Nephrol Dial Transplant Research Articles

Formation of lymphoid-like tissue in the kidney--is there a role for chemokines?

Leucocyte recruitment is a hallmark of almost every inflammatory reaction. The time course of leucocyte subset infiltration, along with the tissue distribution of lymphocytes, is a highly regulated process. An increasing number of recent studies have shown the existence of dense leucocyte clusters with separated Tand B-cell zones in chronic autoimmune diseases, including inflammatory kidney disease [1–3]. The highly organized structure of these aggregates is reminiscent of lymph follicles in secondary lymphatic organs, hence they are termed ‘tertiary’ lymphoid tissue. Questions arising from this observation concern the mechanisms that underlie the formation of these lymphoid follicles and their functional role in the immune response. The molecule family of chemokines and their receptors play a central role in leucocyte trafficking. A specific subset, the so-called lymphoid chemokines (Table 1), is responsible for the development and structural integrity of secondary lymphoid organs [4]. These chemokines are therefore primary candidates for leucocyte cluster formation in non-lymphoid organs. Their expression patterns induce and maintain the microarchitecture of lymphoid tissue with compartmentalization in T-cell and B-cell areas. They regulate the homing of circulating immune cells to lymphatic organs, and mediate the complex processes of cross talk between antigen-presenting dendritic cells (DCs), T lymphocytes and B lymphocytes. Recently, our group demonstrated the expression of lymphoid chemokines in rejecting renal transplants [5]. Approximately one-third of patients with acute allograft rejection developed dense intragraft B-cell clusters resembling lymphoid tissue. These B cells express the chemokine receptor CXCR5 and co-localize to areas of elevated intrarenal BCA-1/CXCL13 expression, the only chemokine ligand of CXCR5 known to date. Another lymphoid chemokine described in acute renal transplant rejection by us [5] and by Kerjaschki et al. [6] is SLC/CCL21, which is expressed in lymphatic vessels in renal allografts. The latter study showed that acute transplant rejection with nodular mononuclear infiltrates is accompanied by extensive intrarenal lymphangiogenesis with podoplanin and SLC/CCL21-positive lymphatics. Furthermore, the cognate receptor of SLC/CCL21, CCR7 is expressed on a number of cells in the vicinity of SLC/CCL21positive vessels in organs undergoing acute rejection. The authors speculated that neo-lymphangiogenesis might on the one hand be an important exit route for the inflammatory infiltrates, but may on the other hand also contribute to the maintenance of an alloreactive immune response and could thus trigger recurrent episodes of rejection [6]. Unlike BCA-1/ CXCL13 expression, SLC/CCL21 is not associated with lymph follicle-like clusters, but it is generally found in lymphatics surrounding inflammatory processes in the kidney. Recent data extend the observation of intrarenal lymphoid chemokine expression to human and murine experimental glomerulonephritis. As in transplant rejection, about one-third of patients with lupus nephritis display dense intrarenal CXCR5-positive B-cell clusters, which are also exclusively localized to areas of BCA-1/CXCL13 expression. SLC/CCL21 is expressed by lymphatic endothelium in inflamed regions of the kidney, with no special association to the follicles [7]. A similar phenomenon is observed in patients with anti neutrophil cytoplasmatic antibody-associated glomerulonephritis as well as in murine lupus nephritis. This conserved expression profile of lymphoid chemokines in different pathologies and species argues for a specific functional role. Intrarenal expression of BCA-1/CXCL13 probably leads to the influx of B cells, which carry the corresponding receptor CXCR5. This assumption is underlined by a study performed by Luther et al. [8], who demonstrated that ectopic pancreatic expression of BCA-1/CXCL13 in transgenic mice is sufficient to induce lymphoid-like Correspondence and offprint requests to: Rolf A. K. Stahl, III. Medizinische Klinik, Zentrum fur Innere Medizin, Universitatsklinikum Hamburg Eppendorf, Martinistrasse 52, 20246, Hamburg Germany. Email: rstahl@uke.uni-hamburg.de Nephrol Dial Transplant (2007) 22: 350–352

Understanding recent haemoglobin trials in CKD: methods and lesson learned from CREATE and CHOIR

