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Background & Aims: Detection of hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells (PBMC) and/or hepatocytes in absence of HCV RNA in serum, designated as ‘occult HCV infection’, has been a matter of controversy in recent years. We investigated for the first time the prevalence of occult HCV infection in large cohorts of chronic hemodialysis (CHD) and kidney transplant (KTx) patients. Methods: We enrolled 417 CHD patients, 417 KTx recipients and 2 control groups – 25 anti-HCV (antibody against HCV)-positive and HCV RNA-positive patients with chronic hepatitis C, and 40 anti-HCV-, HCV RNA-, and HBsAg-negative healthy subjects. HCV RNA was tested in serum and PBMC using a sensitive commercial assay. Results: In CHD patients, the prevalence of anti-HCV was 3.6% (15/417) and of positive serum HCV RNA 2.4% (10/417). HCV RNA was detected in PBMC in 1/407 (0.25%) HCV serum RNA-negative patients (“occult HCV infection”). In KTx recipients, prevalence of anti-HCV was 4.8% (20/417) and of positive serum HCV RNA 4.6% (19/417). Occult HCV infection was found in 2/398 (0.5%) serum HCV RNA-negative patients. On a mean longitudinal follow-up of 30months of the 3 patients with occult HCV infection, there was no clinical or virological evidence of HCV infection. Conclusions: The prevalence of occult HCV infection was very low in our CHD and KTx patients, and it did not appear to be clinically relevant. Further studies in geographic populations with high HCV endemicity are required to clarify the significance of occult HCV infection in these patient groups. [Copyright &y& Elsevier]

Background: In older adults, current equations to estimate glomerular filtration rate (GFR) are not validated and may misclasslfy elderly persons in terms of their stage of chronic kidney disease. Objective: To derive the Berlin Initiative Study (BIS) equation, a novel estimator of GFR in elderly participants. Design: Cross-sectional. Data were split for analysis into 2 sets for equation development and internal validation. Setting: Random community-based population of a large insurance company. Participants: 610 participants aged 70 years or older (mean age, 78.5 years). Intervention: lohexol plasma clearance measurement as gold standard. Measurements: GFR, measured as the plasma clearance of the endogenous marker iohexol, to compare performance of existing equations of estimated GFR with measured GFR of the gold standard; estimation of measured GFR from standardized creatinine and cystatin C levels, sex, and age in the learning sample; and comparison of the BIS equations (BIS1: creatinine-based; BIS2: creatinine- and cystatin C-based) with other estimating equations and determination of bias, precision, and accuracy In the validation sample. Results: The new BIS2 equation yielded the smallest bias followed by the creatinine-based BIS1 and Cockcroft-Gault equations. All other equations considerably overestimated GFR. The BIS equations confirmed a high prevalence of persons older than 70 years with a GFR less than 60 mL/min per 1.73 m2 (BIS1, 50.4%; BIS2, 47.4%; measured GFR, 47.9%). The total mlsclasslficatlon rate for this criterion was smallest for the BIS2 equation (11.6%), followed by the cystatin C equation 2 (15.1%) proposed by the Chronic Kidney Disease Epidemiology Collaboration. Among the creatinine-based equations, BIS1 had the smallest misclassrfication rate (17.2%), followed by the Chronic Kidney Disease Epidemiology Collaboration equation (20.4%). Limitation: There was no validation by an external data set. ..ASA-Conclusion: The BIS2 equation should be used to estimate GFR in persons aged 70 years or older with normal or mild to moderately reduced kidney function. If cystatin C Is not available, the BIS1 equation is an acceptable alternative. Primary Funding Source: Kuratorium für Dialyse und Nierentrans-platation (KfH) Foundation of Preventive Medicine. [ABSTRACT FROM AUTHOR]

Transplant glomerulopathy (TG) has received much attention in recent years as a symptom of chronic humoral rejection; however, many cases lack C4d deposition and/or circulating donor-specific antibodies (DSAs). To determine the contribution of other causes, we studied 209 consecutive renal allograft indication biopsies for chronic allograft dysfunction, of which 25 met the pathological criteria of TG. Three partially overlapping etiologies accounted for 21 (84%) cases: C4d-positive (48%), hepatitis C-positive (36%), and thrombotic microangiopathy (TMA)-positive (32%) TG. The majority of patients with confirmed TMA were also hepatitis C positive, and the majority of hepatitis C-positive patients had TMA. DSAs were significantly associated with C4d-positive but not with hepatitis C-positive TG. The prevalence of hepatitis C was significantly higher in the TG group than in 29 control patients. Within the TG cohort, those who were hepatitis C-positive developed allograft failure significantly earlier than hepatitis C-negative patients. Thus, TG is not a specific diagnosis but a pattern of pathological injury involving three major overlapping pathways. It is important to distinguish these mechanisms, as they may have different prognostic and therapeutic implications. [ABSTRACT FROM AUTHOR]

Regional transplant practices may affect clinical outcomes within multinational studies. This study evaluated whether the overall results from the Symphony study can be generalized to the participating countries. De novo adult renal transplant recipients ( n = 1645) were randomized to receive standard-dose cyclosporine, or daclizumab induction plus low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus, all in addition to mycophenolate mofetil and steroids. Data for the highest patient-recruiting countries, Spain ( n = 275), Germany ( n = 316) and Turkey ( n = 258), were compared. Patient transplant characteristics were different among the country subsets; only deceased donors in Spain, more expanded criteria donors in Germany, and mainly living donors in Turkey. Efficacy results for the three countries were consistent with that of the overall study – renal function and biopsy-proven acute rejection (BPAR) rates were superior with low-dose tacrolimus. Turkey had higher mean calculated glomerular filtration rate across all treatment groups (60.6–72.2 ml/min) compared with that of Spain (51.1–57.5 ml/min) and Germany (51.3–62.9 ml/min). Spain and Turkey had lower BPAR rates across the four treatment groups compared with the overall study; Germany had much higher rates (21.0–54.2%). These findings confirm the general applicability of the Symphony study results and highlight the importance of inclusion of patients from different geographic origins in randomized clinical trials. [ABSTRACT FROM AUTHOR]

Background. In adult cardiac surgery, the predictive value for AKI of neutrophil gelatinase-associated lipocalin (NGAL) appears to have wide variability. The choice of definition of acute kidney injury (AKI) might, at least in part, account for such variability. [ABSTRACT FROM PUBLISHER]

Background. Preconditional activation of HIF with specific prolyl-hydroxylase inhibitors (PHD-I) attenuates proximal tubular injury, induced by warm ischaemia/ reperfusion (Bernhardt, JASN, 2006). Distal tubular damage occurs in humans with acute kidney injury (AKI), in experimental contrast media-induced nephropathy (CIN), as well as in cell-free isolated perfused kidneys (IPKs). Since in the IPK distal tubular damage inversely correlates with HIF activation (Rosenberger, KI, 2005), we explored the potential of PHD-I to improve morpho-functional outcome in this model. [ABSTRACT FROM PUBLISHER]

Amino-acid-based peritoneal dialysis (PD) fluids have been developed to improve the nutritional status of PD patients. As they may potentially exacerbate acidosis, an amino-acid-containing solution buffered with bicarbonate (Aminobic) has been proposed to effectively maintain acid-base balance. The aim of this study was to evaluate the mesothelial biocompatibility profile of this solution in comparison with a conventional low-glucose-based fluid. Omentum-derived human peritoneal mesothelial cells (HPMC) were preexposed to test PD solutions for up to 120 min, then allowed to recover in control medium for 24 h, and assessed for heat-shock response, viability, and basal and stimulated cytokine [interleukin (IL)-6] and prostaglandin (PGE2) release. Acute exposure of HPMC to conventional low-glucose-based PD solution resulted in a time-dependent increase in heat-shock protein (HSP-72) expression, impaired viability, and reduced ability to release IL-6 in response to stimulation. In contrast, in cells treated with Aminobic, the expression of HSP-72 was significantly lower, and viability and cytokine-producing capacity were preserved and did not differ from those seen in control cells. In addition, exposure to Aminobic increased basal release of IL-6 and PGE2. These data point to a favorable biocompatibility profile of the amino-acid-based bicarbonate-buffered PD solution toward HPMC. [ABSTRACT FROM AUTHOR]

