Characteristics of urinary and serum soluble Klotho protein in patients with different degrees of chronic kidney disease

Background

Klotho is a single-pass transmembrane protein, which appears to be implicated in aging. The purpose of the present study was to characterize the relationship between the soluble Klotho level and renal function in patients with various degrees of chronic kidney disease (CKD).

Methods

The levels of soluble Klotho in the serum and urine obtained from one hundred thirty-one CKD patients were determined by a sandwich enzyme-linked immunosorbent assay system.

Results

The amount of urinary excreted Klotho during the 24 hr period ranged from 1.6 to 5178 ng/day (median 427 ng/day; interquartile range [IR] 56.8-1293.1), and the serum Klotho concentration ranged from 163.9 to 2123.7 pg/ml (median 759.7 pg/ml; IR 579.5-1069.1). The estimated glomerular filtration rate (eGFR) was significantly correlated with the log-transformed values of the amount of 24 hr urinary excreted Klotho (r?=?0.407, p?<?0.01) and the serum Klotho levels (r?=?0.232, p?<?0.01). However, a stepwise multiple regression analysis identified eGFR to be a variable independently associated only with the log-transformed value of the amount of 24-hr urinary excreted Klotho but not with the log-transformed serum Klotho concentration. Despite the strong correlation between random urine protein-to-creatinine ratio and the 24 hr urinary protein excretion (r?=?0.834, p?<?0.01), a moderate linear association was observed between the log-transformed value of the amount of 24 hr urinary excreted Klotho and that of the urinary Klotho-to-creatinine ratio (Klotho/Cr) in random urine specimens (r?=?0.726, p?<?0.01).

Conclusions

The amount of urinary Klotho, rather than the serum Klotho levels, should be linked to the magnitude of the functioning nephrons in CKD patients. The use of random urine Klotho/Cr as a surrogate for the amount of 24-hr urinary excreted Klotho needs to be evaluated more carefully.

     

Improving survival during heart transplantation: diagnosis of antibody-mediated rejection and techniques for the prevention of graft injury

The diagnosis of antibody-mediated rejection (AMR) has presented a challenge due to the pleiomorphic immunologic responses that represent the condition. A consensus with regard to its pathological diagnosis continues to evolve. Due to an increasing number of sensitized patients undergoing heart transplantation, its incidence appears to be on the rise and the condition is associated with worse outcomes than acute cellular rejection. Treatment of AMR is also more difficult and response to increases in conventional immunosuppression is often limited. Risk factors for AMR include the use of ventricular assist devices, prior exposure to blood products, allografts and multiparity. Detection of alloantibodies with a high specificity and sensitivity allows risk stratification of recipients at potential risk of AMR. Desensitization and AMR treatment strategies are focused on several therapeutic targets, including suppression of T and B cells and elimination or inhibition of circulating antibodies.     

The rat suprachiasmatic nucleus: the master clock ticks at 30?Hz

AbstractThe suprachiasmatic nucleus (SCN) of the hypothalamus has an essential role in orchestrating circadian rhythms of behaviour and physiology. In the present study, we recorded from single SCN neurons in urethane‐anaesthetized rats, categorized them by the statistical features of their electrical activity and by their responses to light, and examined how activity in the light phase differs from activity in the dark phase. We classified cells as light‐on cells or light‐off cells according to how their firing rate changed in acute response to light, or as non‐responsive cells. In both sets of light‐responsive neurons, responses to light were stronger at subjective night than in subjective day. Neuronal firing patterns were analysed by constructing hazard functions from interspike interval data. For most light‐responsive cells, the hazard functions showed a multimodal distribution, with a harmonic sequence of modes, indicating that spike activity was driven by an oscillatory input with a fundamental frequency of close to 30 Hz; this harmonic pattern was rarely seen in non‐responsive SCN cells. The frequency of the rhythm was the same in light‐on cells as in light‐off cells, was the same in subjective day as at subjective night, and was unaffected by exposure to light. Paired recordings indicated that the discharge of adjacent light‐responsive neurons was very tightly synchronized, consistent with electrical coupling.     

