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Background Prepubertal patients receiving chemotherapy are relatively resistant to cyclophosphamide-induced germinal cell alterations. We studied the possible protective effect of testosterone and triptorelin to inhibit gonadal activity in men and women receiving cyclophosphamide, respectively. Study Design Nonrandomized trial. Setting & Participants 28 consecutive patients, 11 men and 17 women, from a university medical center with various forms of glomerulonephritis, treated with cyclophosphamide. Intervention Men received cyclophosphamide plus testosterone; women were divided into 2 groups: 13 patients (group A) received cyclophosphamide plus triptorelin; 4 (group B) received only cyclophosphamide. Outcomes & Measurements Serum follicle-stimulating hormone (FSH) and serum luteinizing hormone levels and, in addition, sperm counts and testosterone levels in men and estradiol levels in women were measured before and after treatment with cyclophosphamide. Results All 10 men became azoospermic or severely oligospermic during treatment; after 12 months, all except 1 had a normal sperm count and FSH levels were normal. In women during cyclophosphamide therapy, amenorrhea occurred in all patients. After cessation of therapy, all women in group A started to menstruate regularly, and at the end of follow-up, ovulatory cycles were demonstrated in all women. Hormone levels showed no significant changes throughout the observation period. Six women conceived, and the pregnancies were brought to term successfully without complications. In group B, all 4 women developed sustained amenorrhea; serum FSH and luteinizing hormone levels at the end of therapy and follow-up were significantly higher with respect to baseline; estradiol levels at the end of follow-up were significantly lower compared with baseline and corresponding values in group A. Limitations The substudy in men is uncontrolled, the substudy in women is nonrandomized. Conclusions The study suggests a protective effect of testosterone and triptorelin against cyclophosphamide-induced gonadal damage in men and women with various forms of kidney disease, respectively.

Objective To assess the clinical and radiographic features of hand involvement in patients with systemic sclerosis (SSc). Methods Forty-one unselected Sardinian SSc patients (32 women, 9 men; mean age 58.9, range 31–81 years; mean disease duration 11.8 years, range 1–36 years) were evaluated in this observational cross-sectional study. Twenty-six patients had diffuse scleroderma (dSSc) and 15 limited scleroderma (lSSc). Radiological examination of the hands was performed and the films were read by two independent rheumatologists blinded to the diagnosis using a classification system of four predefined radiological patterns (normal/minimal changes, articular degenerative, articular inflammatory and periarticular pattern). Correlations between radiological pattern, clinical and serological features were assessed. Results The skeletal and articular involvement of the hand was frequent in SSc, being clinically evident in 30/41 (73%) and radiologically in 33/41 (80%) of patients. The periarticular pattern (defined as the occurrence of bone resorption of ungueal tufts, soft tissue calcifications and/or flexion deformities) was the most frequent pattern detected (14/41, 34.1%) and finger flexion contractures and bone resorptions were significantly associated with interstitial lung disease, reduced FVC, oesophagus involvement and prostacycline therapy. Calcinosis (29.2%) was found to be associated with erosions, suggesting a pathogenic link. An inflammatory pattern was also radiologically frequent (8/41, 19.5%), but erosions, with the exception of those localized at distal interphalangeal joints, were demonstrated mainly in patients with clinical picture of rheumatoid arthritis overlapped with SSc. We found no significant differences in terms of radiographic findings between lSSc and dSSc with the exception of calcinosis, which was more frequent in patients with lSSc. Conclusion This cross-sectional study confirms that the skeletal and articular involvement of the hand is frequent in SSc.

Resume Objectif Decrire les signes cliniques et radiologiques observes a la main dans la sclerodermie. Patients Nous avons realise une etude descriptive transversale chez 41 Sardes souffrant de sclerodermie (32 femmes et neuf hommes ; mediane de 58,9 ans avec des extremes de 31 et 81 ans), depuis 11,8 ans en moyenne (extremes, 1–36 ans). La maladie etait diffuse chez 26 malades et limitee chez 15 malades. Methodes Une radiographie des mains a ete realisee chez chaque malade. Les radiographies ont ete interpretees de facon independante par deux radiologues tenus dans l’ignorance du diagnostic. Les radiologues ont classe les radiographies en quatre categories : aspect normal ou subnormal, arthrose, arthrite inflammatoire et anomalies periarticulaires. Nous avons ensuite recherche des correlations entre les categories radiographiques et les signes cliniques et serologiques. Resultats Malgre l’absence de groupe temoin et le caractere transversal de l’etude, les resultats confirment la frequence des anomalies osteoarticulaires a la main dans la sclerodermie : des signes cliniques ont ete mis en evidence chez 30 (73 %) malades et des signes radiographiques chez 33 (80 %) malades. Les anomalies periarticulaires (resorption de la phalangette, calcifications des parties molles et/ou flessum) predominaient (14/41, 34,1 %). Le flessum des doigts et la resorption osseuse etaient correles a la presence d’une pneumopathie interstitielle, a une reduction de la capacite vitale forcee, a une atteinte œsophagienne et au traitement par la prostacycline. La calcinose (29,2 % des malades) etait liee a la presence d’erosions, suggerant un lien pathogenique. Un aspect radiologique inflammatoire s’est avere frequent (8/41, 19,5 %). Toutefois, les erosions, situees ailleurs qu’aux interphalangiennes distales, ont ete observees principalement chez les malades qui presentaient un tableau frontiere polyarthrite rhumatoide-sclerodermie. La calcinose etait plus frequente en cas de sclerodermie limitee, mais il n’y avait pas entre les deux groupes d’autres differences dans la prevalence des anomalies radiologiques.