Abstract: Background: A multitude of biomarkers have been suggested for early risk-assessment in patients admitted to the emergency department with suspected acute coronary syndromes. We used logistic regression synergistically with classification and regression tree (CART) analysis to define a multimarker strategy and the cut-off values and sequencing needed to optimize risk stratification in a low to moderate risk population of the emergency department. Methods: 432 unselected patients (59.7±14.5 y, 60.4% male) admitted to the emergency department (ED) with acute coronary syndromes (ACS) were enrolled. Cardiac troponin I (cTnI), N-terminal pro-B-Type natriuretic peptide (NT-proBNP), high sensitivity C-reactive protein (hsCRP), placental growth factor (PlGF), lipoprotein-associated phospholipase A2 (Lp-PLA2) and D-dimers were measured by immunoassay and whole blood choline (WBCHO) and plasma choline (PLCHO) were measured using LC/MS from baseline samples. Logistic regression and CART analysis were used to define the importance of the various biomarkers tested and to define their hierarchy with respect to the prediction of major adverse cardiac events (MACE; cardiac death, non-fatal MI, unstable angina, CHF requiring admission, urgent PCI and CABG) over the 42-day follow-up period. Results: A combination of NT-proBNP, WBCHO and Lp-PLA2 with cutoffs identified by CART-analysis was optimal for risk-stratification and superior to all other possible combinations of markers. Increased concentrations of both NT-proBNP (>1400 ng/l) and WBCHO (>21 μmol/l) identified patients with very high risk (RR=2.4, 39% primary endpoint) while low concentrations of NT-proBNP (≤1400 ng/l), WBCHO (≤17 μmol/l) and LP-PLA2 (≤210 μg/l) indicated very low risk (0% primary endpoint). WBCHO >17 μmol/l additionally identified a subgroup with intermediate risk (RR=3.0, 13.5% primary endpoint) in patients with NT-proBNP concentrations ≤1400 ng/l. Troponin when increased was highly prognostic but was not often positive in this early cohort. Conclusions: A multimarker strategy defined synergistically by logistic regression and by classification and regression tree (CART) analysis can stratify patients into risk groups ranging from very low risk (0% MACE) to very high risk (39.5% MACE) based on admission values. [Copyright &y& Elsevier]

Background: Immunosuppressive regimens with the fewest possible toxic effects are desirable for transplant recipients. This study evaluated the efficacy and relative toxic effects of four immunosuppressive regimens. Methods: We randomly assigned 1645 renal-transplant recipients to receive standard-dose cyclosporine, mycophenolate mofetil, and corticosteroids, or daclizumab induction, mycophenolate mofetil, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus. The primary end point was the estimated glomerular filtration rate (GFR), as calculated by the Cockcroft–Gault formula, 12 months after transplantation. Secondary end points included acute rejection and allograft survival. Results: The mean calculated GFR was higher in patients receiving low-dose tacrolimus (65.4 ml per minute) than in the other three groups (range, 56.7 to 59.4 ml per minute). The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus (12.3%) than in those receiving standard-dose cyclosporine (25.8%), low-dose cyclosporine (24.0%), or low-dose sirolimus (37.2%). Allograft survival differed significantly among the four groups (P=0.02) and was highest in the low-dose tacrolimus group (94.2%), followed by the low-dose cyclosporine group (93.1%), the standard-dose cyclosporine group (89.3%), and the low-dose sirolimus group (89.3%). Serious adverse events were more common in the low-dose sirolimus group than in the other groups (53.2% vs. a range of 43.4 to 44.3%), although a similar proportion of patients in each group had at least one adverse event during treatment (86.3 to 90.5%). Conclusions: A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with standard-dose cyclosporine without induction. (ClinicalTrials.gov number, NCT00231764.) N Engl J Med 2007;357:2562-75. [ABSTRACT FROM AUTHOR]

As cytomegalovirus (CMV) infection frequently occurs in simultaneous pancreas kidney transplantation (SPKT), most centers use general ganciclovir prophylaxis. The aim of the study was to analyze the impact of CMV in a patient cohort with preemptive therapy only. Incidence, course and risk factors of CMV infection were retrospectively analyzed in 94 adult SPK recipients without prophylaxis. Patients with asymptomatic pp65-antigenemia were treated preemptively with intravenous ganciclovir for 14 days. Survival rates after 1, 3, and 5 years were 98%, 97%, and 94% for patients, 96%, 94%, and 88% for renal grafts and 88%, 85%, and 82% for pancreas grafts. CMV infections occurred in 51% of patients and CMV syndrome in 16%. No tissue-invasive disease was observed. Thirty-eight per cent of patients with CMV infection developed a recurrence. Risk factors for CMV in multivariate analysis were the D+/R− constellation, acute rejections, anti-rejection therapy and coronary heart disease. CMV had no impact on patient or graft survival, occurrence of acute or chronic rejection and bacterial infections. Preemptive therapy seems to be safe and effective in SPK recipients, but as the present study was retrospective, prospective randomized studies are needed to confirm our results. [ABSTRACT FROM AUTHOR]

Angiogenesis induced by vascular endothelial growth factor (VEGF) plays an important role in psoriasis. Hypoxic adaptation is conferred through hypoxia-inducible transcription factors (HIFs). VEGF and its receptor Flt-1 are HIF target genes. Growth factors and inflammatory cytokines activate the phosphoinositol-3 kinase pathway, and via activated protein kinase B (phospho-Akt) augment HIF activity. Here, we demonstrate that the major oxygen-dependent HIF isoforms are strongly upregulated in psoriatic skin: HIF-1α mainly in the epidermis, in an expression pattern similar to VEGF mRNA; HIF-2α in both the epidermis and in capillary endothelial cells of the dermis. In contrast, normal human skin shows low expression of HIF-α proteins, with the exception of hair follicles, and glands, which strongly express HIF-1α. In normal human skin, phospho-Akt appeared in the basal epidermal layer, in hair follicles, and in dermal glands. In contrast, in psoriasis, phospho-Akt expression was low in the epidermis, but markedly enhanced in the dermal capillaries and in surrounding interstitial/inflammatory cells. Our data suggest that hypoxia initiates a potentially self-perpetuating cycle involving HIF, VEGF, and Akt activation, which could drive physiologic growth of hair follicles and skin glands. Furthermore, such a cycle may exist in psoriasis in dermal capillaries and contribute to disease progression.Journal of Investigative Dermatology (2007) 127, 2445–2452; doi:10.1038/sj.jid.5700874; published online 10 May 2007 [ABSTRACT FROM AUTHOR]

