Serum procalcitonin in systemic autoimmune diseases--where are we now?

OBJECTIVES: To review the current evidence regarding the value of measuring procalcitonin (PCT) levels in patients with systemic autoimmune diseases, with a focus on the evidence for diagnostic and analytical performance of this biomarker. A brief description of the pathophysiological basis of this biomarker is also included. METHODS: Using PubMed from the National Library of Medicine, relevant English literature on PCT in patients with different systemic autoimmune diseases, from 1990 to 2009, was reviewed. The search used keywords referring to procalcitonin and systemic lupus erythematosus, antineutrophil cytoplasmic antibody-associated systemic vasculitis, Goodpasture syndrome, rheumatoid arthritis, and giant cell arteritis. RESULTS: When used in the appropriate clinical setting, the measurement of serum PCT levels is valuable as a marker of severe systemic bacterial and fungal infections and sepsis. Information regarding plasma PCT levels in patients with active underlying systemic autoimmune diseases is limited, primarily from observational studies and case series, with considerable variability of patient characteristics and clinical settings. In the detection of systemic infection concomitant with autoimmune diseases, PCT had a diagnostic sensitivity of 53 to 100% and a specificity of 84 to 97% (depending on the selection criteria) and was superior to other inflammatory markers tested. Most of the studies used a semiquantitative test for PCT measurement (functional assay sensitivity <0.5 ng/mL), which can explain the low sensitivity of the test. PCT levels were not significantly affected by renal function abnormalities or immunosuppressive agents. Although high PCT levels commonly occurred with infection, elevated levels of PCT could be found in patients with vasculitis without evidence of infection, often correlated with high disease activity scores. CONCLUSIONS: Significantly elevated PCT levels offer good specificity and sensitivity for systemic infection in patients with systemic autoimmune diseases, regardless of the use of corticosteroids or immunosuppressive agents. PCT measurement may add to diagnostic accuracy in patients with systemic autoimmune diseases who present with a febrile illness, especially when highly sensitive PCT assays and specific PCT cutoff ranges are used in a predefined clinical setting (reflecting the likelihood of infection versus an autoimmune disease flare). However, there are limitations when using this biomarker in patients with systemic autoimmune diseases. PCT levels should not replace the necessary extensive diagnostic workup, which should include a thorough history and physical examination, combined with appropriate immunological, microbiological, radiological, and histological data.

Rare manifestations of Churg-Strauss syndrome: coronary artery vasospasm, temporal artery vasculitis, and reversible monocular blindness-a case report.

Churg-Strauss syndrome (CSS) is a rare illness with clinical findings characterized by asthma, eosinophilia, and vasculitis affecting medium and small-sized arteries and veins in a variety of organs. Involvement of the temporal arteries by non-giant cell eosinophilic vasculitis in CSS is quite rare and has only been published as isolated case reports or small patient series. Myocardial infarction due to coronary artery vasospasm is an unusual manifestation of CSS. We describe a case of a 39-year-old woman who had two myocardial infarctions due to severe coronary artery vasospasm and was diagnosed with CSS based on a temporal artery biopsy. During the course of her treatment, she also had another rare manifestation of CSS, monocular blindness reversible with immunosuppressive therapy.

Mevalonate pathway: a review of clinical and therapeutical implications.

Mevalonate pathway is an important metabolic pathway which plays a key role in multiple cellular processes by synthesizing sterol isoprenoids, such as cholesterol, and non-sterol isoprenoids, such as dolichol, heme-A, isopentenyl tRNA and ubiquinone. While extensively studied in regard with cholesterol synthesis and its implications in cardiovascular diseases, in recent years the mevalonate pathway has become a challenging and, in the meantime, fascinating topic, when a large number of experimental and clinical studies suggested that inhibition of non-sterol isoprenoids might have valuable interest in human pathology. These molecules that are essential for cell growth and differentiation appear to be potential interesting therapeutic targets for many areas of ongoing research: oncology, autoimmune disorders, atherosclerosis, and Alzheimer disease. Also, considerable progress has been made in the past decade in understanding the pathophysiology of two auto-inflammatory disorders resulting from an inherited deficiency of mevalonate kinase, the first committed enzyme of the mevalonate pathway. Here we present a brief description of the biochemistry of the mevalonate pathway, together with a review of the current knowledge of the clinical and therapeutical implications of this fascinating and complex metabolic pathway.

Sunitinib malate.

