Primary Aldosteronism Diagnosis

Primary aldosteronism is caused by several difference specific entities. 60 to 70% is due to bilateral idiopathic hyperaldosteronism (idiopathic hyperplasia). Unilateral aldosterone producing adenomas are the cause for 30 to 40%. Less common causes include unilateral hyperplasia, familial hyperaldosteronism, and pure aldosterone producing adrenocortical carcinoma and ectopic aldosterone secreting tumors. The approach to diagnosing primary aldosteronism, with an emphasis on aldosterone-producing adenomas and bilateral idiopathic hyperaldosteronism. The following is my summary of the “The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline” which was published in 2016 (Funder 2016).

To Begin

Is recommended to test for primary aldosteronism in patients with:

1. Resistant hypertension on 3 drugs

2. Controlled hypertension on 4 or more drugs

3. Sustained blood pressure >150/100 

4. Hypertension and an adrenal incidentaloma

5. Hypertension and sleep apnea

6. Hypertension and first degree family members with primary aldosteronism

7. Hypertension and spontaneous or low dose diuretic-induced hypokalemia

8. Family history: of hypertension and CVA that occurred before 40 years of age

How to Interpret the Aldosterone-Renin Ratio (Case Detection)

Firstly, it is important to know that aldosterone-renin ratio (ARR)  is most sensitive when samples are collected in the morning after the patient has been out of bed for at least 2 hours, and usually after they have been seeded for 5 to 15 minutes. Ideally, the patient should have undershirt intake before testing and they should be potassium replete. Mineralocorticoid antagonists  should be withdrawn for at least four weeks before testing. If possible, medications with minimal effects on the plasma aldosterone levels can be used. These medications include slow-release verapamil, hydralazine, prazosin, doxazosin, and terazosin. If all potentially problematic agents cannot be safely withdrawn, the ARR should be performed and the results considered in the light of the potential compounding factors.  For example, in some patients with severe primary aldosteronism, treatment with mineralocorticoid antagonists cannot be safely continued. In this setting, primary aldosteronism related testing can be pursued as long as renin is suppressed.

The ARR is variable and there is no single cutoff value for ARR that lets you know that someone has primary aldosteronism. For case detection, the guidelines place a high value on avoiding the risks associated with missing primary aldosteronism and does for going the opportunity of surgical cure and the reduction for excess cardiovascular morbidity with specific medical treatment.  It places a lower value on avoiding the risk of classifying a hypertensive patient as having primary aldosteronism and exposing then to additional diagnostic testing. The recommendations also place a high value avoiding the risk associated with missing a diagnosis of a unilateral forms of primary aldosteronism and us the opportunity of possibly curative intervention on by unilateral adrenalectomy.  It places a lower value on avoiding the risks associated of expose the patient's with bilateral primary aldosteronism to additional diagnostic testing

Despite the lack of a definite ratio, primary aldosteronism should be suspected when the PRA is suppressed to <1ng/mL/hr and the PAC is greater than 10ng/dL. The greater the ratio, though, the higher the sensitivity.

For example, the combination of a PAC above 20ng/dL and a PAC/PRA ratio >30 had a sensitivity and specificity of 90% for a diagnosis of primary aldosteronism. It is possible, in the context of low renin activity, to have a ratio of >30, but have a low PAC. In one study, four out of 74 patients with PAC <15 ng/dL had unilateral, surgically correctable primary aldosteronism. Around 26 patients out of this 74 patient population had aldosterone which failed to suppress during fludrocortisone suppression testing. There are two conclusions from this study. Firstly, it is possible to have primary aldosteronism with a low PAC. Secondly, it can be inferred that a patient with a relatively low PAC of <15ng/dL is more common in bilateral adrenal hyperplasia than in patients with aldosterone-producing adenomas (Stowasser 2004). 

In addition, the following factors have an impact on renin and aldosterone levels:

Case Confirmation

Confirmatory testing places a high value on sparing patients with false-positive ARR tests from undergoing costly and intrusive lateralization procedures. 

Confirmatory testing does not need to be performed in patients with spontaneous hypokalemia or undetectable plasma renin activity and plasma aldosterone concentration greater than 20 ng/dL. These patients can progress directly to subtype classification.