Two randomized control trials (RCTs), CREATE and CHOIR, recently published in the New England Journal of Medicine, have received intense attention and discussion by the nephrology community [1,2]. Anaemia and its treatment have been the focus of multiple randomized control studies in the recent past, most small and relatively short, so why this amount of discussion now [3–7]? These two new studies by Drueke et al. [1] and Singh et al. [2] represent the largest studies in nondialysis patients published to date; they both tested the hypothesis that higher haemoglobin would lead to improved patient outcomes, and both were negative. The purpose of this editorial is to critically review the two studies, with special attention to the methodology and analysis of both, and by so doing to understand what we can and cannot conclude from them. Importantly, the readership should be informed as to the specific issues related to analysis of randomized control trials, issues of dropout, bias and the impact of censoring, so that interpretation of these trials can be appropriately applied to clinical care. Of note, both are open label, randomized control trials, in non-dialysed CKD patients with primary endpoints that were composite CVD event endpoints. They are similar in many respects, but differ in some: mostly in the authors’ conclusions and applicability of the results. The CREATE study was conducted in Europe, Asia and Mexico, enrolled 600þ patients, and tested the specific hypothesis that treatment of Hgb values to prevent anaemia (defined as <11 g/dl) would lead to improved CVD outcomes. This is a well-conducted RCT, using Erythropoietin (EPO) beta, in patients with stage 4 CKD. Those assigned to the high and low Hgb groups were not statistically significantly different on any parameters at baseline. The separation between Hgb values in the two groups was achieved, 13.5 vs 11.5 g/dl median Hgb in high vs low groups, respectively. The majority of patients completed the study, and there were few protocol violations. There were no differences in primary outcomes, nor was there any difference in left ventricular mass index (LVMI) change over time. The mean GFR of 25ml/min was the same in both groups, as was the mean decline in GFR (3.4ml/min vs 3.1ml/min) over the 3-year period. The authors do point out that the number of patients who went onto dialysis was greater in the higher Hgb group. Because of the non-protocolized nature of dialysis start, and the fact that there were no differences in rate of decline of GFR, or actual GFR at the time of dialysis, this finding should not be overinterpreted. It is possible that the physicians caring for the patients who knew their Hgb values, would decide to commence dialysis when symptoms worsened, in the absence of other explanations for the symptoms, while those in the lower Hgb group, who complained of symptoms, might have delayed dialysis because the symptoms were attributed to anaemia rather than uraemia. The dose of EPO beta in CREATE averaged 5000 IU/per patient; in keeping with all other studies reported previously. The key ‘issue’ with CREATE was that the annual event rate was much lower than expected (6% vs 15%). The sample size calculation was based on observational studies reported from a Canadian cohort assembled almost a decade ago, in 1993, which described left ventricular hypertrophy (LVH) and LVMI differences in those with and without anaemia, and CVD events as well [8]. At that time, the use of ACEi and ARB was not common in the population, target blood pressures were not as low as current levels and treatment of phosphate, PTH and other parameters were not commonplace. The study was a noninterventional, observational study in referred CKD patients across Canada. In CREATE, patients enrolled may be either different than those who were in an original observational cohort, or are treated differently in the course of the study. As the effect of interest was Hgb, all other parameters (such as BP, mineral metabolism abnormalities, etc.) were managed in Correspondence and offprint requests to: Dr A. Levin, Nephrology, Education and Research, 1081 Burrad Street, Room 6010, Vancouver, BC V6Z 1Y6, Canada. Nephrol Dial Transplant (2007) 22: 309–312

Rapid monitoring of bacteria in dialysis fluids by fluorescent vital staining and microcolony methods