Recently, there has been a growing interest in understanding the role of receptor tyrosine kinases (RTK), such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and fms-like tyrosine kinase 3 (FLT3), in promoting tumor angiogenesis, tumor growth and metastasis. Sunitinib (sunitinib malate; SU11248; SUTENT; Pfizer Inc, New York, NY, USA) is a novel, orally bio-available, oxindole, multi-targeted tyrosine kinase inhibitor with high binding affinity for VEGFR and PDGFR which has shown anti-tumor and anti-angiogenic activities. This drug recently received approval from the US Food and Administration (FDA) in two indications simultaneously: advanced renal cell carcinoma (adRCC) and gastrointestinal stromal tumors (GIST), in patients who are resistant or intolerant to the treatment with imatinib. The present article reviews the recent pharmacologic and clinical data related to the use of this new promising drug in the field of oncology.

Treatment of proliferative lupus nephritis--a critical approach.

OBJECTIVES: To discuss the current management of proliferative lupus nephritis (PLN), with a focus on strategies to improve long-term outcome and reduce treatment toxicity while minimizing the risk of relapse. METHODS: The literature on treatment strategies used in systemic lupus erythematosus (SLE) and PLN from 1975 to 2006, using PubMed from the National Library of Medicine, was reviewed. RESULTS: The high efficacy of the standard therapeutic regimen of PLN, traditionally associating cyclophosphamide (CYC) with corticosteroids (CS), has markedly ameliorated the prognosis of the disease, with more than 80% of patients achieving complete or partial remission. The ameliorated renal prognosis has positively influenced the general survival rates. Ten-year survival rates now surpass 75% and continue to improve. In view of the improved survival, the major aims of treatment now include preventing long-term organ damage and minimizing treatment toxicity, which can contribute significantly to the chronic morbidity and mortality of lupus. A number of high-quality trials have been reported, making us more confident of the value of different immunosuppressive protocols, and several novel immunosuppressive drugs are still under investigation. CONCLUSION: Recent basic and clinical research has enormously improved our understanding of the pathogenesis of SLE and has suggested new, targeted approaches to therapy. These targeted novel therapies are expected to help the patients with PLN in the next decade.

Sirolimus--challenging current perspectives.

Sirolimus is a potent immunosuppressant drug with a novel mechanism of action. It inhibits the mammalian target of rapamycin (mTOR) and blocks the cell cycle of various cell types, including T- and B-lymphocytes. Sirolimus is widely used as a maintenance immunosuppressive agent in organ transplantation. Also, a potentially benefit of this valuable drug in some immunologic and malignant diseases is currently under scrutiny.Classical side effects: hematological (anaemia, leucopenia, thrombocytopenia), hypercholesterolemia, arthralgias, extremity oedema and impaired wound healing have been frequently associated with the use of sirolimus. Additionally with its increased use, transplant professionals are encountering a variety of previously unreported and potentially more severe side effects.Here, we review the most recent data on sirolimus unexpected side effects (with an emphasis on pulmonary and renal toxicity), its use in renal transplantation and its new potential therapeutic indications (chronic glomerulopathies, polycystic kidney disease, different types of cancer). A brief description of the current knowledge of sirolimus therapeutic drug monitoring, methods of analysis, pharmacokinetics and drug interactions with calcineurin inhibitors is also included.

[Five years of kidney transplantation in Iasi]. / Cinci ani de transplant renal în centrul universitar Iasi.

The activity of Renal Transplant Center Iasi started in November 2000, when we realized the first renal transplant from a live donor. Since then, 46 renal transplants were successfully realized in our center, to patients aged between 13-47 years (medium age = 30 +/- 5), M/F=27/19, 25 (56.8%) of them selected from HD, 17 (39.9%) from CAPD and 4 (8.7%) pre-emptive. Medium age of donors was 49.1 years (30-64), M/F=29/17. The donors were, in 78.3% of cases, first-degree relatives (parents, siblings). In 10 cases (21.7%) the grafts were donated by "emotionally related"donors (in most cases, spouses). An urologist-cardiovascular surgeon team, performed the transplant operations. There were no important complications during operation. We had one major vascular complication (graft artery thrombosis) in a 13 years recipient, successfully resolved after thrombectomy and stenting. Immunosuppressive therapy associated induction with monoclonal antibodies anti-Tac, cyclosporine, MMF and prednisone. Eight patients from 46 (17.39%) presented acute rejection episodes and all responded at corticosteroids. Medium values of serum creatinine were: 1.54 mg% at 1 month, 1.42 mg% at 6 months, 1.44 mg% at 1 year, 1.21 mg% at 2 years, 1.38 mg% at 3 years, 1.4 mg% at 4 years and 1.2 at 5 years. The survival of patients and donors is 100% and the survival of renal graft--97.1% (one case of chronic allograft nephropathy with lost of renal function). We also present the satisfactory evolution of the 51 renal transplanted patients addressed to our center from different other renal transplantation centers in Romania for management follow-up.

Dynamics of the circadian blood pressure profiles after renal transplantation.