Abstract: Background: Whole blood choline (WBCHO) and plasma choline (PLCHO) concentrations increase rapidly after stimulation of phospholipase D in acute coronary syndromes (ACS). Early risk-stratification was analyzed in 217 patients with suspected ACS and a negative admission troponin T (<0.03 μg/L). Methods: WBCHO and PLCHO were measured using high-performance-liquid-chromatography mass spectrometry. Major cardiac events (MACE) were defined as cardiac death/arrest, coronary intervention or myocardial infarction (MI). Results: WBCHO (≥28.2 μmol/L) was predictive for MACE (hazard ratio [HR] 2.7; p <0.001), cardiac death/arrest (HR 4.2; p =0.015), heart failure (HR 2.8; p =0.003), coronary intervention (HR 2.1; p =0.01) and MI (HR 8.4; p =0.002) after 30 days. PLCHO (≥25.0 μmol/L) was predictive for MACE (HR 2.6; p =0.005), cardiac death/arrest (HR 15.7; p <0.001), heart failure (HR 6.0; p <0.001) but not for coronary intervention and MI. WBCHO and PLCHO were predictive for MACE in multivariate analysis (Odds ratio [OR] 2.7, p =0.009 and OR 3.3, p =0.03) independently of age, gender, prior MI, coronary risk factors and ECG. Conclusions: WBCHO and PLCHO are significant and independent predictors of major cardiac events in admission troponin T negative acute coronary syndromes. Both are predictive for events related to tissue ischemia and WBCHO is capable of detecting risks associated with coronary plaque instability. [Copyright &y& Elsevier]

The transcription factor HIF-1α has been identified as a key regulator in the cellular and systemic response to hypoxia. Because hypoxia is frequently associated with acidosis, like in ischemia or tumour growth, we studied the impact of acidosis on the expression of the HIF-1α and HIF-2α proteins and that of the three HIF target genes carbonic anhydrase-9 (CA-9), glucose transporter-1 (Glut-1) and erythropoietin (EPO). Since the HIF-prolyl hydroxylases (PHD) modulate cellular HIF-α protein levels we also investigated changes in PHD mRNA expression under hypoxia and acidosis. HIF-1α immunoblots revealed, depending on the cell line investigated, a moderate induction of HIF-α protein levels by acidosis in normoxia (Hep3B cells) or hypoxia (HeLa cells). Concordantly, the activity of HIF-driven luciferase reporters was slightly enhanced at pH 7.0. In contrast, HIF target genes exhibited divergent responses to acidosis: basal and hypoxia-induced CA-9 mRNA levels were further increased, whereas hypoxic EPO mRNA induction was attenuated, and Glut-1 mRNA levels were not altered by acidosis. Except from a small increase of hypoxia-induced PHD3 mRNA levels in HeLa cells, there was also no significant effect of acidosis on PHD expression. In conclusion, albeit HIF protein levels slightly induced by acidosis and the inconsistent regulation of HIF target genes under acidosis suggest additional, yet unidentified pH-sensitive factors to be involved in the regulation of these genes. [ABSTRACT FROM AUTHOR]

The association between renal hyperparathyroidism (HPT) and differentiated thyroid carcinoma is discussed. To determine the prevalence and potential risk factors, we performed a retrospective analysis of our patients (1998–2004) and compared the data with the data from other surgical and autopsy studies. At our hospital, a total of 347 parathyroidectomies in 339 patients with renal HPT were performed. Most patients underwent preoperative ultrasound investigation of the thyroid gland and, if indicate, thyroid scintigraphy. Intraoperatively, both thyroid lobes were mobilized and palpated. Detected thyroid nodules were adequately resected and investigated histologically. A systematic analysis of the international literature was performed using the PubMed/MEDLINE system to identify publications on the prevalence of papillary thyroid carcinoma (PTC) in patients with renal HPT and in the overall population. Altogether, 133 patients (39.2%) underwent simultaneous thyroid surgery. The initial operation was hemithyroidectomy in 55 (16.2%), Dunhill operation in 36 (10.6%), unilateral subtotal resection in 17 (5.0%), bilateral subtotal resection in 5 (1.5%), and enucleation of a thyroid nodule in 18 (5.3%). A PTC was found in 8 of 339 patients (2.4%) and a follicular thyroid carcinoma in 1. Among 311 patients with primary cervical operation, 6 (1.9%) had a papillary thyroid carcinoma. All papillary tumors were classified as pT1 with a diameter of 1 to 12 mm; three were bifocal, and only one patient had positive lymph nodes. None of the analyzed factors showed a significant correlation with the occurrence of thyroid carcinoma. Depending on the screening method, the prevalence of occult PTC in European autopsy studies ranged from 5% to 9% and was markedly higher in almost all studies than in the present one. The prevalence of PTC in the present study makes an etiologic association between renal HPT and PTC unlikely. The clinical significance of these tumors remains unclear becauses all incidental tumors were small. However, if easily and safely feasible, relevant thyroid nodules should be removed during parathyroid surgery. [ABSTRACT FROM AUTHOR]

Abstract Background and aims: In contrast to that in patients with primary hyperparathyroidism, the value of intra operative intact parathyroid hormone (iPTH) measurement is still unclear in patients with renal hyper- parathyroid ism and was, therefore, evaluated in a large cohort of patients. Patients: Intra operative iPTH mea- surmount was performed in 153 patients with renal hyperparathyroidism (129 with terminal renal failure and 24 with frmnctioning kidney graft). Subtotal and total parathyroidectomy were performed in 123 and 13 patients, respectively, during initial surgery. In patients with recurrent disease (17), the respective hyper- functioning tissue was removed. Intra operative blood samples were obtained by puncture of the internal jugular vein before preparation of the parathyroids (PTH0) and 15 mm after parathyroidectomy (PTH15). iPTH was measured with the Elecsys 2010 system. Postoperative iPTH levels (PTHPOSI) were determined at postoperative days 1 to 3 and at week 2. Patients were arbitrarily divided in four groups according to the po stop ergative iPTH values: 0-25 pg/ml (group 1), 26-65 pg/ml (group 2), 66-150 pg/ml (group 3) and more than 150 pg/ml (group 4). Results: The mean PTH0 value was 869±57 pg/ml, which decreased to 167±15 pg/ml at PTH15. The mean relative PTH15 value was 2 1.6±1.7%. Postoperatively, iPTH decreased to 42±9 pg/ml. The postoperative iPTH value of the 129 patients with terminal renal failure was 25 pg/ml or less in 99 patients, 26-65 pg/ml in 11 patients, 66-150 pg/ml in eight patients and higher than 150 pg/ml in 11 patients. Two successive criteria of iPTH de- crease were used: first, a PTH15 of s150 pg/ml or, second, a relative PTH15 of S30% less was used. Fifteen patients did not fulfil both criteria. In 13 of them (86.7%) iPTHPOSt was higher than 65 pg (true failure to decline). Of 114 patients who fulfilled the criteria, 108 (94.7%) had normal postoperative iPTH values (true de- cline). Absolute PTH15 values of less than 150 pg/ml predicted normal postoperative iPTH levels in 77 of 78 patients. Conclusion: A PTH15 value of 150 pg/ml or less predicts operative success in patients with renal failure in 98.7% of cases, independently of the relative decay. In contrast, if the relative PTH15 is higher than 30%, high postoperative PTH values are predicted with a probability of 8 6.7%. Although there remain some borderline cases, intraoperative iPTH measurement is accurate and also can be useful in patients with renal hyperparathyroidism. [ABSTRACT FROM AUTHOR]

Background: Medullary hypoxia is believed to play an important role in the pathogenesis of acute renal failure (ARF). Hypoxia-inducible transcription factors (HIF) are recognized as master regulators of hypoxic adaptation, but little is known about their role in renal disease.Methods: A multi-insult rat model of ARF combining the application of contrast medium with nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition was used to study chronology and distribution of the oxygen regulated HIF isoforms HIF-1alpha and HIF-2alpha in comparison with the hypoxia-marker pimonidazole between 10 minutes and 48 hours after injury induction. Treatment with furosemide was used to study HIF expression under conditions of ameliorated tissue injury.Results: Contrast medium in combination with NOS and COX inhibition resulted in widespread induction of HIF in the outer and inner medulla that was initiated within 10 minutes, reached the highest levels at 2 hours and diminished 8 hours to 24 hours thereafter. HIF isoforms were expressed in a cell type-specific fashion: HIF-1alpha in tubular and HIF-2alpha in interstitial and endothelial cells. The degree of HIF-1alpha accumulation varied between nephron segments, being much stronger in collecting ducts than in medullary thick ascending limb of the loop of Henle (mTAL). Comparison with pimonidazole staining and the effect of furosemide indicated that HIF induction in mTAL is maximal with moderate hypoxia and declines with increasing severity of hypoxia.Conclusion: A complex pattern of HIF activation appears to play an important role in tissue preservation as a response to regional renal hypoxia. The limited capacity of mTAL cells for HIF activation may explain their susceptibility to injury. [ABSTRACT FROM AUTHOR]