Bacterial contamination of dialysis fluids can cause inflammation and pyrogenic reactions in patients. Bacteria can grow more rapidly in dialysis fluids than in the high quality water used for their preparation, because dialysis fluids contain nutrients and electrolytes. Rapid determination of the microbiological quality of dialysis fluids is important, as it may aid in the reduction of instances of endotoxaemia. Microbiological contamination in dialysis systems should be detected as quickly as possible in order to provide dialysis fluid to patients with safety. Microbial contamination in dialysis fluids is usually assessed by culture-dependent methods such as plate counting. Arvanitidou et al. [1] examined dialysis fluids collected from 85 haemodialysis centres in Greece and found a total of 3500 5000 colony-forming units (CFUs)/ml of heterotrophic bacteria in 40% of measured samples [1]. Oie et al. [2] reported that dialysis fluids are more frequently contaminated than the water, acid or bicarbonate concentrates used for dialysis fluid preparation, and that the bacterial count in 42.5% of 40 dialysis fluid samples was >2000CFU/ml. These data indicate that the microbial contamination levels in a considerable proportion of dialysis fluid samples are relatively high. However, culture-dependent methods often underestimate bacterial numbers, because many bacterial species such as mycobacteria cannot be cultivated by conventional means [3], thus potentially placing the patients at a higher risk of inflammation and pyrogenic reactions. In addition, plate counting can require up to several days to detect bacteria. Therefore, microbiological qualities of dialysis fluids are often evaluated by measuring the endotoxin level. The endotoxin assays are simple and require a few hours to obtain results. However, endotoxin levels are often not correlated with numbers of CFU, and high numbers of colonyforming cells are sometimes detected in dialysis fluids with significantly low endotoxin level [4]. Simple, rapid and accurate methods of enumeration without longtime (e.g. 7 days) culture are essential, in order to maintain microbiological quality of dialysis fluids. Fluorescent staining is widely applied to detect bacteria rapidly [5]. Fluorescent dyes stain the nucleic acid and/or protein within the bacterial cells, and these cells can be counted by fluorescent microscopy, laser scanning cytometry and flow cytometry. Fluorescent vital staining such as 40,6-diamidino-2-phenylindole (DAPI) – carboxyfluorescein diacetate (CFDA) double staining can simultaneously determine the total bacterial count and the number of physiologically active bacteria (bacteria with enzymatic activity), not only in environmental samples (river water, pond water, ground water) but also in medical and pharmaceutical samples (pharmaceutical water [6] and herbal medicines [7]). By this technique, numbers of total bacteria (both active and inactive cells) are determined by DAPI staining, and physiologically active cells are selectively enumerated with CFDA staining, without the need for culture. DAPI is used for total direct counting of microbial cells in aquatic environments, because of its high stainability [5]. CFDA is a popular, ultra-sensitive, fluorescent substrate for estimating esterase activity in live micro-organisms (bacteria, yeast and fungi) [5]. Activity of cytoplasmic esterase of micro-organisms is an indicator of their physiological activity. Not only cells with growth potential but also dormant or injured cells can be stained with CFDA. Many bacteria in water with low nutrient concentrations cannot form large colonies which are Correspondence and offprint requests to: Masao Nasu, Environmental Science and Microbiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan. Email: nasu@phs.osaka-u.ac.jp Nephrol Dial Transplant (2007) 22: 612–616

Renal artery stent revascularization with embolic protection in patients with ischemic nephropathy

A prospective analysis of renal artery stent revascularization with distal embolic protection in a high-risk patient population with ischemic nephropathy is presented. A total of 63 patients (median age 70.2 years, range 54-86 years) had significant atherosclerotic stenosis of 83 renal arteries documented on pre-procedural imaging. All patients had baseline chronic renal insufficiency with a documented deterioration in renal function in the 6 months before revascularization. The endovascular technique used in all patients involved primary passage of an embolic filter into the distal main renal artery followed by primary stent deployment with a balloon expandable stainless steel stent. The filter baskets were recaptured and contents submitted for pathological analysis. At 6 months post-intervention, 97% of patients demonstrated stabilization or improvement in renal function. Only 3% of patients had an inexorable decline in renal function, unchanged by the intervention. After a mean follow up of 16.0 months (6-27), 94% of patients demonstrated stabilization or improvement in renal function. One patient suffered an acute post-procedural deterioration in renal function. In total, 60% of the filter baskets contained embolic material. This study confirms the technical feasibility of renal artery stent deployment with adjuvant embolic protection. The excellent results for renal preservation at 6 months post-intervention also suggest that a distal embolic protection device may improve the impact of percutaneous renal revascularization on progressive deterioration in renal function. The postulated mechanism is through the prevention of atheromatous embolization and the embolic yield from the distal filters supports this hypothesis. Patients most likely to receive the greatest benefit are those with mild baseline chronic renal insufficiency and a recent decline in renal function.

The Enigma of Hypertensive ESRD: Observations on Incidence and Trends in 18 European, Canadian, and Asian-Pacific Populations, 1998 to 2002

Despite improved treatment of hypertension and decreasing rates of stroke and coronary heart disease, the reported incidence of hypertensive end-stage renal disease (ESRD) increased during the 1990s. However, bias, particularly from variations in acceptance into ESRD treatment (ascertainment) and diagnosis (classification), has been a major source of error when comparing ESRD incidences or estimating trends. Age-standardized rates were calculated in persons aged 30 to 44, 45 to 64, and 65 to 74 years for 15 countries or regions (separately for the Europid and non-Europid populations of Canada, Australia, and New Zealand), and temporal trends were estimated by means of Poisson regression. For 10 countries or regions, population-based estimates of mean systolic blood pressures and prevalences of hypertension were extracted from published sources. Hypertensive ESRD, comprising ESRD attributed to essential hypertension or renal artery occlusion, was least common in Finland, non-Aboriginal Australians, and non-Polynesian New Zealanders; intermediate in most European and Canadian populations; and most common in Aboriginal Australians and New Zealand Maori and Pacific Island people. Rates correlated with the incidence of all other nondiabetic ESRD, but not with diabetic ESRD or community rates of hypertension. Between 1998 and 2002, hypertensive ESRD did not increase in Northwestern Europe or non-Aboriginal Canadians, although it did so in Australia. Despite the likelihood of classification bias, the probability remains of significant variation in incidence of hypertensive ESRD within the group of Europid populations. These between-population differences are not explained by community rates of hypertension or ascertainment bias.