The current literature does not identify a gold standard confirmatory test for primary aldosteronism.  Four testing protocols; oral sodium loading, saline infusion, fludrocortisone suppression, and Captopril challenge are in common use.  There is no definitive evidence that one single test is optimal. The choice of confirmatory test is commonly determined by considering cost, patient appliance, laboratory routine, and local expertise.

The UpToDate author for this particular topic, uses oral sodium loading as the confirmatory test. For oral sodium loading, after hypertension and hypokalemia are controlled, a high-sodium diet is given for 3 Days. Patients should be given instructions on the sodium content of foods they need in order to consume 5000mg of sodium per day. If a patient is unable to tolerate these high sodium foods, they can be given sodium chloride tablets, 2g three times daily. Since sodium loading typically increases kaliuresis and hypokalemia, serum potassium should be measured daily and aggressive replacement of potassium chloride should be prescribed and monitored almost daily. On the third day of the high-sodium diet, serum electrolytes are measured and a 24-hour urine specimen is collected for measurement of aldosterone, sodium, and creatinine. The 24-hour urine sodium excretion should exceed 200 mEq (4600 mg) to document adequate sodium loading. Urine aldosterone excretion >12 mcg/24 hours in this setting is consistent with hyperaldosteronism.

Subtype Classification

Adrenal CT is recommended. MRI has no advantage over CT as it is more expensive and has less spatial resolution. 

Imaging though, cannot reliably visualized microadenomas or distinguish nonfunctioning incidentalomas from aldosterone producing adenomas with confidence.  This means that adrenal vein sampling is the most accurate means of differentiating unilateral from bilateral forms of primary aldosteronism. Because ARR is often associated with false positives, patient's should only undergo adrenal vein sampling if they have positive confirmatory testing as adrenal vein sampling is extensive and invasive the sensitivity and specificity of adrenal vein sampling is 95 and 100%, respectively for detecting unilateral aldosterone excess.  Adrenal vein sampling is the gold standard test to distinguish unilateral from bilateral primary aldosteronism. 

Treatment

Adrenalectomy is preferred for unilateral primary aldosteronism . Blood pressure should be well controlled preoperatively. Potassium supplementation and spironolactone should be discontinued on postoperative day one. Postoperatively, the patient should be allowed to have a liberal salt diet to prevent hyperkalemia due to contralateral adrenal gland suppression. Patient should be allowed to have a liberal salt diet to prevent hyperkalemia due to contralateral adrenal gland suppression from primary hyperaldosteronism. If the patient does not want surgery or if surgery is not appropriate, then spironolactone should be started at 12.5mg daily and increased gradually to a maximum dose of 100mg daily. Gynecomastia occurs in 6.9% of patients with a spironolactone dose <50mg daily and in more than 50% in those with doses >50mg daily. Epleronone has half the mineralocorticoid effect as spironolactone, but is reasonable if the patient cannot tolerate spironolactone. 

References

Stowasser, M., & Gordon, R. D. (2004). Primary aldosteronism—careful investigation is essential and rewarding. Molecular and cellular endocrinology, 217(1-2), 33-39.

Funder, J. W., Carey, R. M., Mantero, F., Murad, M. H., Reincke, M., Shibata, H., ... & Young Jr, W. F. (2016). The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 101(5), 1889-1916.

ACE and ARB Comparison

When seeing a new patient, we sometimes find that they are on an ACE or ARB which is different from the typical agents we use. Also, certain ACE/ARB medications cost more than others. I made this table to facilitate the titration of a medication or the conversion of one ACE/ARB to more appropriate agents. Dosing frequency comes from Lexicomp. Cost data comes from a combination of Arkansas Blue Cross and Blue Shield, Lexicomp, and the Walmart $4 drug list. Dosing frequency comes from Lexicomp.

The Gut Microbiome in Chronic Kidney Disease

There are 130 uremic solutes according to the research group, EuTox. Blood urea nitrogen and creatinine are only two of these solutes and are simply used as surrogate markers for the other 128. Of  these uremic solutes, two of the most extensively studied are indoxyl sulfate and p-cresyl sulfate. They have been shown to have a variety of deleterious effects on body tissues including tubular cell damage, coagulation disturbances, endothelial dysfunction, leukocyte activation, cardiac fibrosis and hypertrophy, and insulin resistance (Vanholder 2014)).