Background: Hypoxia is believed to play an important role in the pathogenesis of acute and chronic kidney disease. However, the impact of low oxygen tensions on cellular functions in the kidney and potential adaptive responses are poorly understood. Methods: In order to assess the effects of regional hypoxia, we induced large segmental renal infarcts in rats by renal artery branch ligation to create an oxygen gradient vertical to the corticomedullary axis and studied the effects on cell morphology, the induction of hypoxia-inducible transcription factors (HIF), the expression of HIF target genes, and cell proliferation. Results: Pimonidazol protein adduct immunohistochemistry, a marker for severe tissue hypoxia, verified a continuous area of hypoxic renal tissue extending from the cortex to the papilla, in which tubular necrosis developed subsequently. Within this area local sparing of pimonidazol staining and tissue preservation was found around arcuate veins, indicating regional oxygen supply via diffusion from venous blood. HIF-1alpha was up-regulated within 1 hour and for up to 7 days predominantly in the border zone of the infarct in tubular cells, glomerular cells, resident interstitial cells, capillary endothelial cells, and infiltrating macrophages. HIF-2alpha expression was less prominent and confined to resident and infiltrating peritubular cells in the cortex. HIF expression was colocalized with regional up-regulation of the hypoxia-inducible genes heme oxygenase-1 and vascular endothelial growth factor (VEGF), and was followed by capillary and tubular proliferation. Conclusion: Our findings illustrate a marked potential of renal tissue to respond to regional ischemia and initiate adaptive reactions, including angiogenesis. [ABSTRACT FROM AUTHOR]

Hypertension increases expression of growth factors and MHC II in chronic allograft nephropathy. Background. Hypertension of the recipient is strongly associated with chronic allograft nephropathy. It is unclear, however, whether hypertension is the cause or the consequence of chronic allograft nephropathy. Methods. The present study was performed in the Fisher to Lewis rat kidney transplant model. Transplanted rats (N = eight in each group) received either no treatment or were made hypertensive by administration of deoxycorticosteron acetate (DOCA) and salt. Proteinuria and systolic blood pressure was measured monthly, grafts were harvested at 3 and 6 months for semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and for immunohistology. Results. Systolic blood pressure was markedly elevated in rats receiving DOCA/salt. Allografts of hypertensive animals contained significantly more cells expressing the proliferating cell nuclear antigen compared to isografts and to allografts from normotensive animals (P < 0.05). Histologic staining and mRNA expression of major histocompatibility complex (MHC) II was markedly increased in allografts of hypertensive animals compared to all other groups (P < 0.05). Expression of mRNA for platelet-derived growth factor-B (PDGF-B), transforming growth factor-β (TGF-β) and collagen was higher in allografts than in isografts and was highest in hypertensive animals. Conclusion. We conclude that hypertension augments the expression of growth factors in the allograft possibly aggravating the intimal hyperplasia observed in chronic allograft nephropathy. By increasing the expression of MHC II antigens, hypertension may render the allograft more susceptible to alloantigen-dependent damage. Hypertension and alloantigen-dependent factors appear to exert additive or synergistic effects on inflammatory pathways leading to graft injury. [ABSTRACT FROM AUTHOR]

Background: Changes in renal blood flow are considered to play a significant role in the induction and maintenance of kidney failure, but are difficult to monitor with currently available techniques. The objective was to validate renal flow measurements with Doppler guidewires and to apply this technique to assess dose and time dependency of the renal vascular effects of norepinephrine (NE). Methods: In 10 anesthetized pigs, flow velocity in renal arteries (FVart) and veins (FVvein) and volumetric renal blood flow (VBF) were measured before and after intravenous bolus application of incremental doses of NE (2 to 200 microg). Results: FVart curves exactly reflected the changes in VBF. Beat-to-beat analysis revealed a strong linear correlation over a mean VBF range of less than 0.05 to 0.35 L/min (median correlation coefficient with FVart, r = 0.998), and significant but less close relationships were also found between VBF and FVvein. Ten seconds after the administration of 200 microg NE, FVart dropped from 71 to 6 cm/sec and was 90% reversible after 48 seconds. Similarly, the renal vascular resistance temporarily rose from 988 to 13711 mm Hg. min/L. In contrast, NE-induced increases in systemic vascular resistance were on average a maximum of 1.5-fold but persisted for more than 60 seconds. Conclusions: Doppler flow measurements in the renal artery provide an excellent surrogate of volumetric blood flow, which may be useful for continuous monitoring of renal hemodynamics. The renal vasculature is more sensitive when compared with the systemic vasculature, but also appears to evoke more efficient counter-regulatory mechanisms in response to NE. [ABSTRACT FROM AUTHOR]

We describe a young woman whose initial presentation was dominated by acute diarrhoea. Life-threatening multiorgan failure rapidly ensued and necessitated mechanical ventilation and dialysis treatment. An initially elongated activated partial thromboplastin time prompted further coagulation tests that led to the detection of positive lupus anticoagulant, a highly elevated IgG-anticardiolipin (aCL) antibody titre, and prolonged dilute Russell's viper venom time. Histological examination of samples obtained during endoscopy revealed widespread intestinal thrombotic microangiopathy. In view of these serologic and histologic features, a diagnosis of the malignant variant of the antiphospholipid syndrome (APS), also termed 'catastrophic APS', was established. In spite of this syndrome's grim prognosis, the patient recovered following intensive anticoagulation and adjunct treatment with steroids and immunoglobulins. [ABSTRACT FROM AUTHOR]

Aims: Recent studies have demonstrated the safety and efficacy of catheter-based renal sympathetic denervation (RDN) for the treatment of resistant hypertension. We aimed to determine the cost-effectiveness of this approach separately for men and women of different ages., Methods and Results: A Markov state-transition model accounting for costs, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness was developed to compare RDN with best medical therapy (BMT) in patients with resistant hypertension. The model ran from age 30 to 100 years or death, with a cycle length of 1 year. The efficacy of RDN was modelled as a reduction in the risk of hypertension-related disease events and death. Analyses were conducted from a payer's perspective. Costs and QALYs were discounted at 3% annually. Both deterministic and probabilistic sensitivity analyses were performed. When compared with BMT, RDN gained 0.98 QALYs in men and 0.88 QALYs in women 60 years of age at an additional cost of €2589 and €2044, respectively. As the incremental cost-effectiveness ratios increased with patient age, RDN consistently yielded more QALYs at lower costs in lower age groups. Considering a willingness-to-pay threshold of €35 000/QALY, there was a 95% probability that RDN would remain cost-effective up to an age of 78 and 76 years in men and women, respectively. Cost-effectiveness was influenced mostly by the magnitude of effect of RDN on systolic blood pressure, the rate of RDN non-responders, and the procedure costs of RDN., Conclusion: Renal sympathetic denervation is a cost-effective intervention for patients with resistant hypertension. Earlier treatment produces better cost-effectiveness ratios.