Costs and benefits of improving renal failure treatment—where do we go?

Less than 50 years ago, a therapeutic revolution totally changed the inevitable lethal prognosis of established chronic kidney disease (CKD), as maintenance dialysis methods and renal transplantation (TX) proved the possibility of prolonged survival for patients with endstage renal failure (ESRF). The first priority of clinical nephrologists in developed countries has, therefore, been the struggle for the widest possible implementation of dialysis and transplant facilities, and the training of medical, nursing and technical staff in these new areas of medical practice. By the end of 2004, close to 1.8 million patients were treated worldwide with renal replacement therapy (RRT), 77% on maintenance dialysis and 23% living with a functional transplant [1]. To date, about 90% of patients benefiting from RRT live in the more developed countries of the Western hemisphere, Japan and Australia, while sadly, more than 5.2 billion people, 82% of the of the total world population, still have no, or only severely rationed, access to these expensive life-saving technologies [1,2]. In recent years, the skyrocketing costs of CKD/endstage renal disease (ESRD) management in developed countries due to the relentlessly increasing number of incident and prevalent patients requiring RRT has strongly stimulated the clinical applications of the ‘nephroprotection concept’ aimed at the early detection and subsequent prevention of progression of CKD, mainly through lifestyle adjustment and the use of new pharmacological agents [3]. Following this line of thought, the objective assigned to nephroprotection is, from the earliest stage of diagnosed CKD, to retard (or even avoid) progression to ESRF, while providing the patients with the longest survival, lowest morbidity, best social rehabilitation and optimal quality of life, at the lowest cost for health care public or private fund-providers. Meeting this ‘global challenge’ [4] has to take into account the quite frightful forecast of the CKD/ESRF economics, based on the current and future increase of prevalent and incident CKD/ESRD patients. These trends are mainly due to ageing of the general populations in developed countries, which increases the frequency of arterial hypertension and other vascular complications, amongst which renal atherosclerosis, together with the epidemic of type 2 diabetes mellitus [1,2,5–7]. According to the current demographic projections, by the year 2030, there will be about 360 million diabetics worldwide, among whom one in three people might (will?) develop CKD. It is clear that no country and no health care system will be able to offer adequate RRT, and that early detection and prevention are the only means of escape from a scenario of inadequate and unequal distribution of life-saving measures such as RRT [8]. International scientific organizations have thus recently called for action to promote early detection of CKD, primarily in populations at risk (patients with diabetes or hypertension, or those with a history of family renal disease) and implementing on the widest possible scale the currently established prevention strategies aimed at slowing down the progression of CKD; these strategies are listed in Table 1 [9]. All these features play a positive role in the prevention of aggravation of CKD. Modifications of lifestyle, required especially for populations living in Western-style societies, are not limited by financial constraints, but by even more powerful barriers, of a socio-psychological nature. [10]. In fact, control of blood pressure (BP) is the cornerstone of any prevention strategy for reducing cardiovascular and renal morbidity/mortality. A review of nine meta-analyses conducted between 1992 and 2003, among which two included non-diabetic patients [11,12], four included diabetics [13–16] and three included mixed populations [17–19], yielded following conclusions [20]: (i) protective treatment includes angiotensin-converting enzyme inhibitors (ACE-Inhs) or angiotensin receptor Correspondence and offprint requests to: Dr C. Jacobs, Service de Nephrologie, Hopital de la Pitie, 83, Boulevard de l’Hopital 75013, Paris, France. Email: claude.jacobs@psl.aphp.fr; claude.jacobs@psl.ap-hop-paris.fr Nephrol Dial Transplant (2006) 21: 2049–2052

