Hypoxia is not the primary mechanism contributing to exercise-induced proteinuria

Abstract

Introduction: Proteinuria increases at altitude and with exercise, potentially as a result of hypoxia. Using urinary alpha-1 acid glycoprotein (α1-AGP) levels as a sensitive marker of proteinuria, we examined the impact of relative hypoxia due to high altitude and blood pressure-lowering medication on post-exercise proteinuria.

Methods: Twenty individuals were pair-matched for sex, age and ACE genotype. They completed maximal exercise tests once at sea level and twice at altitude (5035 m). Losartan (100 mg/day; angiotensin-receptor blocker) and placebo were randomly assigned within each pair 21 days before ascent. The first altitude exercise test was completed within 24-48 hours of arrival (each pair within ~1 hour). Acetazolamide (125 mg two times per day) was administrated immediately after this test for 48 hours until the second altitude exercise test.

Results: With placebo, post-exercise α1-AGP levels were similar at sea level and altitude. Odds ratio (OR) for increased resting α1-AGP at altitude versus sea level was greater without losartan (2.16 times greater). At altitude, OR for reduced post-exercise α1-AGP (58% lower) was higher with losartan than placebo (2.25 times greater, p=0.059) despite similar pulse oximetry (SpO₂) (p=0.95) between groups. Acetazolamide reduced post-exercise proteinuria by approximately threefold (9.3±9.7 vs 3.6±6.0 μg/min; p=0.025) although changes were not correlated (r=-0.10) with significant improvements in SpO₂ (69.1%±4.5% vs 75.8%±3.8%; p=0.001).

Discussion: Profound systemic hypoxia imposed by altitude does not result in greater post-exercise proteinuria than sea level. Losartan and acetazolamide may attenuate post-exercise proteinuria, however further research is warranted.

Keywords: altitude; exercise physiology; kidney; mountain.

Figure 1

(A) Visual representation of the study design. Step 1: Participants were matched for: ACE genotype (II, ID or DD; see table 3), age, sex previous altitude exposure, and GFR. Step 2: Within each pair, participants were randomly assigned to placebo or losartan groups. Step 3: Baseline characteristics were recorded and baseline exercise tests were conducted (4 weeks before ascent) and were followed by the initiation of losartan administration (21 days before ascent). Step 4: Ascent is initiated with both groups ascending together in accordance with (B). Step 5: The first round of altitude exercise tests were conducted for members of both groups (5035 m). Step 6: Immediately following the first altitude exercise tests, acetazolamide was administered (125 mg orally, two times per day) and continued for 48 hours until next exercise test. Step 7: Repeat altitude exercise tests were conducted for all individuals (only placebo group data reported). (B) Expedition ascent profile. Day 0: Birmingham, UK (130 m), day 1: Quito, Ecuador (2800 m), day 2: Quito, Ecuador (2800 m), day 3: bus to Chunquiragua in Chaupi (3400 m), day 4: bus to Estrella del Chimborazo MARCO cruz (3950 m), day 5: Estrella del Chimborazo MARCO cruz (3950 m) with day hike to 5000 m and back, day 6: bus to Carrel hut (4800 m), days 7–10: Whymper hut (5035 m). GFR, glomerular filtration rate.

Figure 2

Daily measures of blood pressure and 24-hour urinary α1-AGP excretion rates with ascent. (A) Daily SBPs (mm Hg). (B) Daily DBPs (mm Hg). Data are plotted as daily medians with error bars representing the respective IQRs. (C) Log-transformed 24-hour urinary α1-AGP excretion rates (μg/min) by days with ascent. Data are plotted as the mean log of 24 hours α1-AGP with error bars representing SD of the respective group mean on each day. Twenty-four-hour urinary α1-AGP excretion collectively increased with ascent (p<0.01) with no difference between groups (p=0.97). α1-AGP, alpha-1 acid glycoprotein; DBPs, diastolic blood pressures; SBPs, systolic blood pressures.

Figure 3

Pre-exercise and post-exercise urinary α1-AGP excretion (μg/min) rates. (A) Comparisons between placebo versus losartan groups at baseline sea level; (B) comparisons between placebo versus losartan groups at altitude (first altitude exercise); (C) comparisons between placebo versus placebo +acetazolamide at altitude (second altitude exercise); (D) comparisons between baseline versus altitude in both placebo and losartan groups (change in α1-AGP from pre-60 min to post-60 min, Δα1-AGP) and (E) comparisons between placebo versus placebo +acetazolamide. Results are plotted as the group median (or individual values, D) with error bars representing the relative IQRs of the group. Significance was set to p value ≤0.05 unless otherwise indicated. Representing significance: * for the significant effect of exercise on urinary α1-AGP excretion; ** for the significant difference between groups at post-60 min and *** for the significant difference between placebo and placebo +acetazolamide for Δα1-AGP (D) or for the trend (p=0.059) of difference between baseline and the first altitude for Δα1-AGP (E). α1-AGP, alpha-1 acid glycoprotein.