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The use of conventional intermittent hemodialysis (IHD) represents a mainstay of supportive care of patients with acute kidney injury (AKI). However, a number of fundamental questions regarding the optimal management of IHD remain unanswered after more than six decades of renal replacement therapy (RRT). This review summarizes current evidence regarding the timing of initiation of intermittent hemodialysis, the comparative outcomes (mortality and recovery of renal function), the prescription of the intensity of this therapy and discontinuation of dialysis. The way conventional IHD is performed has an impact on the outcome of sick patients with AKI. The value of regular education and training of those who provide IHD cannot be emphasized enough. However, we must be realistic in our expectations that no mode of RRT per se will substantially alter the excessive mortality of critically ill-patients with AKI.

The purpose of this study was to characterize the changes in noradrenergic blood pressure regulation and the causes of this dysregulation in patients with histologically proven primary hyperparathyroidism before and after parathyroidectomy. In untreated hypertensive patients with primary hyperparathyroidism slightly higher plasma levels of norepinephrine, enhanced cardiovascular reactivity to norepinephrine (p0.05) and increased cytosolic free calcium concentration in platelets (p0.05) were found. Parathyroidectomy resulted in the correction of noradrenergic blood pressure dysregulation and in the reduction of cytosolic free calcium and led to normotension. In vitro incubation of platelets from normal subjects with heterologous plasma ultrafiltrates from either hypertensive patients with primary hyperparathyroidism or normotensive uremic patients with secondary hyperparathyroidism led to raised platelet calcium in primary hyperparathyroidism but not in secondary hyperparathyroidism, although in both conditions intact parathormone levels were elevated equally. Furthermore, when platelets of normotensive subjects were preincubated with commercially available parathormone, no effect on resting platelet cytosolic calcium was observed. Our results suggest that hypertension in primary hyperparathyroidism may be caused in part by noradrenergic blood pressure dysregulation and seems to be causally linked to the secretion of a parathyroid hypertensive factor, which increases cytosolic calcium and alters vascular tone and reactivity.

Introduction Current assessments of renal function by serum creatinine or blood urea nitrogen display poor sensitivity and specificity for indicating early changes in kidney function and do not differentiate between causes of acute kidney injury (AKI). The discovery, characterization and validation of novel biomarkers specific for structural kidney damage, such as neutrophil gelatinaseassociated lipocalin, kidney injury molecule-1, interleukin-18 and liver fatty acid binding protein enable a timely diagnosis of AKI through better reflection of real-time damage of AKI, promise discrimination of the underlying aetiology and may enable incremental risk identification for worsening AKI, need of renal replacement and death. However, case-mix, comorbidities, aetiology of the renal insult, timing of measurements and selected thresholds for diagnosis influence the performance of these novel biomarkers. Additional studies are necessary before novel biomarkers can be used in routine clinical practice. To answer the question of how to optimally utilize novel biomarkers (the right test, at the right time, on the right patient, for the right clinical setting of AKI) all promising AKI biomarkers should undergo systematic evaluation in various clinical setting of AKI in order to validate the temporal expression patterns of these biomarkers for early detection of AKI, to determine how to combine multiple biomarkers for earlier diagnosis and to discover how the temporal course relates to onset, severity and outcome of AKI. There is a vital need that large future investigations demonstrate the association between biomarkers and hard clinical outcomes independent of serum creatinine concentrations. It needs to be shown that early renoprotective treatment for AKI based on high biomarker levels actually results in an improved outcome. The aim of this review is to discuss early diagnosis of acute kidney injury in critically ill patients by novel biomarkers. Conclusion Until effective renoprotective therapies are available, there is little benefit from early diagnosis of AKI during critical illness. Introduction Acute kidney injury in the intensive care setting (ICU AKI) is a complex disorder with multiple aetiologies and risk factors, various clinical presentations and unpredictable outcomes. Various combinations of ischemic, septic and nephrotoxic effects are the main causes of hospitalacquired AKI in critically ill patients. Today, ICU AKI is often found in the setting of multiple organ failure and occurs rarely as single organ dysfunction. In general, the incidence of hospital-acquired AKI is increasing as physicians subject an increasingly aged patient population to major surgery, aggressive medical therapeutics and extended radiologic interventions. AKI is widespread and occurs in up to 18% of all hospital admissions with reports of up to 67% in critically ill patients in the ICU. ICU AKI represents a continuum of morbidity that can vary from subclinical injury, in which serum creatinine changes minimally, to severe oligoanuric kidney failure requiring renal replacement therapy (up to 4–6%)1. The diagnosis of AKI has a significant negative impact on the prognosis of critically ill patients and is associated with a poor shortand long-term outcome. Recently, it has been recognized that kidney function does not completely recover in many patients and that AKI represents an antecedent to the development to chronic kidney failure, particularly in patients with preexisting chronic kidney disease2. Even the mildest forms of AKI are independently associated with increased, early as well as late, mortality, and the risk increases in the wake of increasingly severe renal injury1. Current management of ICU AKI is restricted to supportive care. Reports on specific pharmacologic interventions to treat established AKI showed minimal effects, if any. The attributable mortality of hospital-acquired AKI, however, remains distressingly high (up to 70%), despite numerous advances in intensive care medicine and renal replacement therapy1. This review discusses targeted renoprotection used in earlier diagnosis of acute kidney injury in critically ill patients. * Corresponding author Email: h-schiffl@t-online.de 1 Department of Internal Medicine IV, University Hospital Munich, University of Munich, Munich, Germany 2 Medizinische Klinik, SRH Wald-Klinikum Gera, Gera, Germany A na es th es io lo gy , P er io pe ra tiv e & Cr iti ca l C ar e M ed ic in e

