Stephen Ting

α-Klotho Expression in Human Tissues

Context: α-Klotho has emerged as a powerful regulator of the aging process. To date, the expression profile of α-Klotho in human tissues is unknown, and its existence in some human tissue types is subject to much controversy. Objective: This is the first study to characterize systemwide tissue expression of transmembrane α-Klotho in humans. We have employed next-generation targeted proteomic analysis using parallel reaction monitoring in parallel with conventional antibody-based methods to determine the expression and spatial distribution of human α-Klotho expression in health. Results: The distribution of α-Klotho in human tissues from various organ systems, including arterial, epithelial, endocrine, reproductive, and neuronal tissues, was first identified by immunohistochemistry. Kidney tissues showed strong α-Klotho expression, whereas liver did not reveal a detectable signal. These results were next confirmed by Western blotting of both whole tissues and primary cells. To validate our antibody-based results, α-Klotho-expressing tissues were subjected to parallel reaction monitoring mass spectrometry (data deposited at ProteomeXchange, PXD002775) identifying peptides specific for the full-length, transmembrane α-Klotho isoform. Conclusions: The data presented confirm α-Klotho expression in the kidney tubule and in the artery and provide evidence of α-Klotho expression across organ systems and cell types that has not previously been described in humans.

Functional Cardiovascular Reserve Predicts Survival Pre-Kidney and Post-Kidney Transplantation

Exercise intolerance is an important comorbidity in patients with CKD. Anaerobic threshold (AT) determines the upper limits of aerobic exercise and is a measure of cardiovascular reserve. This study investigated the prognostic capacity of AT on survival in patients with advanced CKD and the effect of kidney transplantation on survival in those with reduced cardiovascular reserve. Using cardiopulmonary exercise testing, cardiovascular reserve was evaluated in 240 patients who were waitlisted for kidney transplantation between 2008 and 2010, and patients were followed for ≤5 years. Survival time was the primary endpoint. Cumulative survival for the entire cohort was 72.6% (24 deaths), with cardiovascular events being the most common cause of death (54.2%). According to Kaplan-Meier estimates, patients with AT <40% of predicted peak VO2 had a significantly reduced 5-year cumulative overall survival rate compared with those with AT ≥40% (P<0.001). Regarding the cohort with AT <40%, patients who underwent kidney transplantation (6 deaths) had significantly better survival compared with nontransplanted patients (17 deaths) (hazard ratio, 4.48; 95% confidence interval, 1.78 to 11.38; P=0.002). Survival did not differ significantly among patients with AT ≥40%, with one death in the nontransplanted group and no deaths in the transplanted group. In summary, this is the first prospective study to demonstrate a significant association of AT, as the objective index of cardiovascular reserve, with survival in patients with advanced CKD. High-risk patients with reduced cardiovascular reserve had a better survival rate after receiving a kidney transplant.

Reduced functional measure of cardiovascular reserve predicts admission to critical care unit following kidney transplantation

Background There is currently no effective preoperative assessment for patients undergoing kidney transplantation that is able to identify those at high perioperative risk requiring admission to critical care unit (CCU). We sought to determine if functional measures of cardiovascular reserve, in particular the anaerobic threshold (VO2AT) could identify these patients. Methods Adult patients were assessed within 4 weeks prior to kidney transplantation in a University hospital with a 37-bed CCU, between April 2010 and June 2012. Cardiopulmonary exercise testing (CPET), echocardiography and arterial applanation tonometry were performed. Results There were 70 participants (age 41.7±14.5 years, 60% male, 91.4% living donor kidney recipients, 23.4% were desensitized). 14 patients (20%) required escalation of care from the ward to CCU following transplantation. Reduced anaerobic threshold (VO2AT) was the most significant predictor, independently (OR = 0.43; 95% CI 0.27–0.68; p<0.001) and in the multivariate logistic regression analysis (adjusted OR = 0.26; 95% CI 0.12–0.59; p = 0.001). The area under the receiver-operating-characteristic curve was 0.93, based on a risk prediction model that incorporated VO2AT, body mass index and desensitization status. Neither echocardiographic nor measures of aortic compliance were significantly associated with CCU admission. Conclusions To our knowledge, this is the first prospective observational study to demonstrate the usefulness of CPET as a preoperative risk stratification tool for patients undergoing kidney transplantation. The study suggests that VO2AT has the potential to predict perioperative morbidity in kidney transplant recipients.