Aim: The goal was to analyze the link between blood levels of calcidiol and all-cause, cardiac and infectious diseases, and mortality due to cancer in hemodialysis patients., Patients and Methods: This study retrospectively evaluated a representative sub-cohort (n=6,518) of German hemodialysis patients from the incidence cohorts 1997-2006., Results: Most (58.8%) were found to be vitamin D deficient (25(OH)D<20 ng/ml), with 41.2% being severely deficient (25(OH)D<12.5 ng/ml). All-cause mortality risk more than doubled in patients with severe deficiency (adjusted odds ratio (aOR)=2.67; 95% confidence interval (CI)=2.30-3.10; p<0.0001). Comparable data were obtained for mortality from cardiac disease (aOR=1.57; 95% CI=1.30-1.88; p<0.0001), infectious disease (aOR=1.48; 95% CI=1.15-1.90; p=0.0026), and cancer (aOR=1.51; 95% CI=1.09-2.08; p=0.0121), respectively., Conclusion: These data highlight the need to ensure primarily adequate 25(OH)D levels in dialysis patients for an advantage of survival.

Background: C-reactive protein (CRP) is a possible causative factor of the destructive processes observed during the weeks after myocardial infarction., Methods: We developed a clinically relevant animal model including the removal of CRP from blood plasma utilizing a specific CRP adsorber and the visualization of the infarct scar in the living animal by cardiovascular magnetic resonance imaging as a tool to investigate the impact of CRP after acute myocardial infarction., Results: We describe the facets of this model system and kinetics of clinical blood parameters like CRP and troponin. In addition, we demonstrate the potency of CRP apheresis reducing CRP levels by ~70% in the established treatment system., Conclusion: We showed for the first time that it is possible to conduct apheresis at the following 2 days after acute myocardial infarction in a porcine infarction model and to analyze the infarct by cardiovascular magnetic resonance imaging at day 1 and 14., (Copyright © 2010 S. Karger AG, Basel.)

The Symphony study assessed whether mycophenolate mofetil (MMF)-based regimens containing reduced doses of adjunct immunosuppressants could reduce toxicity while maintaining efficacy. Here, we examined the impact of acute rejection and associated risk factors. The incidence of biopsy-proven acute rejection in the low-dose tacrolimus group was approximately half that of the standard-dose cyclosporine and low-dose cyclosporine groups, and a third of that in the low-dose sirolimus group. The low-dose cyclosporine group had more severe rejection episodes (≥grade II) compared with other groups. Acute rejection was associated with a 10 mL/min glomerular filtration rate (GFR) reduction and a 5.3% absolute increase in graft loss at 12 months. Overall, the highest GFR was found in both rejecters and non-rejecters receiving low-dose tacrolimus, both in an intent-to-treat analysis and in patients successfully treated according to the protocol. In Cox regression models, human leukocyte antigen (HLA) mismatches and expanded criteria donors increased the acute rejection risk, while recipient age, living related donor, and MMF dose were associated with a reduced risk. Acute rejection was associated with worse outcome but did not entirely explain the differences among the treatment groups. The 2 g MMF plus low-dose tacrolimus combination appears to be the most efficient of all regimens examined regardless of acute rejection., (© 2009 John Wiley & Sons A/S.)

Background: Tubular toxicity and renal ischaemia have been implicated in the pathogenesis of radiocontrast media induced nephropathy (CIN), but their respective role remains unclear. Aims. In order to evaluate changes in renal blood flow in response to intra-arterial contrast media administration, we aimed to continuously measure renal arterial perfusion by means of renal blood flow velocity (RBFV) during left ventricular and coronary angiography and subsequent coronary intervention in patients with chronic kidney disease (CKD)., Patients and Methods: Ten patients (7 males, 63.4 +/- 11.7 years) with serum creatinine (SCr) >1.5 mg/dl participated in the study. The first five patients received low-osmolar iopromide and the others iso-osmolar iodixanol contrast medium. RBFV was measured using a 0.014-inch Doppler guide wire, which was inserted through a separate contralateral femoral sheath via a 5 F Cobra diagnostic catheter into the renal artery. Data were recorded at 500 Hz to allow beat-to-beat analysis of RBFV and pressure. All patients were pre-treated with acetylcysteine and hydration., Results: Immediately after left ventricular angiography no significant changes in RBFV were detected. Over time, however, following repeated administration of the additional contrast medium into the coronary arteries, RBFV decreased significantly from baseline until the end of the investigation, 28.4 (19.1/42.7) to 22.9 (16.9/30.6) cm/s (median and quartiles; P = 0.005), in the absence of significant changes in systemic arterial blood pressure. In individual patients the reduction in RBVF varied from 3.7% to 39.5%. On average the decline in RBFV was more pronounced in patients receiving iopromide (from 41.6 cm/s to 29.3 cm/s) than in those receiving iodixanol (from 19.3 to 17.8 cm/s; P = 0.008 for the difference of relative decline). However, in the iopromide treated patients, coronary intervention was more frequently performed (5/5 versus 2/5) and the median duration of the procedure tended to be longer [85 (32-150) min versus 38 (27-110) min; P > 0.2]., Conclusions: The administration of non-ionic low-osmolal contrast media has no immediate effect on renal perfusion in patients with CKD. However, during the course of coronary angiography a gradual decline in renal blood flow may occur, the extent of which varies, presumably depending on individual pre-disposition as well as on the amount of the contrast medium.

Background: Indirect evidence suggests that hypoxia contributes to the pathophysiology of rhabdomyolysis-induced acute kidney injury (AKI). However, the cellular location and kinetics of hypoxia, as well as potential hypoxia adaptation are unclear., Methods: Rhabdomyolysis was induced in rats by IM glycerol (GLY) injection, which largely recapitulates the full clinical syndrome. Additional rats received IV myoglobin (MYO), in order to assess the contribution of MYO per se. We performed immunohistochemistry for hypoxia markers [pimonidazole (PIM) adducts and hypoxia-inducible factors (HIFs)] and the cell-protective HIF target gene heme oxygenase-1 (HO-1). Furthermore, we sought a potential negative feedback loop to terminate HIF activation, driven by HIF prolyl-hydroxylase-2 (PHD-2)., Results: In GLY, progressive tubular injury, mainly of proximal tubules (PT), developed over time, but its extent was heterogeneous. PIM, HIFalpha and HO-1 were all absent in controls, but strongly positive in GLY, with a specific spatio-temporal pattern. In PT, (a) PIM was detectable throughout the study with a maximum at 6 h, (b) HIF was activated only at 3 h and (c) HO-1 and PHD-2 appeared at 6 h and persisted at a lower level at 24 h. Apart from tubular cast formation, MYO did not cause overt tissue damage, but led to strong activation of HIFs, in a pattern similar to 3 h of GLY., Conclusions: Our data suggest that renal hypoxia occurs in rhabdomyolysis, and that MYO, at least partly, contributes to hypoxia generation. Since in the most affected tubules transcriptional hypoxia adaptation is transient and inhomogeneous, pharmacologic HIF enhancement holds the potential to improve outcome in rhabdomyolysis-induced AKI.

Background: Sound data about the prevalence of acute renal failure (ARF) among patients with severe sepsis and septic shock are lacking. Further, it is not known whether ARF is an independent risk factor for mortality in septic patients or merely an indicator of disease severity., Methods: A prospective cross-sectional one-day prevalence study was carried out in a representative sample of German ICUs, divided into five strata (< 200 beds; 201-400 beds; 401-600 beds; > 600 beds; university hospitals). 3877 patients were screened of whom 415 had severe sepsis and septic shock., Results: Fourteen patients (3.4%) had chronic dialysis-dependent RF and were excluded from analysis. Of the remaining 401 patients, 166 (41.4%) had ARF, as defined by a rise in creatinine above twice the upper limit of normal and/or a drop in urine output to < 0.5 ml/kg bodyweight. Median APACHE II score was 22 in patients with ARF and 16 in patients without ARF (p< 0.0001). Patients with severe sepsis/septic shock had an overall hospital mortality of 55.2%. Hospital mortality in patients with ARF was 67.3% and without ARF 42.8% (p< 0.0001). After adjustment for APACHE II score and age, ARF remained a significant independent risk factor for death [odds ratio (OR) 2.11, 95% confidence interval (CI) 1.27-3.52]. Mortality in septic patients was not associated with pre-existing, non-dialysis-dependent chronic kidney disease, whereas in dialysis-dependent patients with sepsis mortality increased to 86%., Conclusion: In this representative survey in patients with severe sepsis/septic shock, prevalence of ARF is high with 41.4%. ARF represents a significant independent risk factor for mortality in these patients.