Recovery of renal function after acute renal injury is an important clinical determinant of patient morbidity and mortality. However, studies covering this field are scarce and nonhomogeneous.Despite success in animal models, translation of current pharmacologic strategies to limit the extent of kidney dysfunction or to hasten renal recovery from acute kidney injury (AKI) in human studies has failed. Renal replacement therapy is the mainstay of supportive care in patients with AKI. However, its performance can have untoward effects that contribute to the prolongation of the course of AKI or impede the ultimate recovery of complete renal function. Use of biocompatible membranes, daily hemodialysis, advanced intermittent hemodialysis (IHD) technology or continuous RRT (CRRT) have been coupled with shortened renal recovery after AKI. Rate of renal recovery to RRT independence is variable when judged at hospital discharge. The frequency of end-stage renal disease in survivors from AKI is highest in severe acute parenchymal renal disease and lowest in acute tubular necrosis (ATN). Renal recovery is less likely in patients with preexisting renal disease. Renal recovery at hospital discharge may underestimate the true rate of renal recovery. The overwhelming majority of patients (more than 85 %) with severe ATN precipitating on normal renal function recover and maintain complete renal function or any degree of chronic renal functional impairment within 6-12 months after AKI. Partial or nonrecovery of renal function represents an independent predictor of long-term mortality for survivors from AKI. Re-need for RRT occurs in a small portion of survivors of severe ATN (less than 5%).Severe AKI necessitating RRT should no longer simply be viewed as just an acute reversible complication of critical illness or short-term illness. Persistent reduction in renal function will exhibit independent effects on patient survival that extends well beyond discharge from the hospital.