BACKGROUND: Abnormalities of diurnal blood pressure (BP) rhythm ("nondipping") are well-described in dialysis patients, and have prognostic importance. It is controversial whether successful renal transplantation (RTx) improves diurnal BP rhythm. To date, no study has attempted to define and model the evolution of diurnal BP rhythm profiles from dialysis to engraftment, focusing on the immediate (4-6 weeks) and medium-term (>1 year) postengraftment periods. METHODS: To test if kidney transplantation normalizes the BP profile, ambulatory blood pressure monitoring (ABPM) was performed in 20 living related transplants (age, 30.3+/-5.1 years; 11 males, on dialysis for 25.6 months) 1 month preRTx and repeated 1 month and >1 year (ABPM3) after successful RTx. Dipping was defined as a sleep-to-awake ratio>0.92 (for systolic BP) and >0.90 (for diastolic BP). RESULTS: PreRTx only 15% patients were dippers. At 1 month postRTx (creatinine clearance, 65.8 ml/min), all patients were complete nondippers. However, after >1 year postRTx (creatinine clearance, 70.4 ml/min), 40% were now dippers. Most importantly, overall, 30% of the patients improved significantly their circadian rhythm (35.3% of the initial preRTx nondippers). Despite successful renal transplantation, 55% patients maintained unchanged their nondipping profile throughout all three ABPM recordings. The only determinants of "long-term" postRTx circadian rhythm are the contemporary level of the renal function and the baseline, dialysis dipping profile: SBP3 sleep-to-awake ratio is related with serum creatinine3 (r=0.58, P=0.001), creatinine clearance (r=-0.41, P=0.036) and SBP1 sleep-to-awake ratio (r=0.48, P=0.034); similarly DBP3 sleep-to-awake ratio is related with serum creatinine3 (r=0.63, P=0.001), creatinine clearance (r=-0.471, P=0.036) and SBP1 sleep-to-awake ratio (r=0.53, P=0.016). In all, 57% of the variance in dipping status can be attributed and explained by the contribution of renal function and initial circadian variability. CONCLUSIONS: Half of the nondipper dialysis patients maintain a permanently abnormal circadian rhythm, despite successful RTx. In the short term, RTx is associated with a highly abnormal diurnal profile, exclusively related to ciclosporin dose and levels. However, in the longer term, renal transplantation leads to a significant improvement of the circadian blood pressure profile, influenced by the renal function level and by the pretransplantation dipping profile.

New immunosuppressive therapies in renal transplantation: monoclonal antibodies.

Remarkable advances in understanding the mechanisms of immune recognition and allograft rejection have been made in the past few years, leading to the development of innovative immunosuppressive strategies in the field of renal transplantation. Monoclonal antibodies (mAbs) have emerged as a new class of immunosuppressive agents, which appear to be effective (in both the treatment and the prevention of acute rejection) and well-tolerated in renal transplant recipients. The highly specific effects of these drugs make them less toxic than the oral long-term maintenance agents such as corticosteroids and the calcineurin inhibitors. Some of these mAbs have already confirmed their efficacy in preventing acute rejection in clinical phase III studies, and are now part of the well-established immunosuppressive regimens; these are the anti-CD25 mAbs (basiliximab and daclizumab). Other recently developed mAbs, like anti-CD52 (Campath-1H), anti-CD20 (rituximab), anti-LFA-1, anti-ICAM-1 and anti-tumour necrosis factor (TNF)-alpha (infliximab), are currently being tested, and show encouraging immunosuppressive potential. Blocking either the binding of cell-surface molecules or intracellular signal transduction, these mAbs could become an effective method to promote the holy grail of solid-organ transplantation, antigen-specific tolerance.

Systemic vasculitis: still a challenging disease.

The efficacy of current therapeutic regimens in patients with systemic vasculitis is high, at the expense of considerable treatment toxicity. Optimal therapy for patients with these potentially life-threatening diseases is still debated. Our increased understanding of the pathogenetic mechanisms of systemic vasculitis has led to the development of new therapeutic alternatives, with better potential specificity for both the inflammation and immunologic causes of vasculitis: new immunosuppressive drugs (mycophenolate), monoclonal antibody modulators of lymphocyte function (rituximab), and cytokine-directed therapies (infliximab and eternacept). The safety and efficacy of such agents increasingly are being investigated in patients with systemic vasculitis. Additionally, many randomized prospective clinical trials have been completed to determine the precise roles for more conventional treatments (cyclophosphamide, azathioprine, and plasma exchange), providing an expanding evidence base to guide therapy in these challenging diseases. There now is clear evidence that duration of cyclophosphamide therapy can be relatively short (3 months), long-term maintenance therapy is needed to avoid relapse (often azathioprine), and patients at relatively greater risk for relapse can be identified. We review the most recent data on the current management of systemic antineutrophil cytoplasmic antibody-associated vasculitis, with emphasis on strategies to improve long-term outcome and reduce treatment toxicity while minimizing the risk for relapse.