Quality of life measures predict cardiovascular health and physical performance in chronic renal failure patients.

Background Patients with advanced chronic kidney disease (CKD) experience complex functional and structural changes of the cardiopulmonary and musculoskeletal system. This results in reduced exercise tolerance, quality of life and ultimately premature death. We investigated the relationship between subjective measures of health related quality of life and objective, standardised functional measures for cardiovascular and pulmonary health. Methods Between April 2010 and January 2013, 143 CKD stage-5 or CKD5d patients (age 46.0±1.1y, 62.2% male), were recruited prospectively. A control group of 83 healthy individuals treated for essential hypertension (HTN; age 53.2±0.9y, 48.22% male) were recruited at random. All patients completed the SF-36 health survey questionnaire, echocardiography, vascular tonometry and cardiopulmonary exercise testing. Results Patients with CKD had significantly lower SF-36 scores than the HTN group; for physical component score (PCS; 45.0 vs 53.9, p<0.001) and mental component score (MCS; 46.9 vs. 54.9, p<0.001). CKD subjects had significantly poorer exercise tolerance and cardiorespiratory performance compared with HTN (maximal oxygen uptake; VO2peak 19.9 vs 25.0ml/kg/min, p<0.001). VO2peak was a significant independent predictor of PCS in both groups (CKD: b = 0.35, p = 0.02 vs HTN: b = 0.27, p = 0.001). No associations were noted between PCS scores and echocardiographic characteristics, vascular elasticity and cardiac biomarkers in either group. No associations were noted between MCS and any variable. The interaction effect of study group with VO2peak on PCS was not significant (ΔB = 0.08; 95%CI -0.28–0.45, p = 0.7). However, overall for a given VO2peak, the measured PCS was much lower for patients with CKD than for HTN cohort, a likely consequence of systemic uremia effects. Conclusion In CKD and HTN, objective physical performance has a significant effect on quality of life; particularly self-reported physical health and functioning. Therefore, these quality of life measures are indeed a good reflection of physical health correlating highly with objective physical performance measures.

Feasibility and effects of intra-dialytic low-frequency electrical muscle stimulation and cycle training: A pilot randomized controlled trial

Background and objectives Exercise capacity is reduced in chronic kidney failure (CKF). Intra-dialytic cycling is beneficial, but comorbidity and fatigue can prevent this type of training. Low–frequency electrical muscle stimulation (LF-EMS) of the quadriceps and hamstrings elicits a cardiovascular training stimulus and may be a suitable alternative. The main objectives of this trial were to assess the feasibility and efficacy of intra-dialytic LF-EMS vs. cycling Design, setting, participants, and measurements Assessor blind, parallel group, randomized controlled pilot study with sixty-four stable patients on maintenance hemodialysis. Participants were randomized to 10 weeks of 1) intra-dialytic cycling, 2) intra-dialytic LF-EMS, or 3) non-exercise control. Exercise was performed for up to one hour three times per week. Cycling workload was set at 40–60% oxygen uptake (VO2) reserve, and LF-EMS at maximum tolerable intensity. The control group did not complete any intra-dialytic exercise. Feasibility of intra-dialytic LF-EMS and cycling was the primary outcome, assessed by monitoring recruitment, retention and tolerability. At baseline and 10 weeks, secondary outcomes including cardio-respiratory reserve, muscle strength, and cardio-arterial structure and function were assessed. Results Fifty-one (of 64 randomized) participants completed the study (LF-EMS = 17 [77%], cycling = 16 [80%], control = 18 [82%]). Intra-dialytic LF-EMS and cycling were feasible and well tolerated (9% and 5% intolerance respectively, P = 0.9). At 10-weeks, cardio-respiratory reserve (VO2 peak) (Difference vs. control: LF-EMS +2.0 [95% CI, 0.3 to 3.7] ml.kg-1.min-1, P = 0.02, and cycling +3.0 [95% CI, 1.2 to 4.7] ml.kg-1.min-1, P = 0.001) and leg strength (Difference vs. control: LF-EMS, +94 [95% CI, 35.6 to 152.3] N, P = 0.002 and cycling, +65.1 [95% CI, 6.4 to 123.8] N, P = 0.002) were improved. Arterial structure and function were unaffected. Conclusions Ten weeks of intra-dialytic LF-EMS or cycling improved cardio-respiratory reserve and muscular strength. For patients who are unable or unwilling to cycle during dialysis, LF-EMS is a feasible alternative.

