We thank Drs. Sasaki and Tsuboi for their thoughtful Letter to the Editor regarding our recent publication on a morphometric approach to analyze the size of different nephron segments.1 We agree that this approach has the potential to help us understand how different medications may affect the human kidney. Specifically, this approach can be used to study the association between various medications and the size of different nephron segments. Medications that associate with enlarged glomeruli, proximal tubules, or distal tubules may be less beneficial to the kidney. To test this approach, we reviewed the medical records of all 921 patients in our cohort with prenephrectomy hypertension to determine the classes of antihypertensive medications, including diuretics, that they were taking before their nephrectomy. Of the 921 patients, 804 were on at least one, 539 were on at least two, 259 were on at least three, and 83 were on at least four antihypertensive medications. We assessed the association of each medication class with each nephron segment size (averaged across all cortical depths of the kidney biopsy wedge section).
As presented in the Table 1, calcium channel blockers and diuretics associated with larger nephron segments, particularly larger glomeruli and wider distal tubules even after adjusting for clinical factors associated with nephron size. It is reassuring that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were not associated with larger nephron segments given their renal protective effects. Beta blockers were not associated with larger nephron segments and may also be renal protective.2 Calcium channel blockers impair autoregulation in the kidney, but this autoregulation protects against the transmission of systemic pressures that cause nephron hypertrophy.3 Diuretics have been linked to CKD progression, although this has generally been attributed to clinical factors that lead to diuretic use.4 Limitations of these data include small sample size, confounding by indication for specific classes of antihypertensive medications, use of multiple antihypertensive medication classes by most patients as there may be interactions between different classes, lack of data regarding the duration of use for each medication class, and lack of data regarding recently discontinued medication classes. Nonetheless, future studies could explore whether these measurements could be applied to patients who undergo kidney biopsy to improve clinical outcomes. This approach may be particularly helpful for identifying “nephron overload” by the detection of enlarged nephron segments regardless of the underlying cause of CKD.5
Table 1.
Unadjusted and multivariable adjusted associations between antihypertensive medication class and nephron segment size among 921 patients with hypertension
| Antihypertensive Medication Class | Unadjusted | Adjusteda | ||||
|---|---|---|---|---|---|---|
| Glomerular Volume | Mean Proximal Tubular Diameter | Mean Distal Tubular Diameter | Glomerular Volume | Mean Proximal Tubular Diameter | Mean Distal Tubular Diameter | |
| % Difference (95% CI) (P Value) |
% Difference (95% CI) (P Value) |
% Difference (95% CI) (P Value) |
% Difference (95% CI) (P Value) |
% Difference (95% CI) (P Value) |
% Difference (95% CI) (P Value) |
|
| Calcium channel blocker (n=235) | 5.5% (0.2 to 10.0) (0.04) |
1.7% (0.1 to 3.4) (0.04) |
2.0% (0.7 to 3.4) (0.003) |
5.8% (0.8 to 10.9) (0.02) |
1.5% (−0.1 to 3.2) (0.07) |
1.7% (0.4 to 3.0) (0.01) |
| Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (n=492) | 3.7% (−0.8 to 8.4) (0.11) |
0.2% (−1.2 to 1.6) (0.79) |
0.5% (−0.7 to 1.7) (0.40) |
0.4% (−3.8 to 4.8) (0.85) |
−0.4% (−1.8 to 1.1) (0.60) |
0.1% (−1.0 to 1.3) (0.84) |
| β blocker (n=409) | −1.0% (−5.4 to 3.5) (0.66) |
−0.8% (−2.2 to 0.6) (0.25) |
−0.2% (−1.4 to 0.9) (0.72) |
−1.3% (−5.5 to 3.0) (0.55) |
−1.4% (−2.8 to 0.0) (0.05) |
−0.8% (−2.0 to 0.4) (0.18) |
| Any diuretic (n=408) | 7.3% (2.6 to 12.2) (0.002) |
1.1% (−0.4 to 2.5) (0.15) |
1.8% (0.7 to 3.0) (0.002) |
6.6% (2.2 to 11.2) (0.003) |
0.6% (−0.9 to 2.0) (0.46) |
1.5% (0.3 to 2.7) (0.01) |
| Thiazide diuretic (n=314) | 6.0% (1.1 to 11.1) (0.02) |
1.1% (−0.4 to 2.7) (0.13) |
1.6% (0.4 to 2.9) (0.009) |
5.1% (0.8 to 10.0) (0.02) |
1.0% (−0.5 to 2.5) (0.19) |
1.5% (0.4 to 2.8) (0.01) |
| Loop diuretic (n=99) | 6.1% (−1.3 to 14.0) (0.11) |
0.2% (−2.1 to 2.5) (0.88) |
1.6% (−0.3 to 3.5) (0.10) |
5.3% (−1.7 to 12.8) (0.14) |
−0.8% (−3.1 to 1.5) (0.48) |
0.8% (−1.1 to 2.7) (0.43) |
| Potassium sparring diuretic (n=95) | 5.9% (−1.6 to 13.9) (0.13) |
2.5% (0.2 to 4.9) (0.03) |
2.1% (0.2 to 4.0) (0.03) |
7.4% (0.4 to 15.0) (0.04) |
2.2% (−0.1 to 4.6) (0.07) |
1.7% (−0.2 to 3.6) (0.08) |
| Other (n=52) | −3.5% (−12.4 to 6.2) (0.46) |
3.0% (−0.1 to 6.1) (0.06) |
0.0% (−2.5 to 2.5) (0.99) |
−4.2% (−12.5 to 4.9) (0.35) |
2.7% (−0.4 to 5.9) (0.08) |
−0.5% (−2.9 to 2.0) (0.68) |
Adjusted for age, sex, diabetes, body mass index, presurgery eGFR, systolic blood pressure, diastolic blood pressure, and 24-hour urine protein. Due to missing data, blood pressure values were imputed in 216 and 24-hour urine protein values were imputed in 110 for the adjusted analysis.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
See related letter to the editor, “Morphometric Approach to Different Nephron Segments,” on pages 2053–2054, and original article “Tubular and Glomerular Size by Cortex Depth as Predictors of Progressive Chronic Kidney Disease after Radical Nephrectomy for Tumor,” in Vol. 34, Iss. 9, 1535–1545.
Disclosures
A.D. Rule reports Patents or Royalties: UpToDate; and Advisory or Leadership Role: JASN—Associate Editor, and Mayo Clinic Proceedings—Section Editor. All remaining authors have nothing to disclose.
Funding
This study was supported with funding from the National Institutes of Health and National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK090358).
Author Contributions
Conceptualization: Andrew D. Rule.
Data curation: Aperna Fnu, Mahesh Kumar.
Formal analysis: Aleksandar Denic.
Supervision: Andrew D. Rule.
Writing – original draft: Andrew D. Rule.
Writing – review & editing: Aleksandar Denic, Aperna Fnu, Mahesh Kumar.
Data Sharing Statement
Data cannot be shared without a data use agreement and Institutional Review Board approval.
References
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Data Availability Statement
Data cannot be shared without a data use agreement and Institutional Review Board approval.