Acute effect of CyA A (Neoral) on large artery hemodynamics in renal transplant patients.

BACKGROUND: CyA A (CyA) may induce intrarenal vasoconstriction, endothelial dysfunction, and hypertension. There are only two contradictory reports describing the acute effect of CyA on renal resistances measured by color Doppler flowmetry. Therefore, we studied the acute influence of oral CyA on arterial haemodynamics by assessing simultaneous changes in blood pressure, applanation tonometry-derived pulse wave analysis and duplex ultrasound-derived intrarenal resistance indices. METHODS: Augmentation index (AIx) (difference between the first and second systolic peak on the aortic pressure waveform divided by the pulse pressure = AIx) was determined from contour analysis of arterial waveforms recorded by applanation tonometry using the AtCor device in 18 live-related renal transplants (11 females/7 males, age = 32.0 +/- 8.1 years, transplantation duration = 17.5 +/- 16.1 months, and mean serum creatinine = 133 +/- 70 micromol/L). All studies were performed just before (C0), and 2 hours after (C2) the oral administration of CyA. At the same C0 and C2 moments the resistive index (RI) = (peak systolic frequency shift - minimum diastolic frequency shift)/peak systolic frequency shift, and pulsatility index (PI) = (peak systolic frequency shift - minimum diastolic frequency shift)/mean frequency shift were calculated from Doppler recorded waveforms. RESULTS: Blood pressure and heart rate did not differ significantly at C0 and at C2 serum levels: 134.3/82.9 vs. 128.1/80.0 mm Hg and 72.0 vs. 71.0 beats/min, respectively, despite a marked increase in whole blood concentration (CyA(C0)= 90.8 +/- 45.9 vs. CyA(C2)= 547.4 +/- 251.3 ng/mL) (P= 0.05). Mean AIx fell significantly from 17.2 +/- 13.8 to 12.9 +/- 14.2 (P < 0.0001). There was no correlation between the extent (expressed as absolute or relative change) of the measured alteration in AIx and total administered CyA dose, or increment in blood level between C0 and C2. In support, the intake of CyA did not induce a significant increase in Doppler resistance (RI(C0)= 0.68 +/- 0.08 vs. RI(C2)= 0.70 +/- 0.09) and pulsatility indices (PI(C0)= 1.32 +/- 0.31 vs. PI(C2)= 1.33 +/- 0.28). Finally, three patients were studied twice (>1 week): one under two levels of creatinine, one with no antihypertensives, and a third receiving verapamil initially. All these maintained a significant decrease in AIx at C2 from C0 supporting the reproducibility of the phenomenon. CONCLUSION: We demonstrate that Neoral CyA acutely improves large arterial compliance function and does not induce an acute rise in intrarenal resistance in stable renal transplant subjects with normal renal function. We speculate that there may be an effect of vitamin E, the diluent vehicle in which CyA is carried (1000 IU/100 mg CyA), shown to improve endothelial function.

[Drug-induced dermatological pathology in renal transplantation patients]. / Patologia dermatologica iatrogena la pacientii cu transplant renal.

The broad spectrum of muco-cutaneous manifestations of renal transplantation patients correlates mainly with immunosuppressive therapy. Our study refers to 56 patients with renal transplantation (29 women and 27 men) followed up in the Dialysis and Renal Transplantation Center of Parhon University Hospital Iasi from November 2000 till October 2003. The most frequent muco-cutaneous manifestations were: infectious complications in 18 cases (32.1%), gum hyperplasia in 14 cases(25%), acne in 11 cases (19.6%), skin hyperpigmentation in 7 cases (12.5%), oral candidiasis in 6 cases (10.7%), vascular fragility in 5 cases (8.9%), hypertrichosis in 5 cases (8.9%), itching in 3 cases (5.3%), facial erythema in 3 cases (5.3%), full-moon facies in 3 cases (5.3%). These manifestations, often with unclear pathogenesis, are dose-related and almost unavoidable.

Oculo-renal disorders in infectious diseases.

BACKGROUND: The aim of this article is to review the potential ocular and renal disorders in infectious diseases to which humans are susceptible and to determine prevalence of these diseases. METHODS: Published cases of oculo-renal disorders associated with various infectious diseases were collected from the international literature by searching the MEDLINE database (PUBMED 1970-2004) for original reports and review articles published in English. Citations from papers retrieved were screened and retrieved papers were evaluated. RESULTS: Based on the screened data, we propose a practical, structure-oriented checklist of such lesions divided into bacterial, viral, parasital, and fugal infections. CONCLUSION: The oculorenal manifestations of infectious diseases may be flagrant or subtle. Awareness of the signs and symptoms of infections allows early recognition and prompt, appropriate management. The clinical presentation and relative frequency of those manifestations are reviewed.