Clarithromycin-induced granulomatous tubulointerstitial nephritis

Acute interstitial nephritis is an important cause of acute renal dysfunction, accounting for up to 15% of patients hospitalized for acute renal dysfunction. Drug-induced interstitial nephritis represents 4% of all cases studied histologically, with an estimated frequency of 8% [1]. We present a case of granulomatous interstitial nephritis in a 38-year-old woman prescribed clarithromycin for pharyngitis. A 38-year-old woman was admitted with a history of abnormal renal function. She was seen by her GP with a history of sore throat and nasal discharge for which she was started on a course of clarithromycin. Whilst on these medications, she developed fever, night sweats, headache, rash and mouth ulcers. A subsequent blood test, done because of her worsening symptoms, revealed deranged renal function, following which she was referred to the hospital. Her past medical history included reactive arthritis requiring a short period of methotrexate more than 2 years previously but this was currently quiescent. She denied any drug allergy but was on clarithromycin and homeopathic medication (transfer factor: an immuno-modulating drug). On examination she was apyrexial, tachycardic (pulse103 bpm) and had a blood pressure of 152/92. General and systemic examination was unremarkable. Investigations revealed: urine analysis pH-5.0, leucocytes<10/mm, and few squamous cells; no blood or protein was detected; haemoglobin 10.2 g/dl, white cell count 9.2 10/l (Neu-8.47, Eos-nil), platelets 513 10/l, erythrocyte Sedimentation Rate (ESR) 136; sodium 137mmol/l, potassium 4.4mmol/l, bicarbonate 20mmol/l, urea 17.3mmol/l, creatinine 654mmol/l, calcium 2.56mmol/l, phosphate 1.38mmol/l, albumin 30 g/l and C-reactive protein (CRP) 84. Autoantibody screen, Anti-glomerular basement membrane (GBM) and anti-neutrophilic Cytoplasmic Antibody (ANCA) were negative. Ultrasound of kidneys was normal. Subsequent renal biopsy showed diffuse inflammatory cell infiltrate within the interstitium, comprising of lymphocytes, plasma cells and numerous eosinophils with non-caseating epitheloid granuloma. A diagnosis of Tubulinointerstitial Nephritis (TIN) was made, all medication was stopped and the patient was started on a short course of oral steroids, following which she made a complete recovery. Drug-induced acute tubulointerstitial nephritis is an inflammatory process involving the tubules, the space between the tubules and the glomeruli. It is mediated by T-cell hypersensitivity reaction and cytotoxic T-cell injury. Renal biopsy is the gold standard for diagnosis. Stopping the suspected medication forms the main component of treatment, with most patients recovering rapidly on withdrawal of the offending drug. Corticosteriod and immunosuppresants, in cases where there is no significant improvement in the renal function, may be of value. Recovery is more rapid in those individuals who have been exposed to the drug for <2 weeks, in comparison to those who have taken the suspected medication for more than 3 weeks. Epithelioid and non-caseating giant-cell granulomas are found in some cases, especially those in which acute interstitial nephritis is secondary to drugs [2]. Granulomatous TIN has been described with drugs like fluoroquinolines and lamotrigine [3,4]. There has been one report of granulomatous reaction in a patient on a combination of dihydrocodeine, amoxicillin, erythromycin and phenylpropanalamine [5]. Other reported cases of granulomatous TIN are seen in infections (tuberculosis), Wegener’s granulomatosis and in sarcoidosis. Idiopathic granulomatous TIN in the absence of features of extra-renal sarcoid has also been described, but these patients may have associated features of hypercalcaemia and raised serum angiotensin converting enzyme [6,7], which were absent in our patient. In our case, the patient was on both clarithromycin and homeopathic medication, which was discontinued immediately after the initial diagnosis was made. Correspondence and offprint requests to: Dr V. K. Audimoolam, 72, Scotney Garden, St Peter Street, Maidstone, Kent, ME16 0GR, UK. Email: vindok@hotmail.com Nephrol Dial Transplant (2006) 21: 2654–2655

Effects of vitamin C infusion and vitamin E-coated membrane on hemodialysis-induced oxidative stress

Chronic hemodialysis (HD) patients manifest anemia and atherosclerosis with associated oxidative stress. We explored whether intravenous infusion of vitamin C (VC) and/or use of vitamin E (VE)-coated dialysis membrane could palliate HD-evoked oxidative stress. Eighty patients undergoing chronic HD were enrolled and randomly assigned into four groups: HD with intravenous VC (n=20), HD with VE-coated dialyzer (n=20), HD with both (n=20), and HD with neither (n=20). We evaluated oxidative stress in blood and plasma, erythrocyte methemoglobin/ferricyanide reductase (red blood cells (RBC)-MFR) activity, plasma methemoglobin, and pro-inflammatory cytokines in these patients. All patients showed marked increases (14-fold) in blood reactive oxygen species (ROS) after HD. The types of ROS were mostly hydrogen peroxide, and in lesser amounts, O2*- and HOCl. HD resulted in decreased plasma VC, total antioxidant status, and RBC-MFR activity and increased plasma and erythrocyte levels of phosphatidylcholine hydroperoxide (PCOOH) and methemoglobin. Intravenous VC significantly palliated HD-induced oxidative stress, plasma and RBC levels of PCOOH, and plasma methemoglobin levels and preserved RBC-MFR activity. The VE-coated dialyzer effectively prevented RBCs from oxidative stress, although it showed a partial effect on the reduction of total ROS activity in whole blood. In conclusion, intravenous VC plus a VE-coated dialyzer is effective in palliating HD-evoked oxidative stress, as indicated by hemolysis and lipid peroxidation, and by overexpression of proinflammation cytokines in HD patients. Using VE-coated dialyzer per se is, however, effective in reducing lipid peroxidation and oxidative damage to RBCs.

