Resistance-Based Muscle Therapy, Frailty, and Muscle Biopsy Findings in Kidney Transplant Candidates: A Clinical Trial

Abstract

Rationale & objective: Frailty is associated with increased morbidity and mortality in kidney transplant recipients. We hypothesized that frailty may be attributable to diminished muscle function associated with muscle morphologic changes. This trial in kidney transplant candidates tested the reversibility of frailty by specifically targeting the affected major muscle groups.

Study design: Randomized clinical trial.

Setting & participants: Kidney transplant candidates.

Exposure: Supervised, resistance-based muscle therapy program delivered for 1 hour, 2 times per week for 1 year.

Outcomes: Baseline, 6-month, and 12-month Short Physical Performance Battery, gait speed, grip strength, sit-to-stand in 30 s, 36-item Short Form Survey, Patient-Reported Outcomes Measurement Information System-29, and muscle biopsy light and electron microscopy and immunohistochemistry.

Analytic approach: Paired 2-tailed t test, 1-way repeated measures analysis of variance.

Results: Twenty-nine participants (mean age, 55 years; female, 55%; African American, 65%) were analyzed: 23 intervention and 6 control. Exercise intervention participants had significant improvements in Short Physical Performance Battery, baseline 5.2 (95% CI, 3.6-6.7) versus 6 months, 6.9 (95% CI, 5.2-8.5; P < 0.001) and 12 months, 7.2 (95% CI, 5.6-8.8; P < 0.001); baseline hand grip, 14.3 kg (95% CI, 10.3-18.4) versus 6 months, 16.9 kg (95% CI, 13.1-20.8; P < 0.05) and 12 months, 17.4 kg (95% CI, 13.9-21.0; P < 0.05); and baseline sit-to-stand in 30 s, 8.0 (95% CI, 3.8-12.2) versus 6 months, 12.7 (95% CI, 8.2-17.1; P < 0.001) and 12 months, 16.2 (95% CI, 10.7-21.7; P < 0.001). The exercise group 12-month muscle fiber diameter increased by 18.6 μm (95% CI, 8.4-28.5; P = 0.003). Expression of immunohistology markers of muscle atrophy decreased significantly. The mean difference in immunohistology score of mitochondrial oxidative function improved for cytochrome c oxidase complex IV, 1.00 (95% CI, 0.71-1.29; P < 0.001) and ATP5I increased by 0.74 (95% CI, 0.49-0.99; P < 0.001). Increased mitochondrial count did not achieve statistical significance (P = 0.096). Controls showed no improvement in either physical performance or histology.

Limitations: Significant under-enrollment in the control group required a paired t test analysis of experimental participants.

Conclusions: One year of muscle rehabilitation therapy resulted in significant improvements in physical performance metrics accompanied by significant improvements in muscle morphology.

Keywords: Immunochemistry; kidney transplant; mitochondria; muscle biopsy; rehabilitation.

Figure 1

Consolidated Standards of Reporting Trials diagram: 204 patients were contacted, 117 were assessed for eligibility, 48 were enrolled and randomized; 23 intervention and 6 control patients completed the study and were the basis for analysis. One control patient did not have 6-month follow-up data due to COVID but did complete the 12-month follow-up. Six intervention patients had missing values at baseline, 6, or 12 months. Our intent-to-treat analysis used the last value carried forward method.

Figure 2

(A) Representative bright field images of hematoxylin and eosin (H&E) staining of patient muscle samples for visit-1 and visit-2. Patient GHD58 is shown. The scale bar is 50 μm. Measurement of muscle fiber diameter for visit-1 vs visit-2 (n = 9), paired samples t test, P = 0.003. Immunohistochemistry (IHC) staining and IHC score for (B) Atrogin-1, P = 0.001 and MuRF-1, P < 0.001; (C) NF-κB, P = 0.003 and Phospho-NF-κB, P = 0.013.

Figure 3

(A) Representative immunohistochemistry (IHC) images and quantification of COX IV expression in visit-1 and visit-2 muscle samples from patient GHD58. Scale bar is 50 μm. IHC scoring criteria: 0: no staining, 1+: weakly positive, 2+: moderate positive, and 3+: strongly positive. Data are presented as mean ± SD. Visit-1 vs visit-2, P < 0.001, paired samples t test. (B) Representative electron micrographs showing mitochondria (yellow arrows) in visit-1 and visit-2 muscle samples from patient GHD37. Magnification: 25,000×. Data are presented as mean ± SD. Visit-1 vs visit-2, P = 0.096, t test. (C) Representative IHC images and quantification of ATP5I in visit-1 and visit-2 muscle samples from patient GHD58. Scale bar is 50 μm. IHC scoring criteria: 0: no staining, 1+: weakly positive, 2+: moderate positive, and 3+: strongly positive. Data are presented as mean ± SD. Visit-1 vs Visit-2, P < 0.001, paired samples t test.