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Patients with CKD exhibit significant within-patient hemoglobin (Hb) level variability, especially with the use of erythropoiesis stimulating agents (ESAs) and iron. Analyses of dialysis cohorts in the United States produced conflicting results regarding the association of Hb variability with patient outcomes. Here, we determined Hb variability in 5037 European hemodialysis (HD) patients treated over 2 years to identify predictors of high variability and to evaluate its association with all-cause and cardiovascular disease (CVD) mortality. We assessed Hb variability with various methods using SD, residual SD, time-in-target (11.0 to 12.5 g/dl), fluctuation across thresholds, and area under the curve (AUC). Hb variability was significantly greater among incident patients than prevalent patients. Compared with previously described cohorts in the United States, residual SD was similar but fluctuations above target were less frequent. Using logistic regression, age, body mass index, CVD history, dialysis vintage, serum albumin, Hb, angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) use, ESA use, dialysis access type, dialysis access change, and hospitalizations were significant predictors of high variability. Multivariable adjusted Cox regression showed that SD, residual SD, time-in-target, and AUC did not predict all-cause or CVD mortality during a median follow-up of 12.4 months (IQR: 7.7 to 17.4). However, patients with consistently low levels of Hb (<11 g/dl) and those who fluctuated between the target range and <11 g/dl had increased risks for death (RR 2.34; 95% CI: 1.24 to 4.41 and RR 1.74; 95% CI: 1.00 to 3.04, respectively). In conclusion, although Hb variability is common in European HD patients, it does not independently predict mortality.

Chronic kidney disease (CKD) guidelines recommend evaluating patients with GFR <60 ml/min per 1.73 m(2) for complications, but little evidence supports the use of a single GFR threshold for all metabolic disorders. We used data from the NephroTest cohort, including 1038 adult patients who had stages 2 through 5 CKD and were not on dialysis, to study the occurrence of metabolic complications. GFR was measured using renal clearance of (51)Cr-EDTA (mGFR) and estimated using two equations derived from the Modification of Diet in Renal Disease study. As mGFR decreased from 60 to 90 to <20 ml/min per 1.73 m(2), the prevalence of hyperparathyroidism increased from 17 to 85%, anemia from 8 to 41%, hyperphosphatemia from 1 to 30%, metabolic acidosis from 2 to 39%, and hyperkalemia from 2 to 42%. Factors most strongly associated with metabolic complications, independent of mGFR, were younger age for acidosis and hyperphosphatemia, presence of diabetes for acidosis, diabetic kidney disease for anemia, and both male gender and the use of inhibitors of the renin-angiotensin system for hyperkalemia. mGFR thresholds for detecting complications with 90% sensitivity were 50, 44, 40, 39, and 37 ml/min per 1.73 m(2) for hyperparathyroidism, anemia, acidosis, hyperkalemia, and hyperphosphatemia, respectively. Analysis using estimated GFR produced similar results. In summary, this study describes the onset of CKD-related complications at different levels of GFR; anemia and hyperparathyroidism occur earlier than acidosis, hyperkalemia, and hyperphosphatemia.

Disorders of mineral and bone metabolism are prevalent in patients with chronic kidney disease (CKD). The recent National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines recommend that blood calcium (Ca) be regularly measured in patients with stages 3 to 5 CKD. The Kidney Disease: Improving Global Outcomes (KDIGO) position states that the measurement of ionized Ca (iCa) is preferred and that if total Ca (tCa) concentration is used instead, then it should be adjusted in the setting of hypoalbuminemia. In 691 consecutive patients with stages 3 to 5 CKD, we compared the ability of noncorrected and albumin-corrected tCa concentration to identify low, normal, or high iCa concentration. The agreement between noncorrected or albumin-corrected tCa and iCa was only fair. The risk for underestimating ionized calcium was independently increased by a low total CO(2) concentration when either noncorrected or albumin-corrected Ca was used and by a low albumin concentration only when noncorrected tCa was used. The risk for overestimating iCa was increased by a low albumin concentration only when albumin-corrected Ca was used. In conclusion, albumin-corrected tCa does not predict iCa better than noncorrected tCa. Moreover, both noncorrected and albumin-corrected tCa concentrations poorly predict hypo- or hypercalcemia in patients with CKD.

