Hyporeninemic Hypoaldosteronism Workup

  • Author: James H Sondheimer, MD, FACP, FASN; Chief Editor: Vecihi Batuman, MD, FASN  more...
Updated: Jul 05, 2016

Approach Considerations

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.


Laboratory Studies

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.

Urinary electrolytes

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.

Renin and aldosterone

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—though in cases of clinical uncertainty, they should be obtained

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.

Contributor Information and Disclosures

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: Receive dialysis unit medical director fee (as independ ent contractor) for: DaVita .

Chief Editor

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.

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

  2. Karet FE. Mechanisms in hyperkalemic renal tubular acidosis. J Am Soc Nephrol. 2009 Feb. 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. 1980 Jan. 17(1):89-101. [Medline].

  4. 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].

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

  6. 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].

  7. 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].

  8. 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].

  9. 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].

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

Renin-antiotensin-aldosterone system.
Medscape Consult
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.