Renal transplantation is the optimal treatment for patients of all ages with end-stage renal disease. Life expectancy of the population in general is increasing consistently, as is the age of the dialysis population. Consequently, the average ages of kidney donors and recipients are rising. The combination of a growing number of patients with end-stage renal disease and a shortage of organs poses a significant challenge to the transplant community. Donor shortage is associated with unfavorable consequences (e.g. prolonged waiting time, and compromised graft and patient survival). As such, multidirectional efforts are required to expand the donor pool. Increasing the frequency of living donation seems to be an efficient solution. Living donation is associated with superior results for the recipient, and relatively benign long-term outcomes for donors. Reluctance to use organs from living donors whose eligibility was previously considered marginal (e.g. elderly donors) is declining. Although increased donor age is associated with reduced graft survival rates, this should not preclude use of older living donors; transplantation is definitely superior to remaining on dialysis. Thorough, standardized evaluation and careful screening for premorbid conditions in both elderly donors and elderly recipients are essential. Here, we present various options for expanding the living donor pool, with emphasis on the utilization of elderly living donors and transplantation in elderly recipients.

Although it generally is accepted that renal hypoxia may occur in various situations after renal transplantation, direct evidence for such hypoxia is lacking, and possible implications on graft pathophysiology remain obscure. Hypoxia-inducible factors (HIF) are regulated at the protein level by oxygen-dependent enzymes and, hence, allow for tissue hypoxia detection. With the use of high-amplification HIF-1alpha immunohistochemistry in renal biopsies, hypoxia is shown at specific time points after transplantation with clinicohistologic correlations. Immediately after engraftment, in primarily functioning grafts, abundant HIF-1alpha is present and correlates with cold ischemic time >15 h and/or graft age >50 yr (P < 0.04). In contrast, a low HIF-1alpha score correlates with primary nonfunction, likely reflecting loss of oxygen consumption for tubular transport. Protocol biopsies at 2 wk show widespread HIF-1alpha induction, irrespective of histology. Beyond 3 mo, both protocol biopsies and indicated biopsies are virtually void of HIF-1alpha, with the only exception being clinical/subclinical rejection. HIF-derived transcriptional adaptation to hypoxia may counterbalance, at least partly, the negative impact of cold preservation and warm reflow injury. Transient hypoxia at 2 wk may be induced by hyperfiltration, hypertrophy, calcineurin inhibitor-induced toxicity, or a combination of these. Lack of detectable HIF-1alpha at 3 mo and beyond suggests that at this time point, graft oxygen homeostasis occurs. The strong correlation between hypoxia and clinical/subclinical rejection in long-term grafts suggests that hypoxia is involved in such graft dysfunction, and HIF-1alpha immunohistochemistry could enhance the specific diagnosis of acute rejection.

Background: Hyperlipidemia is highly prevalent in kidney transplant recipients, but the prognostic significance for mortality and allograft survival in these patients has not been established sufficiently., Methods: We prospectively enrolled 733 kidney transplant recipients between 1996 and 1998. Clinical information was collected and blood was drawn for laboratory evaluation. Information on the previous transplantation procedures and organ donor were obtained from the Eurotransplant Foundation database. We used the Austrian Dialysis and Transplantation Registry for follow-up. Using multivariate proportional hazard regression, independent relations of fasting plasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels to risk for death from any cause and risk for kidney allograft loss were examined., Results: During a median follow-up of 6.1 years, 154 patients died and 260 kidney allografts were lost. After careful multivariate adjustment, there were no significant associations between TG and TC levels and patient mortality. Patients in the highest quartile of TG and TC levels had no difference in risks for mortality compared with patients in the lowest quartile of these parameters (hazards ratio, 0.81; 95% confidence interval, 0.51 to 1.28; hazards ratio, 0.68; 95% confidence interval, 0.42 to 1.10, respectively). Similarly, no associations were found with allograft loss. Further analysis of associations between high-density lipoprotein cholesterol or low-density lipoprotein cholesterol categories and patient mortality or kidney allograft loss did not show associations., Conclusion: Elevated levels of TC or its subfractions and elevated TG levels are not associated with increased risk for patient mortality or allograft loss in these kidney transplant recipients.

Background: The aim of this study is to investigate reasons for the large reported differences in renal replacement therapy (RRT) incidence between Germany and England and Wales (E&W)., Methods: Age- and sex-standardized incidence rates were calculated at day 0, day 90, and day 180 by using registry data, and early RRT mortality was studied as an indicator of ascertainment differences. Nationally representative health survey data were analyzed to provide general population prevalence data for major chronic kidney disease risk factors: hypertension, diabetes, vascular disease, obesity, and smoking. Resource data were collected from routine sources and national surveys, and literature searches were performed to explore variation in chronic kidney disease prevalence, late referral, early start, and nondialytic therapy., Results: The gap in RRT incidence between Germany and E&W increased after adjusting for differences in early mortality. The standardized day-90 incidence rate ratio was 1.79 (193.0 per million of the adult population [pmap] in Germany and 107.5 pmap in E&W) diabetes and vascular disease explained 79% of this difference. Diabetes, ischemic heart disease, and hypertension were 1.85-, 1.24-, and 1.18-fold more prevalent in Germany, whereas rates of hypertension control were 0.54-fold lower (20% versus 37% in England). Ischemic heart disease mortality rates were lower in Germany., Conclusion: Much of the difference in RRT incidence between Germany and E&W is explained by a greater prevalence of diabetes, hypertension, and vascular disease in the German general population, particularly those older than 65 years, and lower competing mortality risk.

In the present healthcare system, the physician directly involved in patient care faces developments that are difficult to reconcile with his daily medical activity. He must face that the free choice of a doctor is undermined by access restriction and regulation. The focus of his activity shifts from classical medical examination to documentation and administration of the patients. His professional freedom of action is reduced by economic constraints. The thinning of the political responsibility has the consequence that he is left alone in communicating negative developments to the patients. The culture of clinical research is also increasingly under the pressure of economic constraints. While it must be demanded that physicians adapt to new developments, this must not completely undermine the basic principles of the medical profession.

Objectives: Recently, highly sensitive molecular assays to detect HCMV, HHV-6 and HHV-7 have been developed but their ability to detect patients at high risk for disease is unclear., Methods: The positive predictive values (PPV) of pp65-antigenemia, quantitative plasma DNA and pp67-mRNA for CMV-disease were prospectively compared in 82 transplant recipients (72 renal, 10 pancreas-kidney) without CMV-prophylaxis. In addition, the prevalence of HHV-6 and HHV-7 infection were assessed using qualitative PCR. The assays were performed weekly., Results: Three patients (3,7%) developed CMV-disease and were effectively treated. They were positive in all three CMV-assays. The PPVs of pp65-Ag, DNA viral load and pp67-mRNA were 33%, 20% and 25% in CMV-positive and 100%, 67% and 50% in seronegative recipients. Sensitivity and negative predictive value were 100% for all assays. Using cut-offs, PPVs were 75% (pp65-Ag > or = 20/200.000 cells) and 100% (PCR > or =30.000 copies/ml). Transfusion of >2 packed red cells, rejection and non-functioning graft were risk factors for CMV Five patients and one patient were positive for HHV-6 and HHV-7 resp.; both were symptomless and did not have a HCMV infection., Conclusions: Therefore, pp65-antigenemia and plasma PCR with a cut-off could be useful for monitoring preemptive therapy.

