O. Systemic lupus erythematosus associated with type 4 renal tubular acidosis: a case report and review of the literature. J Med Case Rep. 2011 Mar 24. 5:114. [Medline].

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. 2009 Sep. 25(9):2287-301. [Medline].

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

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

Haas CS, Pohlenz I, Lindner U, Muck PM, Arand J, Suefke S. Renal tubular acidosis type IV in hyperkalaemic patients–a fairy tale or reality?. Clin Endocrinol (Oxf). 2013 May. 78(5):706-11. [Medline].

Lehnhardt A, Kemper MJ. Pathogenesis, diagnosis and management of hyperkalemia. Pediatr Nephrol. 2011 Mar. 26(3):377-84. [Medline]. [Full Text].

James H Sondheimer, MD, FACP, FASN Associate Professor of Medicine, Wayne State University School of Medicine; Medical Director of Hemodialysis, Harper University Hospital at Detroit Medical Center; Medical Director, DaVita Greenview Dialysis (Southfield)

James H Sondheimer, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Nephrology

Disclosure: Nothing to disclose.

Vecihi Batuman, MD, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

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

Additional Contributors

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.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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 Heart Association, American Society of Nephrology, and Royal College of Physicians

Disclosure: Nothing to disclose.

Hyporeninemic Hypoaldosteronism

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