IL-15 exacerbates collagen-induced arthritis with an enhanced CD4+ T cell response to produce IL-17

IL-15 is thought to be involved in the pathogenesis of rheumatoid arthritis (RA). We found that IL-15 plays an important role in the development of murine collagen-induced arthritis (CIA). The incidence and severity of CIA were slightly decreased in IL-15 KO mice but were increased in IL-15 Tg mice compared with wild-type (WT) mice. The levels of type II collagen (CII)-specific IL-17 production were significantly increased in IL-15 Tg mice compared with WT mice with CIA. Expression of IL-23R was up-regulated in CD4(+) T cells in IL-15 Tg mice but down-regulated in IL-15 KO mice compared with WT mice. In correlation with the expression levels of IL-23R, IL-17 production by CD4(+) T cells in response to exogenous IL-23 was increased in IL-15 Tg mice compared with WT mice. Furthermore, exogenous IL-15 synergized with IL-23 to induce CII-specific IL-17 production by CD4(+) T cells in vitro. Taken together, these results indicate that IL-15 plays an important role in the progression of CIA through increasing antigen-specific IL-17 production by CD4(+) T cells.     

Coronary computed tomography–angiography quantitative plaque analysis improves detection of early cardiac allograft vasculopathy: A pilot study

Cardiac allograft vasculopathy (CAV) is an increasingly important complication after cardiac transplant. We assessed the additive diagnostic benefit of quantitative plaque analysis in patients undergoing coronary computed tomography–angiography (CCTA). Consecutive patients undergoing CCTA for CAV surveillance were identified. Scans were visually interpreted for coronary stenosis. Semiautomated software was used to quantify noncalcified plaque (NCP), as well as its components. Optimal diagnostic cut‐offs for CAV, with coronary angiography as gold standard, were defined using receiver operating characteristic curves. In total, 36 scans were identified in 17 patients. CAV was present in 17 (46.0%) reference coronary angiograms, at a median of 1.9 years before CCTA. Median NCP (147 vs 58, P < .001), low‐density NCP (median 4.5 vs 0.9, P = .003), fibrous plaque (median 76.1 vs 31.1, P = .003), and fibrofatty plaque (median 63.6 vs 27.6, P < .001) volumes were higher in patients with CAV, whereas calcified plaque was not (median 0.0 vs 0.0, P = .510). Visual assessment of CCTA alone was 70.6% sensitive and 100% specific for CAV. The addition of total NCP volume increased sensitivity to 82.4% while maintaining 100% specificity. NCP volume is significantly higher in patients with CAV. The addition of quantitative analysis to visual interpretation improves the sensitivity for detecting CAV without reducing specificity.     

Selecting Oversized Donor Cardiac Allografts for Patients With Pulmonary Hypertension May Be Unnecessary

Introduction

There is a tendency to favor oversized donor hearts for heart transplant candidates affected by mild to moderate pulmonary hypertension (PHTN). We hypothesize that both undersized and oversized donor hearts fare equally well in this setting.

Methods

A total of 107 cases from 2003 to 2008 were retrospectively reviewed and subsequently divided into those receiving organs from undersized donors (group 1: donor weight/recipient weight ≤0.90, n = 37) and oversized donors (group 2: donor weight/recipient weight ≥1.2, n = 70). PHTN was identified in the perioperative period in those patients with systolic pulmonary artery pressure (SPAP) ≥40 mm Hg. Endpoints of mortality and hemodynamic data were investigated.

Results

Of 107 patients, 37 received undersized donor allografts, with a mean donor-to-recipient weight ratio of 0.8, and 70 received oversized donors allografts, with a mean donor-to-recipient ratio of 1.4. Perioperative PAH was diagnosed in 20 of the 37 (54%) patients from the undersized group (mean SPAP = 45.9 mm Hg) and 41 of 70 (59%) patients from the oversized group (mean SPAP = 46.5 mm Hg). There was no significant difference in right ventricular function at 1 week, 1 month, or 6 months. Left ventricular function was similar between both groups at 6 months (P = .22). The mean SPAP in the undersized group was 45.9, 33.4, 31.8, and 23.1 mm Hg at the perioperative, 1 week, 1 month, and 6 month time points, respectively. Corresponding mean SPAP for the oversized group was 46.5, 35.0, 29.4, and 26.1 mm Hg. The 1 month, 1 year, and 3 year survivals were similar in both groups.

Conclusions

Oversized and undersized donor hearts fared equally well in the setting of mild to moderate perioperative PAH. This in addition to the propensity for resolution of pulmonary hypertension over time suggests that the current practice of favoring oversized donor hearts for patients with pre-transplantation PAH may be unwarranted.