Introduction: The goal of the Eurotransplant renal allocation scheme is to provide every patient on the waiting list with a reasonably balanced opportunity for a donor offer. New initiatives were taken in order to maximize donor usage while maintaining a successful transplant outcome., Methods: Two Eurotransplant projects were launched in order to accommodate changes in donor and recipient profiles. A re-addressing of the non-heart-beating donor pool was undertaken and an allocation scheme in which organs from donors aged >65 are allocated to recipients aged >65 [the Eurotransplant Senior Programme (ESP)] was introduced., Results: Especially in The Netherlands, an enormous increase in the number of non-heart-beating donor kidneys has been observed, however with a pace-keeping reduction in heart-beating donors. The organization-wide implementation of the ESP has been successful. The 3 year graft survival rates for these age-matched transplants were as good as the human leukocyte antigen (HLA)-matched transplants (64 vs 67%) (P = 0.4)., Conclusion: Within the framework of sound research, the utmost flexibility and creativity is needed to keep or even increase the number of renal transplants when faced with a quantitatively stagnating but qualitatively deteriorating donor pool. Both the non-heart-beating donor protocol and the ESP have proven to be quite successful in achieving this goal without compromising the outcome for the individual end-stage renal disease patient.

A number of bacterial cytokine-inducing substances (CIS) such as lipopolysaccharides (LPS) and exotoxins have been detected in dialysate and may contribute to inflammation in hemodialysis patients. Short DNA fragments, oligodeoxynucleotides (ODN) of 6 to 20 nucleotides, are able to bind to Toll-like receptors and are stimulatory on immune cells. ODN induce natural killer cell activity and induce IFN-gamma, TNF-alpha, and IL-6 from mononuclear cells. The presence of ODN in dialysate samples and bacterial cultures was investigated. ODN were extracted from fluids by adsorption to reverse-phase columns. ODN were detected in 18 of 20 investigated dialysate samples, in eight of 10 reverse-osmosis water samples, and in all cultures from various bacterial strains. The presence of bacterial DNA in dialysate was confirmed by PCR specific for bacterial tRNA gene sequences. Saline for intravenous use contained 0.02 +/- 0.01 microg/ml DNA, dialysate samples contained 0.28 +/- 0.02 microg/ml, and Pseudomonas cultures contained 1.0 +/- 0.03 microg/ml DNA. ODN from bacterial cultures were only partially removed by ultrafiltration and were able to diffuse through regular high-flux dialyzer membranes. Synthetic cytosine-guanosine dinucleotide-containing ODN were able to induce IL-6 in human mononuclear cells. It is concluded that short bacterial-derived DNA fragments are present in clinically used fluids, e.g., dialysate. These fragments are of sufficient small size to pass through dialyzer membranes. Bacterial DNA fragments may be an overlooked factor contributing to inflammation in hemodialysis patients.

Objectives: To analyze the predictive values of selective venous sampling (SVS) in our own experience and in a systematic meta-analysis of the international literature and to compare them with the results of noninvasive localization studies before reoperative parathyroid surgery., Data Sources: Twenty-one consecutive patients with persistent or recurrent renal hyperparathyroidism underwent preoperative SVS and noninvasive imaging. These data were added to a systematic review of the literature on localization studies before reoperative surgery. The literature search included localization studies, recurrent hyperparathyroidism, and reoperation. STUDY SELECTION Prospective and retrospective studies that provided at least the true-positive rate of 1 procedure were included. Data from initial surgery, hyperfunctioning autografts, and case reports were excluded., Data Extraction: Thirty-one publications reported on SVS (n = 22), technetium Tc 99m sestamibi scintigraphy (n = 17), thallium-technetium scintigraphy (n = 11), ultrasonography (n = 18), magnetic resonance imaging (n = 12), and computed tomography (n = 13). The overall analysis was performed by dividing the overall number of true- and false-positive results by the total number of patients., Data Synthesis: Localization by SVS was correct in 20 of 21 patients. In 1 patient with 2 localizations, only 1 was predicted correctly. Therefore, the sensitivity of SVS was at least 90%, with no false-positive results. Overall true- and false-positive rates, respectively, in 31 studies were 71% and 9% for SVS, 69% and 7% for technetium Tc 99m sestamibi scintigraphy, 54% and 16% for magnetic resonance imaging, 55% and 15% for thallium-technetium scintigraphy, 50% and 18% for ultrasonography, and 45% and 14% for computed tomography., Conclusions: With its high sensitivity, SVS is the gold standard in patients with persistent or recurrent renal hyperparathyroidism and negative results of noninvasive localization procedures. The noninvasive procedure of choice is now technetium Tc 99m sestamibi scintigraphy, with high sensitivity and a low rate of false-positive results.

A 36-year-old male with a known history of sickle cell disease (SCD) and acute chest syndrome (ACS) was treated in our hospital. Gas exchange deteriorated and the patient was transferred to our intensive care unit (ICU). Low dose inhaled nitric oxide (iNO) during pressure controlled mechanical ventilation (pcMV) induced a clinically relevant increase in arterial oxygenation. The patient was weaned from pcMV after five days and discharged home 14 days later. ACS evolving to acute respiratory distress syndrome (ARDS) is a rare but severe complication. In ACS iNO should be considered a beneficial therapeutic option.

Allocation of kidneys from donors older than 64 years to recipients older than 64 years was started in 1999 to improve use of older donor kidneys. Kidneys are allocated locally without HLA-matching to keep cold ischemia short. We compared survival and rejection rates in elderly patients allocated in the old-for-old program (ESP) to patients aged 60 years and older based on HLA-matching, expected ischemia and waiting time (ETKAS). The 69 ESP patients were older (67.9 +/- 2.5 vs. 63.9 +/- 2.9 years), had older donors (71.2 +/- 3.9 vs. 44.6 +/- 14.5 years) and more HLA-mismatches (4.2 +/- 1.2 vs. 1.6 +/- 1.7) than the 71 ETKAS patients, while ischemia was shorter (7.8 +/- 3.4 vs. 14.2 +/- 5.5 h). ESP and ETKAS had similar graft (1-year: 83.6% vs. 86.9%) and patient survival (85.2% vs. 89.5%). With the introduction of ESP, use of older recipients and donors rose from less than 2% to 16% and 11%, respectively. Incidence of acute rejections was significantly higher in the ESP group (1 year: 43.2% vs. 27.4%) and significantly correlated with the degree of HLA-matching. Introduction of old-for-old allocation allows successful expansion of the donor and recipient pool without affecting patient and graft survival. HLA-matching should not be ignored, as the risk of acute rejection in elderly patients is substantial.

Background: Markers of an acute phase reaction, such as C-reactive protein (CRP) or interleukin-6 (IL-6), are predictive for cardiovascular morbidity and mortality in normal subjects and in hemodialysis (HD) patients. Le-vels of acute phase proteins (APP) may vary with time even in the absence of an acute illness and this may weaken the relationship between APP and clinical outcome. We investigated the intra- and inter-individual patterns of several inflammatory markers in HD patients., Methods: Plasma levels of CRP, IL-10, RANTES, TNF-RI, leptin, ferritin and albumin were measured weekly for 12 weeks after the long inter-dialytic interval by ELISA in ten stable HD patients with no clinical signs of infection., Results: Considerable variability was observed. Intra-individual differences were largest for RANTES (coefficient of variation - CV - 80%, followed by CRP (51%), and low for albumin (11%) and ferritin (12%). Inter-individual variability was highest for IL-10 (135%) followed by CRP (88%)., Conclusions: The present data suggest that single point measurements of APP, particularly CRP, may not be sufficient to assess the cardiovascular risk in HD patients. Even in patients with no apparent signs of infection, there is considerable variability in plasma levels of APP and repeated measurements are recommended to identify patients at high cardiovascular risk.