Hemodialysis reduces inhibitory effect of plasma ultrafiltrate on LDL oxidation and subsequent endothelial reactions

Oxidative modification of low-density lipoprotein (LDL) and its deleterious effect on endothelium is implicated in the pathogenesis of atherosclerosis. Endothelium responds to such an insult by upregulating the synthesis of heme oxygenase-1 (HO-1) and ferritin. Endothelial cell damage and dysfunction have been observed in patients with chronic kidney disease (CKD) on maintenance hemodialysis (HD). We studied the effect of low-molecular-weight components of uremic plasma on LDL oxidation and LDL-oxidation-provoked endothelial cell reactions, such as the induction of cytotoxicity and the upregulation of cell-protective HO-1 and ferritin. Plasma ultrafiltrate (molecular weight<5000 Da) from CKD patients on HD or when treated conservatively exhibited a pronounced inhibition on heme-mediated oxidative modification of LDL. Endothelial cell cytotoxicity provoked by LDL oxidation was also attenuated by plasma ultrafiltrate from CKD patients. During HD treatment, a dramatic drop occurred in the retardation of oxidative reactions, and a loss of endothelial cytoprotection exerted by plasma ultrafiltrate was noted. The upregulation of HO-1 and ferritin in response to oxidative stress of LDL was blunted by uremic plasma ultrafiltrate that was released by the end of HD. The decreased antioxidant capacity of ultrafiltrate after HD occurred as a consequence of the intradialytic removal of L-ascorbic acid, uric acid, bilirubin, 3-indoxyl sulfate, indoxyl-beta-D-glucuronide, p-cresol, and phenol. Intradialytic removal of L-ascorbic acid, uric acid, bilirubin, 3-indoxyl sulfate, indoxyl-beta-D-glucuronide, p-cresol, and phenol increases the risk of LDL oxidation and subsequent endothelial cell damage, which underlines the importance of activation of cytoprotective HO-1 and ferritin in endothelium.

Is tacrolimus superior to ciclosporin microemulsion in preventing long-term acute renal transplant rejection?

Original article Kramer BK et al. (2005) Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results. Nephrol Dial Transplant 20:968–973 PubMed Large-scale trials indicate that tacrolimus has a greater preventive effect on acute renal transplant rejection than ciclosporin.

Iron Chelation and Vascular Function

In 1981, Sullivan suggested that a state of iron depletion (ie, reduced iron stores without anemia) was potentially protective against coronary heart disease (CHD).1 This original “iron hypothesis” was an attempt to explain the known sex difference in cardiovascular (CV) risk and the subsequent loss of the protective effect of female gender with menopause. This initial hypothesis was based in part on the observation that men exhibited an age-dependent increase in the accumulation of iron that was not seen in women until after menopause. This, coupled with the observation that hysterectomy without oophorectomy was associated with an increased CHD risk, supported the concept that a diminution in iron stores was protective against CHD. Basic and clinical data have recently begun to provide plausible explanations for a link between iron and atherosclerosis.2,3 See page 2282 The toxic effect of free iron has been linked to oxidative stress through the Fenton reaction, where Fe2+ oxidizes H2O2 leading to its autooxidation and the generation of hydroxyl radicals4 which in turn initiate lipid peroxidation. In addition, biological forms of iron such as heme have the potential to catalyze other oxidative reactions. For example, heme can initiate the oxidation of isolated LDL in vitro4 and, in contrast to free transition metals, LDL in diluted serum.5 Iron is also essential for the synthesis of enzymes that can play a central role in vascular function and atherosclerosis (eg, eNOS, 5-lipoxygenase, and myeloperoxidase). The amount of free ferrous (Fe2+) iron is normally maintained at a very low level in …

Cardiovascular Disease in Children with Chronic Kidney Disease

In children with end-stage renal disease (ESRD), cardiovascular disease (CVD) mortality has not changed for the past 3 decades. Cardiac disease remains the second most common cause of death. Recent data demonstrate a high incidence and prevalence of traditional and chronic kidney disease (CKD)-related CVD risk factors in children. Early markers of cardiomyopathy, such as left ventricular hypertrophy (LVH) and left ventricular dysfunction (LV dysfunction), and early markers of atherosclerosis, such as increased carotid artery intima-media thickness (IMT) and carotid arterial wall stiffness, are frequently found in this patient population. Early identification of modifiable risk factors and treatment of asymptomatic CVD might lead to decrease of cardiovascular morbidity and mortality in young adults who developed CKD during childhood.

