Danilo Fliser

Fibroblast Growth Factor 23 (FGF23) Predicts Progression of Chronic Kidney Disease: The Mild to Moderate Kidney Disease (MMKD) Study

It has not been firmly established whether disturbed calcium-phosphate metabolism affects progression of chronic kidney disease (CKD) in humans. In this cohort study of 227 nondiabetic patients with CKD, we assessed fibroblast growth factor 23 (FGF23) plasma concentrations in addition to other variables involved in calcium-phosphate metabolism, and we followed 177 of the patients prospectively for a median of 53 months to assess progression of renal disease. In the baseline cohort, we found a significant inverse correlation between glomerular filtration rate and both c-terminal and intact FGF23 levels (both P < 0.001). The 65 patients who experienced a doubling of serum creatinine and/or terminal renal failure were significantly older, had a significantly lower glomerular filtration rate at baseline, and significantly higher levels of intact parathormone, c-terminal and intact FGF23, and serum phosphate (all P < 0.001). Cox regression analysis revealed that both c-terminal and intact FGF23 independently predict progression of CKD after adjustment for age, gender, GFR, proteinuria, and serum levels of calcium, phosphate, and parathyroid hormone. The mean follow-up time to a progression end point was 46.9 (95% CI 40.2 to 53.6) months versus 72.5 (95% CI 67.7 to 77.3) months for patients with c-terminal FGF23 levels above or below the optimal cut-off level of 104 rU/mL (derived by receiver operator curve analysis), respectively. In conclusion, FGF23 is a novel independent predictor of progression of renal disease in patients with nondiabetic CKD. Its pathophysiological significance remains to be elucidated.

Clinical proteomics: A need to define the field and to begin to set adequate standards

The aim of this manuscript is to initiate a constructive discussion about the definition of clinical proteomics, study requirements, pitfalls and (potential) use. Furthermore, we hope to stimulate proposals for the optimal use of future opportunities and seek unification of the approaches in clinical proteomic studies. We have outlined our collective views about the basic principles that should be considered in clinical proteomic studies, including sample selection, choice of technology and appropriate quality control, and the need for collaborative interdisciplinary efforts involving clinicians and scientists. Furthermore, we propose guidelines for the critical aspects that should be included in published reports. Our hope is that, as a result of stimulating discussion, a consensus will be reached amongst the scientific community leading to guidelines for the studies, similar to those already published for mass spectrometric sequencing data. We contend that clinical proteomics is not just a collection of studies dealing with analysis of clinical samples. Rather, the essence of clinical proteomics should be to address clinically relevant questions and to improve the state‐of‐the‐art, both in diagnosis and in therapy of diseases.

ADMA Increases Arterial Stiffness and Decreases Cerebral Blood Flow in Humans

Background and Purpose— Preclinical studies have revealed that the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine (ADMA), increases vascular tone in cerebral blood vessels. Marked elevations of ADMA blood levels were found in patients with diseases characterized by decreased cerebral perfusion, such as ischemic stroke. Arterial stiffness is an independent predictor of stroke and other adverse cardiovascular events. The aim of this study was to investigate the influence of a systemic subpressor dose of ADMA on arterial stiffness and cerebral perfusion in humans. Methods— Using a double-blind, vehicle-controlled study design, we allocated 20 healthy men in random order to infusion of either ADMA (0.10 mg ADMA/kg per min) or vehicle over a period of 40 minutes. Arterial stiffness was assessed noninvasively by pulse wave analysis. All volunteers underwent measurement of cerebral perfusion by dynamic contrast-enhanced perfusion magnetic resonance imaging of the brain. Results— Infusion of ADMA significantly decreased total cerebral perfusion by 15.1±4.5% (P=0.007), whereas blood flow in the vehicle group increased by 7.7±2.8% (P=0.02). ADMA also increased arterial stiffness as assessed by measurement of the augmentation index (−12.6±1.9 to −9.6±1.5, P=0.007). Conclusions— Our results document for the first time that subpressor doses of ADMA increase vascular stiffness and decrease cerebral perfusion in healthy subjects. Thus, ADMA is an important endogenous modulator of cerebral vascular tone and may be involved in the pathogenesis of cerebrovascular disease.

Technology Insight: treatment of renal failure in the intensive care unit with extended dialysis

Sustained low-efficiency dialysis (SLED) is an increasingly popular extracorporeal renal replacement therapy for patients with renal failure in the intensive care unit (ICU). Several centers across the world employ this hybrid technique, which has advantages of both intermittent and continuous methods. The goal of these centers is to provide an easy-to-perform treatment with reduced solute clearances for prolonged periods. Many centers use standard, sophisticated dialysis equipment for SLED. An increasing number of hospitals in Europe and South America employ a single-pass batch dialysis system, the procedural simplicity of which makes it an ideal modality for SLED in the ICU. All systems offer the advantages of flexible timing of treatment and reduced costs; their ease of handling means that SLED is readily accepted by ICU staff. Prospective controlled studies have shown that SLED clears small solutes with an efficacy comparable to that of intermittent hemodialysis and continuous venovenous hemofiltration (even when the latter employs high rates of fluid substitution). Cardiovascular tolerability associated with SLED is similar to that associated with continuous renal replacement therapy, even in severely ill patients. Nocturnal dialysis—a special form of SLED—has all the advantages outlined above, with the added benefit of unrestricted physician access to the patient during the day, minimizing the interference of renal replacement therapy with other ICU activities.