Interestingly,  these two solids are derived from the metabolism of the gut microbiome. In an interesting study (Aronov 2011), metabolomic profiles of dialysis patients with colons and without colons or compared. These two compounds are virtually absent in dialysis patients without colons  indicating that they are derived from the gut microbiome. There are multiple other colon-derived uremic solids, but these two in particular are important because they are actually shown to have harmful effects on the body and they are tightly albumin-bound meaning that they have poor clearance with hemodialysis.

In addition to producing uremic solutes, the gut  microbiome has a variety of beneficial effects on the body, including vitamin synthesis, immune system development, and production of short-chain fatty acids which our colon enterocytes use for energy, thus helping maintain the integrity of the gut epithelial barrier (Barrows 2015, Hooper 2002, Kasubuchi 2015).  Unfortunately, chronic kidney disease and some of the medications used in it’s treatment cause dysbiosis, reducing some beneficial effects of the gut microbiome. The field of gut microbiome research is a hot topic right now and it will be an important one to watch in the coming years. It is important for us not only because some uremic solutes are made by the colon, but also because CKD and other treatments for renal disease affect the gut microbiome.

References:

Aronov, P. A., Luo, F. J. G., Plummer, N. S., Quan, Z., Holmes, S., Hostetter, T. H., & Meyer, T. W. (2011). Colonic contribution to uremic solutes. Journal of the American Society of Nephrology, 22(9), 1769-1776.

Barrows, I. R., Ramezani, A., & Raj, D. S. (2015). Gut Feeling in AKI: The Long Arm of Short–Chain Fatty Acids.

Hooper, L. V., Midtvedt, T., & Gordon, J. I. (2002). How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annual review of nutrition, 22(1), 283-307.

Kasubuchi, M., Hasegawa, S., Hiramatsu, T., Ichimura, A., & Kimura, I. (2015). Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation. Nutrients, 7(4), 2839-2849.

Vanholder, R., Schepers, E., Pletinck, A., Nagler, E. V., & Glorieux, G. (2014). The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. Journal of the American Society of Nephrology, 25(9), 1897-1907.

Evidence for Blood Pressure Goals in CKD

In contrast to other aspects of nephrology that are difficult to control (think of the inevitable slow decline of renal function in diabetic nephropathy), blood pressure is one aspect of CKD management we can fix over a realatively short period of time. It’s very satisfying to see a patient who has been battling with uncontrolled blood pressure for over a year and then easily control it over the course of a few clinic visits. When our patients ask us what their blood pressure should be, we can tell them we are shooting for a BP <130/80 in most cases (outside of the very old and frail). We should also be able to let them know how this benefits them and we should also be able to briefly communicate the evidence base to other physicians. Below is the 80/20 summary of the big 2 trials that inform our blood pressure target of 130/80.

In general, lowering blood pressure to <130/80 mmHg (referred to subsequently as intensive BP targets) as compared to <140/90 mmHg is recommended in patients with CKD and provides two major benefits. Firstly, it reduces the risk of ESRD in those with proteinuric CKD (defined in trials as a urine protein-to-creatinine ratio >0.22 g/g). Unfortunately, this benefit does not extend to those without proteinuria. Secondly, it reduces mortality whether or not the patient has proteinuria. These benefits are most evident on long-term follow up of patients.

There are three trials that inform this area – the MDRD study (1994), the AASK trial (2002), and the SPRINT trial (2015). The MDRD study showed that patients excreting more than 1 gram of protein daily had lower rates of CKD progression with an intensive BP target. Long-term follow up of MDRD participants echoed this finding. The original AASK trial showed no benefits to preservation of renal function in the original trial. On long term follow up of AASK trial participants, however, intensive BP targets slowed progression of CKD in those with proteinuria > 0.22 g/g (average daily proteinuria of 1g). The MDRD study and AASK trial show that long-term follow up is vital to seeing the benefit of intensive BP goals.

Lastly, the SPRINT trial showed that aggressive BP targets reduce mortality regardless of the presence of proteinuria.  No benefit was seen for preservation of renal function. Importantly, the risk of a 30% or greater decline in renal function was higher with intensive BP targets. This finding was recently examined in more detail in a study utilizing urinary proteomic biomarkers of kidney injury. It suggested that this decline of renal function in the intensive BP arm of the SPRINT trial was not due to actual damage of the renal parenchyma, but is instead attributable to hemodynamic effects of a lower BP. Thus, targeting an intensive BP target to lower mortality is reasonable.