Age- and sex-tailored serum phosphate thresholds do not improve cardiovascular risk estimation in CKD.

BACKGROUND: Disordered metabolism of phosphorus is one of the hallmarks of chronic kidney disease (CKD), resulting in increased cardiovascular morbidity and mortality. Age and sex may affect the metabolism of phosphorus and subsequently its serum level. We evaluated if age- and sex-specific cutoffs for hyperphosphatemia may define cardiovascular risk better than the current guideline cutoffs. METHODS: We used data from 16,834 subjects participating in the 1999-2006 National Health and Nutrition Examination Survey (NHANES); the prevalence of self-reported cardiovascular disease (CVD) and mortality rates were analyzed in CKD patients for both the classic definitions (CH; i.e., NKF-KDOQI and K-DIGO) and a tailored definition (TH) of hyperphosphatemia by means of regression models adjusted for age, sex, race/ethnicity, smoking status and body mass index. The cutoffs for TH were represented by the 95th percentile of an age- and sex-matched non-CKD population. RESULTS: Serum phosphorus levels showed an inverse correlation with age (r = -0.12; p<0.001); females showed higher levels than males (3.78 ± 0.54 mg/dL vs. 3.62 ± 0.58 mg/dL; p<0.001). Even if the association between the TH definition and CVD was marginally better compared with the CH definition (odds ratio [OR] = 1.49, 95% confidence interval [95% CI], 1.04-2.13; p=0.030 vs. OR=1.55, 95% CI, 0.98-2.44; p = 0.059), the TH model was not superior in predicting CVD or mortality. CONCLUSIONS: Our data suggest that a tailored, age- and sex-specific definition of hyperphosphatemia is not superior to conventional definitions in predicting cardiovascular events in patients with CKD.

Cadmium exposure and kidney stone formation in the general population--an analysis of the National Health and Nutrition Examination Survey III data.

BACKGROUND AND PURPOSE: Cadmium exposure has been associated with a greater risk of kidney stone formation in occupational exposure studies, but data on such an association in the general population are scarce. SUBJECTS AND METHODS: We assessed the National Health and Nutrition Examination Survey data from 1988 to 1994 in terms of the risk of stone formation. Persons reporting a history of kidney stones were defined as stone formers (n=749), and the association between a positive history of kidney stones and high environmental cadmium exposure levels (defined as urinary cadmium >1 µg/g) was analyzed by logistic regression analysis, stratifying by sex and adjusting for age, race/ethnicity, body mass index, smoking habits, region of residence, and daily intake of calcium and sodium. RESULTS: The odds ratio of lithiasis associated with urinary cadmium >1 µg/g was 1.40 (95% confidence interval 1.06, 1.86) in females (P = 0.019). The association between urinary cadmium and kidney stones was not significant in males. CONCLUSIONS: These findings suggest that moderately high levels of urinary cadmium are associated with a greater propensity for kidney stone formation in females in the general population.

Disinfection of dialysis monitors.

In recent years the concept of biocompatibility is not limited to the dialytic membranes, but has been substituted by a more general viewpoint where all the parameters of the dialytic treatment are taken into consideration: the interaction of blood-surfaces (the dialyzer in all its components and the hematic lines), the sterilization of all materials, the quality of the solutions utilized for dialysis and reinfusion. Numerous studies have shown that the inflammatory response in dialysis is the cause of many of the side effects of dialytic treatment itself both acute and chronic. Hypoxemia, 'first use' syndrome, hypotension, allergic-anaphylactic reactions (short-term side effects); microinflammation, malnutrition, accelerated arteriosclerosis, anemia, beta2 microglobulin amyloidosis, immunodeficiency, bone mass loss (long-term side effects), have all been reported. In this review, we will focus on the fluids utilized for hemodialysis (HD) and hemodiafiltration (HDF); we will describe the process of disinfection of the machines which produce the dialytic solutions.

Effect of daily hemodialysis on monocytes apoptosis.