Subpressor Dose Asymmetric Dimethylarginine Modulates Renal Function in Humans through Nitric Oxide Synthase Inhibition

Increased blood concentrations of the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) have been linked to high blood pressure and to cardiovascular mortality. We evaluated the effects of a subpressor ADMA dose on NO production, renal hemodynamics, sodium handling and active renin and noradrenalin plasma concentrations in 12 healthy subjects (age 26 ± 1 year) using a double-blind placebo-controlled study design. Infusion of ADMA caused a significant decrease in plasma cyclic guanosine monophosphate (cGMP) levels, i.e. the second messenger of NO (from 6.1 ± 0.4 to 4.3 ± 0.3 pmol/l; p < 0.05). In parallel, effective renal plasma flow (ERPF) decreased while renovascular resistance (RVR) increased significantly (ERPF from 667 ± 9 to 603 ± 10 ml/min/1.73 m²; RVR from 79 ± 2 to 91 ± 2 ml/min/mm Hg; both p < 0.05 vs. baseline). Infusion of placebo did not cause significant changes in plasma cGMP levels, ERPF and RVR (cGMP from 5.7 ± 0.5 to 5.9 ± 0.6 pmol/l; ERPF from 665 ± 12 to 662 ± 11 ml/min/1.73 m²; RVR from 79 ± 2 to 78 ± 2 ml/min/mm Hg; all non-significant). Moreover, urinary sodium excretion was significantly lower with infusion of ADMA as compared with placebo infusion (128 ± 8 vs. 152 ± 7 µmol/min; p < 0.05). In contrast, blood pressure, active renin and noradrenalin plasma concentrations did not change significantly with either infusion protocol. Acute infusion of a subpressor ADMA dose modulates several aspects of renal function in humans without affecting the activity of the renin-angiotensin and sympathetic system. Whether chronic (intrarenal) NO synthase inhibition in individuals with increased ADMA blood levels may cause persistent renal vasoconstriction and sodium retention must be evaluated.

EPO: renoprotection beyond anemia correction

Until recently the major physiological function of erythropoietin (EPO) was thought to be the induction of erythropoiesis. However, a growing body of evidence indicates that EPO has tissue-protective properties and prevents ischemia induced tissue damage in several organs including the kidney. A pivotal intracellular pathway mediating the beneficial effects of EPO is the activation of Akt, i.e. serine/threonine protein kinase B. As a result, Akt phosphorylates the proapoptotic factor Bad, which in turn causes inhibition of programmed cell death (apoptosis). In the present article we review data on the non-hematological effects of recombinant human EPO (rHuEPO) in different experimental settings of acute and chronic kidney injury, and discuss clinical renoprotective strategies with rHuEPO or analogues substances that are not related to anemia correction.

Mechanisms of Disease: erythropoietin—an old hormone with a new mission?

The major physiological function of erythropoietin is the induction of erythropoiesis. A growing body of evidence indicates, however, that this hormone has tissue-protective effects and prevents tissue damage during ischemia and inflammation. This review article summarizes the present knowledge on the cardiovascular and renal protective effects of erythropoietin and discusses the possible underlying mechanisms.

Efficiency of high-flux hemodialysis in the treatment of valproic acid intoxication.

Abstract Recently, highly efficient (i.e., high volume) dialysis systems have been successfully introduced for the treatment of critically ill patients in the intensive care unit. They also can be a safer, more effective, and less costly alternative to traditional extracorporal techniques in the treatment of severe intoxication. This holds true even if the substance to be eliminated is believed to be a poor candidate for dialysis treatment. We report a case of successful treatment of potentially life‐threatening intoxication, with valproic acid (VPA) using a GENIUS® batch dialysis system for combined standard and extended high‐volume hemodialysis therapy. Concentration of VPA in the total collected dialysate were measured.

Two Cardiovascular Risk Factors in One? Homocysteine and Its Relation to Glomerular Filtration Rate

Background: Hyperhomocysteinemia is thought to be an independent risk factor for cardiovascular disease, but the association between renal dysfunction and homocysteine may not have been fully taken into account. We performed a meta-analysis of studies that report correlations between glomerular filtration rate (GFR) and homocysteine plasma levels. Methods: Using a prespecified research strategy, we identified 41 studies involving 26,617 participants that reported Pearson or Spearman correlation coefficients for the association between 1/GFR and homocysteine. The summary correlation coefficients with 95% CI were obtained by pooling the logarithmic Z values derived from the individual trial correlation coefficients. Subgroup analysis was performed to compare results for measured GFR using clearance methods and various estimates of GFR. Results: The pooled correlation coefficient between homocysteine and 1/GFR was 0.37 (CI 0.32–0.40, p < 0.0001). The correlation coefficient based on various estimates of GFR was 0.33 (CI 0.29–0.38, p < 0.0001), and for measured GFR it was 0.45 (CI 0.39–0.51, p < 0.0001). The correlation coefficient was higher when GFR was measured using clearance methods compared with various estimates GFR (1.36 [CI 1.13–1.65], p = 0.0014). Conclusions: Homocysteine plasma levels significantly depend on renal function. This correlation is even more robust when GFR is measured using clearance methods. Therefore, in order to assess whether homocysteine is an independent cardiovascular risk factor, accurate adjustments for renal dysfunction are essential.

Insulin Resistance and Renal Disease

In non-diabetic patients with (primary) kidney diseases a syndrome of insulin resistance can be diagnosed even before the onset of impaired renal function and uremia. It is presenting with hyperinsulinemia, glucose intolerance, hyperglycemia and dyslipidemia. As a result, patients with kidney diseases own the same metabolic cardiovascular risk factors as patient with the classic metabolic syndrome. Thus, this renal insulin resistance syndrome may not only contribute to the excessive cardiovascular risk of patients with kidney diseases, but may also help to explain why even a minor impairment of renal function is a significant and independent cardiovascular risk factor in the general population.