Layer-specific strain in hypertensive patients with and without mild diastolic dysfunction

This study sought to examine layer-specific longitudinal and circumferential systolic and diastolic strain, strain rate (SR) and diastolic time intervals in hypertensive patients with and without diastolic dysfunction. Fifty-eight treated hypertensive patients were assigned to normal diastolic function (NDF, N = 39) or mild diastolic dysfunction (DD, N = 19) group. Layer-specific systolic and diastolic longitudinal and circumferential strains and SR were assessed. Results showed no between-group difference in left ventricular mass index (DD: 92.1 ± 18.1 vs NDF: 88.4 ± 16.3; P = 0.44). Patients with DD had a proportional reduction in longitudinal strain across the myocardium (endocardial for DD −13 ± 4%; vs NDF −17 ± 3, P < 0.01; epicardial for DD −10 ± 3% vs NDF −13 ± 3%, P < 0.01; global for DD: −12 ± 3% vs NDF: −15 ± 3, P = 0.01), and longitudinal mechanical diastolic impairments as evidenced by reduced longitudinal strain rate of early diastole (DD 0.7 ± 0.2 L/s vs NDF 1.0 ± 0.3 L/s, P < 0.01) and absence of a transmural gradient in the duration of diastolic strain (DD endocardial: 547 ± 105 ms vs epicardial: 542 ± 113 ms, P = 0.24; NDF endocardial: 566 ± 86 ms vs epicardial: 553 ± 77 ms, P = 0.03). Patients with DD also demonstrate a longer duration of early circumferential diastolic strain (231 ± 71 ms vs 189 ± 58 ms, P = 0.02). In conclusion, hypertensive patients with mild DD demonstrate a proportional reduction in longitudinal strain across the myocardium, as well as longitudinal mechanical diastolic impairment, and prolonging duration of circumferential mechanical relaxation.

Hypercalcemia in testicular tuberculosis.

CASE A 55-year-old Caucasian man presented with lethargy and generalized muscle aches. He had an acute kidney injury (AKI) whereby serum creatinine was 565 μmol/l (estimated glomerular filteration rate (eGFR) 10 ml/min/1.73 m) and adjusted calcium was 3.47 mmol/l (2.10–2.58 mmol/l). Myeloma screen was normal. Intact parathormone was appropriately suppressed at 0.8 pmol/l (1.1–4.2 pmol/l), but serum angiotensin-converting enzyme was raised at 138 units/l (20–95 units/l). High-resolution computed tomography did not show any pulmonary infiltrates, and there were no osteolytic metastases on nuclear bone scan of the whole body. On native kidney biopsy, there was mild acute tubular injury with moderate interstitial fibrosis in the cortex. No granuloma was seen. Thus, an assumptive diagnosis of sarcoidosis was made, and oral steroid was commenced in addition to intravenous saline. Serum calcium normalized 6 days later. Six months following the initial presentation, serum creatinine was 142 μmol/l (eGFR 45 ml/min/1.73 m) and corrected calcium remained normal at 2.44 mmol/l. Incidentally, the patient’s primary care physician and urologist had treated him with antibiotics for recurrent testicular discomfort due to epididymitis 4 months preceding the onset of AKI and during the following 6 months. An ultrasound scan of the testes performed at the latter point revealed isoechoic lesions with microcalcification in both epididymides (Figure 1, arrow). Histology of the epididymis and testis demonstrated the presence of multiple granulomata, as well as necrotizing granuloma (Figure 2, arrow). Furthermore, scanty presence of acid-fast bacilli was confirmed on the Ziehl–Neelsen stain (Figure 2 inset, arrow). Oral steroid was stopped, and the patient was commenced on anti-tuberculous therapy. http://www.kidney-international.org nephro logy image