Haemodialysis (HD) patients with meticillin-resistant Staphylococcus aureus (MRSA) infections face high morbidity and mortality. Nasal carriage of Staphylococcus aureus is known to play an important role as an endogenous source for HD-access-related infections that contribute significantly to morbidity, mortality and cost of end-stage renal disease (ESRD) management. This prospective investigation in regular out-clinic haemodialysis patients was undertaken to estimate the prevalence of S.aureus nasal carriage, to define patient groups at risk and to evaluate the effect of elimination on outcomes among outclinic haemodialysis patients.136 HD patients without signs of overt clinical infection (48 women, 88 men, age 22-88 years) were screened at least twice for the nasal carriage for meticillin-susceptible SA (MSSA) or meticillin-resistant SA (MRSA). Nasal carriage of S. aureus was related to demographic (age, gender, duration on HD), comorbidity (diabetes, malignancy) and exposure to health care (dialysis staff, hospitalisation). Nasal carriers for MRSA received standardized mupirocin therapy and were followed up for elimination and infections for 1 year.The prevalence of nasal carriage for staphylococcus aureus was 53 % (41 % MSSA, 12 % MRSA). Compared with patients showing no colonization or with MSSA carriers, the 16 patients with nasal carriage for MRSA were older and more likely to have acquired the bacteria while hospitalised. Genotyping of MRSA isolates revealed different strains in patients and care-providers. Mupirocin eliminated MRSA in all patients, none of these patients experienced an infection caused by staphylococcus aureus, confirming the known value of MRSA elimination from other studies.Elderly patients hospitalised for surgery constitute a high risk group for nasal carriage for MRSA. Early diagnosis may help prevent clinically relevant infection. Elimination of colonization by mupirocin appears to be an attractive preventive strategy.

The residual uraemic syndrome that is inadequately cleared by diffusion is thought to contribute to the poor outcome of maintenance dialysis patients. Haemodiafiltration combines diffusion and convection in a single therapy, conferring theoretical benefits over haemodialysis. However, only few randomised comparisons have been carried out.The prospective crossover clinical evaluation of high-flux ultrapure haemodialysis and online haemodiafiltration included 76 clinically stable patients on low-flux conventional bicarbonate buffered haemodialysis. They were randomized to high-flux haemodialysis or online haemodiafiltration (24 months) and switched to the alternative treatment (24 months).Removal of urea (Kt/V) and phosphate was significantly greater for online haemodiafiltration than for haemodialysis. Both high-flux haemodialysis and haemodiafiltration were associated with sustained reductions of pretreatment beta 2 microglobulin levels, however, the decrease was greater with haemodiafiltration. Both modes of renal replacement therapy significantly improved nutritional status and the haematopoietic response to rHu EPO. Under unmatched conditions (sodium and energy balance) haemodiafiltration was associated with a lower number of hypotensive episodes and partial improvement of quality of life. The incidence of death was low in both groups and did not differ among the two modes of renal replacement therapy.Online haemodiafiltration is a safe, effective and well tolerated therapy for end-stage renal disease patients even in the long run. Whether the dismal mortality rates of unselected end-stage renal disease patients can be changed by online haemodiafiltration remains to be shown in large scale long-term trials.

Acute renal failure (ARF) is associated with poor clinical outcome, particularly in critically ill patients. Different renal replacement techniques are available for treatment of ARF, but a general consensus of standardization of treatment dose is lacking. Recent prospective investigations in critically ill patients with ARF utilizing either intermittent or continuous renal replacement therapy established a clear dose-outcome relationship. However, several surveys of current practices of renal replacement therapy dosing in acute renal failure revealed, that the majority of ICU patients with ARF received dialysis doses lower than prescribed for stable end-stage renal disease patients. Most nephrologists did not perform formal dose calculation. Future patterns of dosing renal replacement therapy should focus both on an earlier start and a higher dose to reduce the excess mortality associated with ARF in critically ill patients.