Ischemic acute renal failure is characterized by damages to the proximal straight tubule in the outer medulla. Lesions include loss of polarity, shedding into the tubule lumen, and eventually necrotic or apoptotic death of epithelial cells. It was recently shown that peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) increases keratinocyte survival after an inflammatory reaction. Therefore, whether PPARbeta/delta could contribute also to the control of tubular epithelium death after renal ischemia/reperfusion was tested. It was found that PPARbeta/delta+/- and PPARbeta/delta-/- mutant mice exhibited much greater kidney dysfunction and injury than wild-type counterparts after a 30-min renal ischemia followed by a 36-h reperfusion. Conversely, wild-type mice that were given the specific PPARbeta/delta ligand L-165041 before renal ischemia were completely protected against renal dysfunction, as indicated by the lack of rise in serum creatinine and fractional excretion of Na+. This protective effect was accompanied by a significant reduction in medullary necrosis, apoptosis, and inflammation. On the basis of in vitro studies, PPARbeta/delta ligands seem to exert their role by activating the antiapoptotic Akt signaling pathway and, unexpectedly, by increasing the spreading of tubular epithelial cells, thus limiting potentially their shedding and anoikis. These results point to PPARbeta/delta as a remarkable new target for preconditioning strategies.

Interstitial fibrosis plays a key role in the progression of chronic kidney diseases. Analysis of the biologic effects of erythropoietin and of the pathophysiology of interstitial fibrosis suggest that treatment with epoetin may slow the progression of chronic kidney disease, both by decreasing interstitial fibrosis and by protecting against its consequences. The results of two small prospective studies and of a retrospective one also suggest that treatment with epoetin may have such protective effects.

Increasing evidence supports a role of cytokines, tumor necrosis factor alpha (TNF alpha), interleukin-1 (IL-1), and IL-6 in the development of endotoxin-induced acute renal failure. Several activities of these cytokines require a local rather than a systemic production and function. Thus, this study investigates the chronology of cytokine expression in glomeruli isolated from normal rats or rats given iv lipopolysaccharide injections. Detectable levels of TNF alpha could be found in glomeruli isolated from normal rats as assessed by L-929 fibroblast lytic assay and ELISA. Glomeruli isolated from rats given lipopolysaccharide transiently released increased amounts of TNF alpha in relation to the dose of lipopolysaccharide (10 to 500 micrograms/kg body wt) and the lag period between lipopolysaccharide injection and glomerular isolation (20 to 120 min). TNF alpha was released in similar amounts by glomeruli from normal rats that were exposed in vitro to lipopolysaccharide challenge (0.01 to 10 micrograms/mL), indicating that lipopolysaccharide had direct effects on the release of TNF alpha from glomerular cells. These cells consisted mainly of resident cells because reduction of glomerular infiltration by bone marrow-derived cells after the irradiation of normal rats did not affect TNF alpha release. Glomerular IL-1 and IL-6 production was evaluated by specific bioassays under identical conditions. No IL-1 activity could be detected in the medium or within the glomerular cells at any time within 120 min after lipopolysaccharide injection. By contrast, glomerular IL-6 production was induced after lipopolysaccharide challenge both in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

There is considerable evidence suggesting that reactive oxygen species (ROS; superoxide anion, hydrogen peroxide, hydroxyl radical, hypochlorous acid) are implicated in the pathogenesis of toxic, ischemic, and immunologically mediated glomerular injury. The capacity of glomerular cells, especially mesangial cells, to generate ROS in response to several stimuli suggests that these autacoids may play a role in models of glomerular injury that are independent of infiltrating polymorphonuclear leukocytes and monocytes. The mechanisms whereby ROS formation results in morphologic lesions and in modifications of glomerular permeability, blood flow, and filtration rate have been inferred from in vitro studies. They involve direct and indirect injury to resident cells (mesangiolysis) and glomerular basement membrane (in concert with metalloproteases) and alteration of both the release and binding of vasoactive substances, such as bioactive lipids (e.g., prostaglandin E2, prostacyclin, thromboxane), cytokines (e.g., tumor necrosis factor alpha), and possibly endothelium-derived relaxing factor. The importance of such processes appears to be modulated by the intrinsic antioxidant defenses of the glomeruli. Further studies are needed to address the role of ROS in human glomerular diseases.