Uremia is associated with a state of immune dysfunction with increased susceptibility to infection and malignancy possibly related to dysregulation of immune system cell apoptosis. Peritoneal dialysis can restore plasma apoptosis activity on monocytes compared to intermittent hemodialysis. Whether the continuous modality or diverse clearance mechanisms involved are responsible is unknown. Apoptosis rates correlate with phagocytic function highlighting the benefit of efficient toxin clearance. The plasma of 16 patients on daily hemodialysis (D-HD) was incubated with U937 monocytes and compared to 18 hemodialysis (HD) patients, 5 chronic renal failure (CRF) subjects and 5 healthy volunteers (controls). Apoptosis was evaluated by immunofluorescence microscopy dyes (Hoechst 33342, propidium iodide) and annexin V cytoflowmetry at 96 h. Plasma-induced U937 apoptosis (mean values) was significantly enhanced in D-HD (18.8 +/- 4.1), HD (19.67 +/- 5.5) and CRF patients (20.8 +/- 4.7) compared to controls (9.6 +/- 3.6; p < 0.05 for CRF vs. controls, HD vs. controls and D-HD vs. controls). No significant differences were observed between D-HD, HD and CRF sera on apoptosis rate, caspase-3 activity and phagocytic capacity of U937 monocytes. This study demonstrates that the plasma of various HD schedules was unable to reduce monocyte apoptosis induced by uremia.

Rasburicase therapy in acute hyperuricemia and renal dysfunction.

Neoplastic disorders may be complicated by acute renal failure (ARF). Different tumors may cause ARF: solid tumors involving the kidney, solid tumors not of hematological origin and not primarily involving the kidney or, more frequently, rapidly developing hematological tumors. The pathogenesis of ARF is different depending on the type of cancer, but the most frequent clinical feature is the acute tumor lysis syndrome, characterized by hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia and acute, frequently oliguric, ARF. The presence of a neoplastic disorder and associated acute illness may sometimes lead to the presence of immunodysfunction, septic complications and multiple organ dysfunction. In these settings patients develop systemic inflammation and diffuse endothelial damage, related to different mediators. Among these substances, in cancer patients, high circulating levels of uric acid are a common finding. Hyperuricemia is caused by the increase of purine metabolism, which is result of the increased cellular turnover or the aggressive cancer chemotherapy regimens that worsen cell lysis and release of purine metabolites. Even if hyperuricemia is not the first insult to the kidney, its development might represent a concomitant factor aggravating other previous or simultaneous insults. The most efficient therapy for lowering uric acid is rasburicase, a recombinant form of urate oxidase, a nonhuman proteolytic enzyme that oxidizes uric acid to allantoin. It is efficacious in reducing serum uric acid levels with associated diuresis more effectively and much faster than allopurinol, and to correct renal dysfunction more rapidly than allopurinol.

Protective effect of urate oxidase on uric acid induced-monocyte apoptosis.

Uremic patients have a higher risk of infection and malignancy than normal subjects. Previous studies have deomonstrated that monocytes isolated from uremic patients display an increased apoptosis rate compared to normal subjects; furthermore uremic plasma can increase apoptosis rates on U937, a human monocytic cell line. In several pathological conditions, precipitation of uric acid crystals can lead to renal insufficiency or acute renal failure by different mechanisms. In recent studies uric acid has been shown to induce inflammatory response from monocytes and it has been suggested to be involved in cell dysfunction. Rasburicase is a new recombinant urate oxidase developed to prevent and treat hyperuricaemia in patients with cancer or renal failure; it degrades uric acid to allantoin, a less toxic and more soluble product. In the present study, we aimed at determining whether uric acid may be a factor affecting U937 apoptosis, and whether urate oxidase may reduces or even prevent uric acid induced cell apoptosis. Hoechst staining and internucleosome ledder fragmentation of DNA showed that uric acid increased the percentage of apoptotic cells comparing to the control and that when the U937 cells were incubated with uric acid and urate oxidase the percentage of apoptosis significantly decreased (from 43+/-7% to 19+/- 3%, p<0.05). Also, the activity of caspase-8 and caspase-3 showed the same trend (caspase 3: from 2.7+/-0.53 to 1.6+/-0.42; caspase-8: from 2.2+/-0.43 to 1.3+/-0.57). A reduction of intracellular reduced glutathione (GSH) concentration was found in uric acid treated cells while the addition of urate oxidase in the uric acid incubated cells decreased the GSH extrusion. The concentration of TNF-alpha was increased in the sample incubated with uric acid comparing to the control. Uric acid is an inducer of apoptosis on U937 cell line, and therefore it may be a component of the mosaic of uremic toxins both in acute and chronic renal disease. We can hypothesize that uric acid might be directly involved in the apoptotic process trough the activation of both death receptor and mitochondrial-mediated pathways. We have, also, demonstrated that urate oxidase is able to prevent at least in part, the effect of uric acid on U937 apoptosis. This effect might be a result of different mechanisms of action.