Hypertension complicating the therapy of renal anemia with rHU-EPO is characterized by an increase in total peripheral vascular resistance, but the mechanisms underlying arteriolar vasoconstriction remain unclear. To assess the role of altered cellular calcium metabolism, resting platelet cytosolic calcium was measured in 12 previously normotensive patients with end-stage renal disease before and after 12 weeks of EPO-therapy, after 12 weeks of combined antihypertensive pharmacotherapy of EPO-induced hypertension, and after 12 weeks of concurrent administration of EPO and indomethacin. Patients with EPO-induced hypertension showed a significant raise in platelet calcium by comparison with calcium levels prior to EPO (179 +/- 15 vs 120 +/- 8 nmol/l), and there was a positive correlation between their blood pressure and platelet calcium levels (r = 0.9, p0.001). Antihypertensive therapy of EPO-induced hypertension resulted in a reduction of blood pressure and a reduction of platelet calcium to near normal levels (128 +/- 6 nmol/l). The non-steroidal antiinflammatory drug indomethacin prevented EPO-induced hypertension and EPO-associated alterations in platelet calcium. The results of the present study suggest that EPO-induced hypertension might be related to altered cellular calcium homeostasis. If EPO therapy induces alterations in calcium metabolism not only in platelets but also in vascular smooth muscle cells, these changes in calcium influx may contribute to arteriolar vasoconstriction during EPO therapy.

Severe acute tubular necrosis (ATN) in critically ill patients is associated with considerable morbidity, mortality and use of health resources. Its precise long-term outcomes, however, have not been well described. The objectives of this observational study were to establish long-term survival and renal recovery for severe ATN in a well-defined population.

1 The effects of a single oral dose of 600 mg of prizidilol on renal function were studied 5 to 6 h after dosing in six normal subjects and eight patients with essential hypertension. 2 Mean arterial blood pressure was reduced to 92% of the control value in normal subjects and to 75% in hypertensive patients. Heart rate increased slightly. 3 In normal subjects, effective renal plasma flow was increased to 107% of control values while glomerular filtration rate (83%), filtration fraction (79%), sodium (84%) and potassium (50%) clearances were significantly decreased. 4 In hypertensive subjects, effective renal plasma flow was increased to 120% of control values, while glomerular filtration rate (67%), filtration fraction (57%), sodium (27%) and potassium (72%) clearances were significantly decreased. 5 Plasma noradrenaline increased significantly in normal subjects (150%) and in patients (173%). Plasma renin activity, aldosterone and epinephrine levels did not change consistently. 6 The results indicate that the acute effects of prizidilol on blood pressure and renal function are more marked in hypertensive than in normotensive subjects. Prizidilol increases renal plasma flow like hydralazine and depresses glomerular filtration rate and fractional sodium excretion like endralazine. In addition to the fall in arterial pressure, efferent vasodilation and/or a specific effect on the glomerular ultrafiltration coefficient Kf may account for the striking decrease in filtration fraction.

Patients with renal functional impairment are prone to develop hypertension and hyperlipidemia, and both abnormalities tend to occur already at an early stage of kidney disease. In 18 patients with mild renal disease (glomerular filtration rate 65 +/- 5 ml/min) and hypertension (mean blood pressure 126 +/- 4 mm Hg), the effect of six weeks of treatment with the loop-diuretic muzolimine on serum lipoproteins was assessed. Compared to placebo values, the diuretic significantly increased serum low-density lipoprotein cholesterol (LDL-C) and apoprotein B (+ 18 and 11%, respectively, P less than 0.005) in 13 men or postmenopausal women, but not in 5 premenopausal women. Serum high-density lipoprotein cholesterol (HDL-C), and total triglycerides or lipoprotein triglyceride fractions were not consistently changed in both subgroups. Thus, the ratio LDL-C/HDL-C was increased from 3.2 +/- 0.3 to 3.9 +/- 0.3 (P less than 0.05) in the men or postmenopausal women, while no such tendency occurred in the premenopausal women (4.1 +/- 0.6 to 3.7 +/- 0.6). Changes in serum LDL-C were not associated with hemoconcentration or alterations in carbohydrate metabolism and were not related to variations in serum potassium or blood pressure. Increased serum levels of the atherogenic LDL-C fraction during diuretic treatment in men or postmenopausal women with renal disease may represent a potentially undesirable effect, particularly since such patients may tend to have hyperlipidemia in the untreated state.

