Podcast Summary: Endocrine Feedback Loop

Episode: EFL056 – Renin Measurements in Primary Adrenal Insufficiency
Date: December 19, 2024
Host: Dr. Chase Hendrickson (Vanderbilt University Medical Center)
Contributors: Dr. Jill Wagner (University of Nebraska Medical Center), Dr. Irina Benkos (Mayo Clinic)

Episode Overview

This episode of the Endocrine Feedback Loop centers on the use of plasma renin measurements in guiding mineralocorticoid replacement for individuals with primary adrenal insufficiency. The hosts dissect a recent study from the Journal of the Endocrine Society (Piazzala et al., Nov 2024), critically evaluating the methodology and real-world implications for clinical endocrinology practice. The discussion highlights ongoing uncertainty in optimal steroid dosing and the utility, limitations, and practicality of renin as a monitoring tool.

Key Discussion Points & Insights

1. Background & Importance of the Topic

• Glucocorticoid and mineralocorticoid management are routine but lack robust data guiding optimal dosing.
• Most endocrinologists use clinical judgment and basic labs (electrolytes, BP, symptoms) rather than evidence-based algorithms.
• Variability in clinical practice is high; thus, studies seeking better biomarkers to guide therapy are welcomed.

Notable Quote

“Fine tuning steroid doses in adrenal insufficiency is something we as endocrinologists do frequently, though without as much guidance in the medical literature as we might like.”
— Dr. Chase Hendrickson [00:01]

2. Existing Guidelines & Gaps

• Standard replacement: hydrocortisone 10–25 mg/day (split), mineralocorticoid 50–100 mcg/day.
• Actual physiologic cortisol production is lower than current recommendations, due to fears of under-replacement and adrenal crisis.
• No standardized method for adjusting mineralocorticoid dose; initial doses are set and adjusted with clinical and biochemical cues.

Notable Quote

“Surprisingly, there is very little data of how to choose either glucocorticoid or mineralocorticoid replacement dose.”
— Dr. Irina Benkos [03:34]

3. Why Use Renin? National vs. International Differences

• French guidelines encourage renin-based titration, but this is not standard elsewhere.
• Overt over/under-replacement is easy to spot; subtle cases are more challenging, especially when symptoms and lab values overlap or are affected by co-morbidities.
• Renin may offer a more sensitive biochemical window, though its interpretation can be confounded by salt/fluid intake and comorbidities like POTS.

Notable Quote

“What is challenging is to detect mild over- and under-replacement and especially to distinguish it from glucocorticoid underreplacement.”
— Dr. Irina Benkos [06:57]

4. Study Design & Methods

• Multi-center French study (2008-2022): Cross-sectional (serial) data from adults on treatment, focusing on those with at least one renin measurement.
• Primary data: glucocorticoid and mineralocorticoid doses (standardized for mineralocorticoid equivalency), labs (Na, K, BP), and renin levels.
• Renin levels categorized as: low (<20), target (20–60), or high (>60; units not standard US, but correlated for reference).
• Key limitations included lack of data on residual adrenal function, sodium/fluid intake, and standardization of renin measurements.

Notable Quotes

“Not all patients with primary adrenal insufficiency have complete deficiency… Some may not even need fludrocortisone because they still have their own endogenous aldosterone.”
— Dr. Irina Benkos [13:56]

“Renin production… is not impaired [in PAI]. Aldosterone is not the only regulator of renin.”
— Dr. Irina Benkos [13:56]

5. Main Findings

• 150 patients: mean age 44, 63% female, various etiologies.
• Huge variation in hydrocortisone/fludrocortisone doses.
• Only 29% achieved renin in the target range; 45% were “undertreated” (high renin by guideline), but 88% had normal Na and K.
• Renin correlated with sodium, systolic BP, potassium—but not with fludrocortisone or glucocorticoid dose.
• Over time, mineralocorticoid doses increased, but renin changes were inconsistent.
• Greatest insight: renin abnormality is much more common than abnormal electrolytes or BP in this population.

Notable Quote

“Renin was above the upper limit of normal, per their definition, in 45%, while 88%… showed normal sodium, normal potassium. Only 29%… were in this ideal renin range.”
— Dr. Jill Wagner [18:44]

6. Critical Appraisal of Study & Author Conclusions

• The study used renin as its defined outcome, so it “performed best” by study design, not because it is the biologically or clinically “best” marker.
• No direct link established between lab markers and patient-important outcomes (e.g., symptoms, QoL, crisis rates).
• Key limitations: confounders (residual mineralocorticoid activity, salt/fluid intake), retrospective design, non-standardized draws, lack of adherence data.
• All hosts agree on value of the study in adding to literature, but caution against overinterpreting renin superiority.

Notable Quotes

“Plasma renin concentration is a more sensitive marker than electrolytes and blood pressure for detecting over or under mineralocorticoid replacement dosing.”
— Study authors, as quoted by Dr. Hendrickson [22:49]

“Renin is far more likely to be abnormal in primary adrenal insufficiency than electrolytes or blood pressure are… If something’s going to be abnormal biochemically, it’s almost certainly going to be the renin level.”
— Dr. Chase Hendrickson [31:58]

“Rhinin is not a miracle biomarker… It helps put that last dot on the clinical assessment… but it would not trump my clinical judgment.”
— Dr. Irina Benkos [32:42]

7. Implications for Clinical Practice

• Renin can be used as an adjunct marker, especially in ambiguous cases where clinical/lab cues are incomplete or overlapping.
• No biochemical index, including renin, should supplant careful clinical assessment and patient-specific variables.
• Calls for future prospective studies focusing on patient-important outcomes and more standardized protocols for sampling and analysis.

Notable Quote

“It’s another piece to the puzzle… nothing is perfect… using that additional piece… is how clinically it can be the most productive.”
— Dr. Jill Wagner [30:48]

Timestamps for Key Segments

• Episode introduction/Article context – [00:01–02:37]
• Replacement regimens & literature gaps – [02:37–05:30]
• Clinical challenges in titration & role of renin – [05:30–09:05]
• Study methods & exposure assessment – [09:22–16:43]
• Renin cutoffs, units, and interpretation – [16:43–18:25]
• Results overview & statistical findings – [18:44–22:49]
• Critical analysis, study limitations – [22:49–29:38]
• Practice implications & final takeaways – [30:16–34:23]

Takeaways

• Renin is frequently abnormal and may catch subtle under/over-replacement—but interpretation is highly context-dependent.
• Renin should be considered as part of a holistic clinical picture, not the sole determinant for dose adjustment.
• The study provides a valuable, if imperfect, addition to the field and highlights the need for prospective research with patient-centered outcomes.