Diabetes and the Kidney

Diabetes and the Kidney

Helicobacter pylorieradication for the treatment of dyspeptic symptoms in chronic renal failure

From Clinical Hospital Split, *Department of Gastroenterology and Hepatology, †Department of Nephrology, ‡Department of Pathology, §Department of Microbiology, Split, CroatiaCorrespondence:Prof. Izet Hozo MD, PhDDepartment of Internal Medicine,Clinical Hospital Split, Soltanska 1, Split, CroatiaTel: 385-21-55-76-58Fax: 385-21-55-76-58Izet.Hozo@st.htnet.hrAccepted for publicationNovember 2004

Cutting Balloon Angioplasty in Arteriovenous Fistulas

CREATED in 1966, the Brescia-Cimino arteriovenous fistula remains the most durable form of long-term hemodialysis access ( 1 Brescia MJ Cimino JE Appel K Hurwich BJ Chronic hemodialysis using venipuncture and a surgically created arteriovenous fistula. N Engl J Med. 1966; 275: 1089-1092 Crossref PubMed Scopus (1301) Google Scholar ). Compared with prosthetic grafts, fistulas generally have fewer complications and better overall patency, and are the preferred form of access by the Dialysis Outcomes Quality Initiative criteria ( 2 III. NKF-K/DOQI Clinical Practice Guidelines for Vascular Access: update 2000. Am J Kidney Dis. 2001; 37: S137-S181 PubMed Google Scholar ). Nonetheless, they remain susceptible to the same problems that plague synthetic grafts. Venous stenoses diminish flow in the conduit, leading to poor dialysis, and may ultimately result in thrombosis. Percutaneous thrombolysis of a thrombosed fistula is technically more difficult than percutaneous treatment of a synthetic graft, and some centers will abandon the access rather than attempt fistula pharmacomechanical or mechanical thrombolysis. In contrast, prophylactic angioplasty of a failing access is usually straightforward and typically less demanding on the patient and physician compared with thrombolysis. Prophylactic angioplasty used in this manner has been shown to prolong the life of the access site and is endorsed by the Dialysis Outcomes Quality Initiative ( 3 Burger H Zijlstra JJ Kluchert SA Scholten AP Kootstra G Percutaneous transluminal angioplasty improves longevity in fistulae and shunts for hemodialysis. Nephrol Dial Transplant. 1990; 5: 608-611 Crossref PubMed Scopus (31) Google Scholar , 4 Glanz S Gordon DH Butt KMH Hong J Lipkowitz GS The role of percutaneous angioplasty in the management of chronic hemodialysis fistulas. Ann Surg. 1987; 206: 777-781 Crossref PubMed Scopus (168) Google Scholar , 5 Schwab SJ Raymond JR Saeed M Newman GE Dennis PA Bollinger RR Prevention of hemodialysis fistula thrombosis. Early detection of venous stenoses. Kidney Int. 1989; 36: 707-711 Crossref PubMed Scopus (396) Google Scholar ). Therefore, identification of venous stenoses through screening programs is vital to preserve the access and prolong the life of the patient receiving dialysis treatment.

Picture quiz

Picture quiz

Validation by Computer Simulation of Two Indirect Methods for Quantification of Free Water Transport in Peritoneal Dialysis

In peritoneal dialysis, approximately 40% of the total osmotic ultrafiltration (UF) induced by glucose can be predicted to be due to "free" water transport across aquaporin-1 (APQ-1). Theoretically, it would be possible to assess the fraction of free water transport in the early phase of a hypertonic dwell, when UF rate is high and the relative contribution of Na+ diffusion is low. La Milia et al. [La Milia V. et al. Fast-fast peritoneal equilibration test (FAST-FAST-PET): a simple method for peritoneal hydraulic permeability study [Abstract]. Nephrol Dial Transplant 2002; 17 (Suppl 1):17-18] suggested a technique to assess sodium-associated water transport based on sodium removal (Na+R) divided by the plasma Na+ concentration during a "fast-fast" (60 minute) peritoneal equilibration test (PET) for 3.86% glucose, yielding an estimate of the UF passing through the small pores (UFSP). Free water transport (UF through ultrasmall pores; UFUSP) was obtained by subtracting UFSP from total UF. Although peritoneal Na+ transport is almost totally convective, this technique will slightly overestimate small-pore UF due to the presence of some small-pore Na+ diffusion from the circulation during the dwell. A way of dealing with this problem was presented recently by Smit (Smit W. et al. Quantification of free water transport in peritoneal dialysis. Kidney Int 2004; 66:849-854). In the present study we used the three-pore model of peritoneal transport to predict the degree of overestimation of UFSP for the technique presented by La Milia et al., and any potential deviations from theory for the technique presented by Smit et at. Simulations were performed under ordinary conditions and during simulated UF failure for 3.86% glucose. The fractional UF coefficient accounted for by APQ-1 was set at 2%. Estimating the UFSP from the sodium-associated water transport according to the method by La Milia et al. consistently overestimated UFSP and underestimated UFUSP. These errors were, however, minimal for dwells lasting between 30 and 80 minutes. The technique by Smit et al. to calculate aquaporin-mediated water flow (UFUSP), using an elaborate correction for Na+ diffusion from the circulation during the dwell, seemed accurate in most situations but, in general, tended to moderately overestimate UFUSP at early dwell times (<30 minutes) and underestimate UFUSP at long dwell times (4 hours). The technique presented by La Milia et at. to calculate free water transport during a fast-fast PET was found to be surprisingly accurate, although the procedure would further improve by the introduction of a correction algorithm. The technique by Smit is even more accurate for dwells up to 4 hours' duration. However, since the Smit technique is elaborate, it is less practical for routine determinations of aquaporin-mediated water transport in peritoneal dialysis.