Unlabelled: On 4 January 1999, the Eurotransplant Senior Program (ESP) was implemented within the Eurotransplant kidney allocation scheme., Patients and Methods: Kidneys obtained from donors aged over 65 years of age (65+) were allocated to a selected group of nonimmunized 65+ patients undergoing their first transplant. All transplants were performed locally to minimize cold-ischemic time. All transplants performed with kidneys from elderly donors that were allocated via ESP (ESP group) were compared to transplants performed with similar kidneys allocated via the standard renal allocation system (control group). Initial kidney function and 1-year graft outcome were assessed., Results: In 1999, 227 ESP and 102 control transplants were performed. The duration of cold-ischemic time was 12 and 19 h for the ESP and control groups, respectively. No rejection episodes occurred in 60% and 67% of the ESP patients and controls, respectively, while a direct kidney function was observed in 59% of ESP and 49% of control patients. The 1-year graft survival rates, censoring for graft losses due to deaths in patients with functioning grafts, were 86% and 79%, respectively., Conclusion: An old-for-old renal allocation algorithm can be successful provided that risk factors, such as cold-ischemic time, are reduced.

Oxygen tensions in the kidney are heterogeneous, and their changes presumably play an important role in renal physiologic and pathophysiologic processes. A family of hypoxia-inducible transcription factors (HIF) have been identified as mediators of transcriptional responses to hypoxia, which include the regulation of erythropoietin, metabolic adaptation, vascular tone, and neoangiogenesis. In vitro, the oxygen-regulated subunits HIF-1alpha and -2alpha are expressed in inverse relationship to oxygen tensions in every cell line investigated to date. The characteristics and functional significance of the HIF response in vivo are largely unknown. High-amplification immunohistochemical analyses were used to study the expression of HIF-1alpha and -2alpha in kidneys of rats exposed to systemic hypoxia bleeding anemia, functional anemia (0.1% carbon monoxide), renal ischemia, or cobaltous chloride (which is known to mimic hypoxia). These treatments led to marked nuclear accumulation of HIF-1alpha and -2alpha in different renal cell populations. HIF-1alpha was mainly induced in tubular cells, including proximal segments with exposure to anemia/carbon monoxide, in distal segments with cobaltous chloride treatment, and in connecting tubules and collecting ducts with all stimuli. Staining for HIF-1alpha colocalized with inducible expression of the target genes heme oxygenase-1 and glucose transporter-1. HIF-2alpha was not expressed in tubular cells but was expressed in endothelial cells of a small subset of glomeruli and in peritubular endothelial cells and fibroblasts. The kidney demonstrates a marked potential for upregulation of HIF, but accumulation of HIF-1alpha and HIF-2alpha is selective with respect to cell type, kidney zone, and experimental conditions, with the expression patterns partly matching known oxygen profiles. The expression of HIF-2alpha in peritubular fibroblasts suggests a role in erythropoietin regulation.

Background: Chronic kidney disease is characterized by increased synthesis and inhibited destruction of collagenous and non-collagenous matrix proteins. Elevation of collagen fragments has been demonstrated in the serum and urine of patients with renal disease, but the dynamics of renal matrix deposition remain difficult to determine., Methods: To obtain a further insight into renal matrix metabolism we have assessed whether serum and urine concentrations of the non-collagenous protein, tenascin, and of the tissue inhibitor of metalloproteinases 1 (TIMP-1) are altered in association with renal disease. Serum and urine concentrations of both proteins were determined using a newly developed magnetic particle enzyme immunoassay and were compared with levels of N-terminal procollagen III-peptide (PIIINP) and related to the degree of renal failure and proteinuria., Results: Circulating levels of tenascin and TIMP-1 were moderately, but significantly, higher in patients with chronic renal disease (n=54; mean creatinine clearance, 62 ml/min) than in healthy controls (n=176). Urine concentrations per mg creatinine of tenascin and TIMP-1 were significantly lower than serum levels, but were on average six- and 18-fold higher, respectively, in patients with renal disease than in controls. Urinary concentrations increased with progressive reduction in renal function, but were unrelated to proteinuria. TIMP-1 concentrations in urine correlated with tenascin, which is compatible with the impact of TIMP-1 on the accumulation of matrix proteins. The concentrations of proteins measured did not differ depending on the aetiology of renal disease., Conclusion: Urinary concentrations of tenascin and TIMP-1 are elevated in association with renal disease and may reflect specific aspects of renal fibrosis.

Since the sixties kidneys have been transplanted successfully at the 2 predecessors of today's transplant center at the Charité. So far, 1,290 kidneys were transplanted resulting in 89.8% overall graft survival at one year and 78.6% at 5 years. Several factors were associated with these results. Ischemia times were very short (11.9 +/- 7.3 hours). Patients with diabetic nephropathy were rarely transplanted without combined pancreas transplantation. Combined with a pancreas transplantation, kidney grafts fared even better than those of non-diabetic patients. The share of living donation is still rising and is associated with a better outcome than cadaveric grafts. In contrast, the effect of HLA mismatches was not very pronounced. Zero- and one-mismatch transplantations had a clear benefit over those with 2-3 mismatches, but higher numbers of mismatches did not lead to worse results. To expand the donor pool with kidneys from old donors (> 64 years) we participate in the Eurotransplant Senior Program (ESP) where these kidneys are allocated locally to recipients aged 65 years and older without HLA matching. The ischemia times for ESP kidneys were shorter (7.3 +/- 3.0 hours) but transplants were less well matched (4.2 +/- 2.1 mismatches). Graft survival was not different from controls aged 60 years and older who received a kidney from a donor under age 65. The ESP patients do not require prolonged hospitalization for transplantation (30.6 +/- 14.6 days versus 35.3 +/- 26.0 days in patients below 60 years). With the introduction of the ESP the number of transplantations in recipients aged 60 years and above have risen considerably.

Bioincompatibility of peritoneal dialysis fluids (PDF) has been linked to the presence of glucose degradation products (GDP). Previous experiments have shown that short-term exposure to several GDP at concentrations found in commercially available PDF had no significant effect on human peritoneal mesothelial cells (HPMC). During continuous ambulatory peritoneal dialysis, however, cells are continually exposed to GDP for extended periods of time. Thus, the impact of GDP on HPMC during long-term exposure was assessed. HPMC were cultured for up to 36 d in the presence of 6 identified GDP (acetaldehyde, formaldehyde, furaldehyde, glyoxal, methylglyoxal, and 5-HMF) at doses that reflect their concentrations in conventional PDF. At regular time intervals, the ability of HPMC to secrete cytokines (interleukin-6 [IL-6]) and extracellular matrix molecules (fibronectin) was evaluated. In addition, cell viability, morphology, and proliferative potential were assessed. Exposure to GDP resulted in a significant reduction in mesothelial IL-6 and fibronectin release. Approximately 80% of this decrease occurred during the first 12 d of the exposure and was paralleled by a gradual loss of cell viability and development of morphologic alterations. After 36 d of exposure, the number of cells in GDP-treated cultures was reduced by nearly 60%. However, GDP-treated cells were able to resume normal proliferation when transferred to a normal GDP-free medium. HPMC viability and function may be impaired during long-term exposure to clinically relevant concentrations of GDP, which suggests a potential role of GDP in the pathogenesis of peritoneal membrane dysfunction during chronic peritoneal dialysis.