Muscle dysfunction is an important cause of morbidity among patients with chronic kidney disease (CKD). Although muscle fibrosis is present in a CKD rodent model, its existence in humans and its impact on physical function are currently unknown. We examined isometric leg extension strength and measures of skeletal muscle fibrosis and inflammation in vastus lateralis muscle from CKD patients ( n = 10) and healthy, sedentary controls ( n = 10). Histochemistry and immunohistochemistry were used to assess muscle collagen and macrophage and fibro/adipogenic progenitor (FAP) cell populations, and RT-qPCR was used to assess muscle-specific inflammatory marker expression. Muscle collagen content was significantly greater in CKD compared with control (18.8 ± 2.1 vs. 11.7 ± 0.7% collagen area, P = 0.008), as was staining for collagen I, pro-collagen I, and a novel collagen-hybridizing peptide that binds remodeling collagen. Muscle collagen was inversely associated with leg extension strength in CKD ( r = −0.74, P = 0.01). FAP abundance was increased in CKD, was highly correlated with muscle collagen ( r = 0.84, P < 0.001), and was inversely associated with TNF-α expression ( r = −0.65, P = 0.003). TNF-α, CD68, CCL2, and CCL5 mRNA were significantly lower in CKD than control, despite higher serum TNF-α and IL-6. Immunohistochemistry confirmed fewer CD68+ and CD11b+ macrophages in CKD muscle. In conclusion, skeletal muscle collagen content is increased in humans with CKD and is associated with functional parameters. Muscle fibrosis correlated with increased FAP abundance, which may be due to insufficient macrophage-mediated TNF-α secretion. These data provide a foundation for future research elucidating the mechanisms responsible for this newly identified human muscle pathology.

No abstract

BACKGROUND Skeletal muscle maladaptation accompanies chronic kidney disease (CKD) and negatively affects physical function. Emphasis in CKD has historically been placed on muscle fiber–intrinsic deficits, such as altered protein metabolism and atrophy. However, targeted treatment of fiber-intrinsic dysfunction has produced limited improvement, whereas alterations within the fiber-extrinsic environment have scarcely been examined. METHODS We investigated alterations to the skeletal muscle interstitial environment with deep cellular phenotyping of biopsies from patients with CKD and age-matched controls and performed transcriptome profiling to define the molecular underpinnings of CKD-associated muscle impairments. We examined changes in muscle maladaptation following initiation of dialysis therapy for kidney failure. RESULTS Patients with CKD exhibited a progressive fibrotic muscle phenotype, which was associated with impaired regenerative capacity and lower vascular density. The severity of these deficits was strongly associated with the degree of kidney dysfunction. Consistent with these profound deficits, CKD was associated with broad alterations to the muscle transcriptome, including altered ECM organization, downregulated angiogenesis, and altered expression of pathways related to stem cell self-renewal. Remarkably, despite the seemingly advanced nature of this fibrotic transformation, dialysis treatment rescued these deficits, restoring a healthier muscle phenotype. Furthermore, after accounting for muscle atrophy, strength and endurance improved after dialysis initiation. CONCLUSION These data identify a dialysis-responsive muscle fibrotic phenotype in CKD and suggest the early dialysis window presents a unique opportunity of improved muscle regenerative capacity during which targeted interventions may achieve maximal impact. TRIAL REGISTRATION NCT01452412 FUNDING NIH, NIH Clinical and Translational Science Awards (CTSA), and Einstein-Mount Sinai Diabetes Research Center

Background Patients with chronic kidney disease commonly experience gait abnormalities, which predispose to falls and fall-related injuries. An unmet need is the development of improved methods for detecting patients at high risk of these complications, using tools that are feasible to implement in nephrology practice. Our prior work suggested step length could be such a marker. Here we explored the use of step length as a marker of gait impairment and fall risk in adults with chronic kidney disease. Methods We performed gait assessments in 2 prospective studies of 82 patients with stage 4 and 5 chronic kidney disease (n = 33) or end-stage renal disease (ESRD) (n = 49). Gait speed and step length were evaluated during the 4-m walk component of the Short Physical Performance Battery (SPPB). Falls within 6 months prior to or following enrollment were identified by questionnaire. Associations of low step length (≤47.2 cm) and slow gait speed (≤0.8 m/s) with falls were examined using logistic regression models adjusted for demographics and diabetes and peripheral vascular disease status. Results Assessments of step length were highly reproducible (r = 0.88, p < 0.001 for duplicate measurements at the same visit; r = 0.78, p < 0.001 between baseline and 3-month evaluations). Patients with low step length had poorer physical function, including lower SPPB scores, slower gait speed, and lower handgrip strength. Although step length and gait speed were highly correlated (r = 0.73, p < 0.001), one-third (n = 14/43) of patients with low step length did not have slow gait speed. Low step length and slow gait speed were each independently associated with the likelihood of falls (odds ratio (OR) 3.90 (95% confidence interval (CI) 1.05–14.60) and OR 4.25 (95% CI 1.24–14.58), respectively). Compared with patients who exhibited neither deficit, those with both had a 6.55 (95% CI 1.40–30.71) times higher likelihood of falls, and the number of deficits was associated with a graded association with falls (p trend = 0.02). Effect estimates were similar after further adjustment for ESRD status. Conclusions Step length and gait speed may contribute additively to the assessment of fall risk in a general adult nephrology population.

Introduction: In patients with advanced cancer, prolongation of life with treatment often incurs substantial emotional and financial expense. Among hospitalized patients with cancer since acute kidney injury (AKI) is known to be associated with much higher odds for hospital mortality, we investigated whether renal replacement therapy (RRT) use in the intensive care unit (ICU) was a significant independent predictor of worse outcomes. Methods: We retrospectively reviewed patients admitted in 2005 to 2014 who were diagnosed with stage IV solid tumors, had AKI, and a nephrology consult. The main outcomes were survival times from the landmark time points, inpatient mortality, and longer term survival after hospital discharge. Logistic regression and Cox proportional regression were used to compare inpatient mortality and longer term survival between RRT and non-RRT groups. Propensity score-matched landmark survival analyses were performed with 2 landmark time points chosen at day 2 and at day 7 from ICU admission. Results: Of the 465 patients with stage IV cancer admitted to the ICU with AKI, 176 needed RRT. In the multivariate logistic regression model after adjusting for baseline serum albumin and baseline maximum Sequential Organ Failure Assessment (SOFA), the patients who received RRT were not significantly different from non-RRT patients in inpatient mortality (odds ratio: 1.004 [95% confidence interval: 0.598-1.684], P = .9892). In total, 189 patients were evaluated for the impact of RRT on long-term survival and concluded that RRT was not significantly associated with long-term survival after discharge for patients who discharged alive. Landmark analyses at day 2 and day 7 confirmed the same findings. Conclusions: Our study found that receiving RRT in the ICU was not significantly associated with inpatient mortality, survival times from the landmark time points, and long-term survival after discharge for patients with stage IV cancer with AKI.