Recurrent high level parvovirus B19/genotype 2 viremia in a renal transplant recipient analyzed by real‐time PCR for simultaneous detection of genotypes 1 to 3

Organ transplant recipients infected with parvovirus B19 frequently develop persistent viremia associated with chronic anemia and pure red cell aplasia. In this study, a male renal transplant recipient who had been infected with parvovirus B19/genotype 2 after renal transplantation at the age of 34 years is described. The patient was repeatedly treated with high dose intravenous immunoglobulin (IVIG) that resulted in the resolvement of symptoms but not in virus eradication. During an observation period of 33 months after transplantation three phases associated with high parvovirus B19 viremia were observed. Both the first and the second viremic phases were combined with severe anemia. Parvovirus B19 specific IgM-antibodies were initially detected at the beginning of the second phase in continually rising concentrations. Initially eradication of the virus by immunoglobulin therapy was reported after the first viremic phase [Liefeldt et al. (2002): Nephrol Dial Transplant 17:1840-1842]. Retrospectively this statement has to be corrected. It was based on the use of a qualitative PCR assay specific for parvovirus B19 genotype 1 associated with reduced sensitivity for detection of genotype 2. After sequence analysis of the viral DNA and adjustment of a real-time PCR assay (TaqMan) for quantitative detection of all three B19 virus genotypes analysis of consecutive serum samples allowed the demonstration of long lasting phases with reduced viral loads following IVIG-treatment. These results demonstrate that IVIG treatment of parvovirus B19-triggered anemia in transplant recipients offers an opportunity to resolve symptoms, but does not guarantee eradication of the virus. Since reactivation of parvovirus B19 infection can result in high virus load associated with the recurrence of symptoms repeated screening for viral DNA is recommended using the TaqMan system established for quantitative detection of all three genotypes of parvovirus B19.

Dialysis catheter-related bacteremia: Treatment and prophylaxis

Dialysis catheter-related bacteremia: Treatment and prophylaxis

Nitric oxide and the regulation of large artery stiffness: from physiology to pharmacology.

The association between arterial stiffening and aging is well described and can be observed in almost all populations worldwide. A number of other cardiovascular risk factors including diabetes and cigarette smoking are also associated with increased large artery stiffness, often referred to as “premature arterial stiffening.” It is now apparent that the aortic pulse wave velocity (PWV), a measure of arterial distensibility, predicts outcome in a variety of different populations, including hypertensives,1 diabetics,2 individuals with end-stage renal disease (ESRD),3 and even in older adults.4 Indeed, in some populations, aortic PWV is a better predictor of future events than peripheral blood pressure.4 Moreover, arterial stiffening may be more than just a marker of cardiovascular risk; stiffening may also play a more direct role in the development of atherosclerotic plaques. Thus, arterial stiffness would appear to be a novel therapeutic target for the prevention of excess cardiovascular morbidity and mortality. To exploit such an exciting prospect fully, it is necessary to understand the factors regulating arterial stiffness. Traditionally, the stiffness of a vessel was viewed as simply a function of the structural elements of the vessel wall and distending (mean arterial) pressure. However, the large arteries also have a generous coat of smooth muscle, which can alter the distribution of stresses between the elastic and collagenous fibers of the vessel wall and thus alter arterial stiffness. Because smooth muscle tone is influenced by a number of circulating and local vasoactive mediators, arterial stiffness may be actively regulated, and indeed modifiable, at least in the short-term. The muscular arteries have a rich sympathetic innervation, and catecholamines are known to alter smooth muscle tone. Moreover, removal of the vascular endothelium in animals alters large artery stiffness,5,6 suggesting that endothelial-derived substances regulate arterial stiffness in vivo. However, the endothelium …