Enhanced cardiovascular pressor reactivity to norepinephrine in mild renal parenchymal disease. The cardiovascular pressor responsiveness to infused norepinephrine (NE) or angiotensin II (AII) as related to endogenous plasma NE or renin levels was assessed in 20 patients with mild parenchymal kidney disease (plasma creatinine 2.20 ± 0.58 mg/dl, ± SEM) and in 20 normal subjects approximately matched for sex and age. The two groups did not differ significantly in mean body weight, heart rate, blood volume, plasma electrolytes, exchangeable or urinary sodium, plasma aldosterone, epinephrine and renin levels, or AII threshold or pressor doses. Basal (including pre-infusion) plasma NE levels, the relationship between plasma NE measured during NE infusion and the corresponding NE infusion rate, as well as the total plasma clearance of NE (5.0 ± 0.8 vs. 5.5 ± 0.5 liter/min) also did not differ significantly between the two groups. In contrast, the threshold or pressor doses of infused NE decreased significantly in the patients with kidney disease (94 ± 11 vs. 134 ± 14 ng/kg/min and 21 ± 3 vs. 40 ± 7 ng/ kg/min; P < 0.05). Moreover, based on analysis of covariance, the individual pressor doses as related to basal plasma NE levels were distributed differently (P < 0.01) between the patients and normal subjects. These findings suggest that the kinetics of plasma NE are unaltered largely in early stage kidney disease. However, such patients tend to develop an exaggerated pressor responsiveness to NE in the presence of normal plasma NE levels. This disturbance may favor the development of hypertension.Stimulation de la réactivité pressive cardiovasculaire à la noradrénaline dans les néphropathies modérées. La réponse pressive cardiovasculaire après perfusion de noradrénaline (NE) ou d'angiotensine II (AII) en fonction des concentrations endogènes de NE ou de rénine plasmatiques a été étudiée chez 20 malades ayant une maladie rénale parenchymateuse modérée (créatininémie 2,20 ± 0,58 (± SEM) mg/dl) et chez 20 sujets normaux d'âge et de sexe voisins. Les deux groupes ne différaient pas significativement par le poids corporel moyen, le rythme cardiaque, le volume sanguin, les électrolytes plasmatiques, le sodium échangeable ou urinaire, l'aldostérone plasmatique, les niveaux d'adrénaline et de rénine, ou les doses seuils ou pressives d'All. Les concentrations plasmatiques de NE basales (y compris les valeurs avant perfusion), la relation entre la NE plasmatique mesurée pendant la perfusion de NE et la vitesse de perfusion de NE correspondante, ainsi que la clearance plasmatique totale de NE (5,0 ± 0,8 contre 5,5 ± 0,5 1/ mn) ne différaient également pas entre les deux groupes. A l'inverse, les doses seuils ou pressives de NE perfusées étaient significativement diminuées chez les malades ayant une néphropathie (94 ± 11 contre 134 ± 14 ng/kg/mn et 21 ± 3 contre 40 ± 7 ng/kg/mn; P < 0,05). En outre, par analyse de covariance, les doses pressives individuelles en fonction des concentrations plasmatiques basales de NE étaient distribuées différemment (P < 0,01) entre les malades et les sujets normaux. Ces résultats suggèrent que la cinétique de la NE plasmatique est en grande partie inchangée au cours des néphropathies au stade initial. Cependant les malades tendent à développer une réponse pressive exagérée à la NE en présence de concentrations plasmatiques de NE normales. Cette anomalie pourrait favoriser le développement d'une hypertension.

In 10 healthy volunteers the renal handling of fluoride was investigated by standard clearance techniques. The renal fluoride clearance ranged from 12.4 to 71.4 ml/ min, values consistently less than corresponding glomerular filtration rates as estimated by the 51Cr-EDTA clearance. The fractional excretion of fluoride correlated with fractional water reabsorption (r = 0.87). It is concluded that renal fluoride excretion is characterized by free filtration at the glomeruli and subsequent net tubular back diffusion.