Extracorporeal therapies in non-renal disease: treatment of sepsis and the peak concentration hypothesis.

In the setting of intensive care, patients with acute renal failure often present a clinical picture of the systemic inflammatory response syndrome (SIRS). SIRS can be caused by bacterial stimuli or by non-microbiological stimuli that induce a significant inflammatory response. When this response is exaggerated, the patient experiences multiple organ system failure and a condition of sepsis also defined as a systemic malignant inflammation. This is mostly characterized by an invasion of cytokines and other pro-inflammatory mediators into the systemic circulation where major biological effects take place, including vasopermeabilization, hypotension and shock. At the same time, the monocyte of the septic patient seems to be hyporesponsive to inflammatory stimuli to a certain extent. In this condition, the patient faces a situation of hyperinflammation but at the same time of immunodepression expressing a clinical entity defined as counter anti-inflammatory response syndrome. The general picture of the clinical disorder is therefore better characterized by an immunodysregulation than by a simple pro- or anti-inflammatory disorder. Due to the short half-life of cytokines and other mediators spilled over into the circulation, it is extremely difficult to approach the problem at the right moment with the right pharmacological agent. For these reasons, the peak concentration hypothesis suggests that continuous renal replacement therapies, due to their continuity and unspecific capacity of removal, might be beneficial in cutting the peaks of the concentrations of both pro- and anti-inflammatory mediators, restoring a situation of immunohomeostasis. Thus the patient may benefit from a lesser degree of immunodysregulation and he/she may restore a close-to-normal capacity of response to exogenous stimuli.

Longitudinal study of apoptosis in chronic uremic patients.

Uremia is associated with a state of immune dysfunction, increasing infection and malignancy rates. Dysregulation of homeostasis may be directly related to abnormal apoptosis regulation, a process which is crucial for the maintenance of the biologic system. Abnormal apoptosis rates (ARs) have been reported in the literature. We performed a longitudinal study over a 10-week period in three groups of uremic subjects-hemodialysis (HD), peritoneal dialysis (PD), and predialysis chronic renal failure (CRF). Our results showed that ARs were consistent over the observed period. Monocytes extracted from HD and CRF subjects had higher ARs compared to PD and controls (HD: 26.06 +/- 8.82; CRF: 26.96 +/- 12.81; PD: 14.77 +/- 5.87; C: 11.42 +/- 4.60) when placed in culture medium. The plasma of HD and CRF subjects when incubated with U937 cells had a stronger apoptogenic potential compared with PD and controls (HD: 26.08 +/- 11.39; CRF: 24.87 +/- 9.07; PD: 12.13 +/- 4.51; C: 11.69 +/- 4.02). Inflammatory markers (C-reactive protein [CRP], procalcitonin) and cytokines (interleukin [IL]-1beta, IL-2, IL-10) had a generally poor correlation except for tumor necrosis factor (TNF)-alpha (p < 0.001). The phagocytic ability of U937 cells when incubated with the various plasma demonstrated impaired response in the HD and CRF subjects (HD: 27.56 +/- 6.67; CRF: 30.24 +/- 9.08; PD: 36.55 +/- 9.80; C: 40.04 +/- 6.98). These results suggest continuous renal purification, such as in continuous ambulatory peritoneal dialysis (CAPD), may have advantages over intermittent therapies in regulating apoptosis and maintaining biologic function and homeostasis.