The factors determining the course of glomerular filtration rate (GFR) and albumin excretion rate (AER) and the expression of mRNA of slit diaphragm (SD) and podocyte proteins in microalbuminuric, hypertensive type II diabetic patients are not fully understood. GFR, AER, and SD protein mRNA were studied in 86 microalbuminuric, hypertensive, type II diabetics at baseline and after 4-year random double-blind treatment either with 40 mg simvastatin (Group 1) or with 30 g cholestyramine (Group 2) per day. Both groups had at baseline a GFR decay per year in the previous 2-4 years of 3 ml/min/1.73 m(2). Both Groups 1 and 2 showed a significant decrease of low-density lipoprotein cholesterol levels after simvastatin and cholestyramine treatment (P

We studied the following in normo- and microalbuminuric hypertensive type 2 diabetic patients: 1) transcapillary escape rate of albumin (TERalb) and 2) expression of mRNA slit diaphragm and podocyte proteins in renal biopsies. Normoalbuminuric subjects had renal cancer, and kidney biopsy was performed during surgery. TERalb was evaluated by clearance of 125I-albumin. Real-time PCR of mRNA slit diaphragm was measured in kidney specimens. Albumin excretion rate (AER) was by definition lower in normoalbuminuric subjects than in microalbuminuric subjects with typical diabetic glomerulopathy (group 1), in microalbuminuric subjects with normal or near-normal glomerular structure (group 2), and in microalbuminuric subjects with atypical diabetic nephropathy (group 3). This classification was based on light microscopy analysis of renal tissue. TERalb (%/h) was similar in normoalbuminuric and microalbuminuric group 1, 2, and 3 diabetic patients (medians: 14.1 vs. 14.4 vs. 15.7 vs. 14.9, respectively) (ANOVA, NS). mRNA expression of slit diaphragm proteins CD2AP, FAT, Actn 4, NPHS1, and NPHS2 was higher in normoalbuminuric patients than in microalbuminuric patients (groups 1, 2, and 3) (ANOVA, P < 0.001). All diabetic patients had greater carotid artery intimal thickness than normal control subjects using ultrasound technique (ANOVA, P < 0.01). In conclusion, the present study suggests that microalbuminuria identifies a subgroup of hypertensive type 2 diabetic patients who have altered mRNA expression of slit diaphragm and podocyte proteins, even before glomerular structure shows abnormalities using light microscopy analysis. On the contrary, altered TERalb and increased carotid artery intimal thickness are shown by all hypertensive type 2 diabetic patients, both with normal and altered patterns of AER.

Objectives Several studies have investigated the cytokine profile of patients with systemic lupus erythematosus (SLE); however, their role is still controversial, mostly because SLE has a heterogeneous disease manifestation. We measured 4 of the most important cytokines in patients with SLE after dividing them in uniform groups according to disease activity and organ involvement. Materials and Methods Eighty-two adult female patients with SLE were divided into 3 groups according to disease activity and organ involvement: Group A (SLE activity index [SLEDAI] score, 7 ± 0.4) included subjects with newly diagnosed, active SLE, investigated before starting therapy. Group B (SLEDAI score, < 6) included patients without renal involvement, treated with prednisone and azathioprine or hydroxychloroquine. Group C (SLEDAI score, < 6) included patients with lupus nephritis, treated with methylprednisolone and cyclophosphamide, reaching complete remission. Fourteen healthy females served as controls. Results Interleukin-1 levels were 1.0, 0.8, 0.7, and 0.25 pg/mL in groups A, B, C, and D, respectively. Interleukin-6 levels were 3.2, 3.6, 4.0, and 1.4 pg/mL in groups A, B, C, and D, respectively; Il-10 levels, 3.05, 1.1, 1.5, and 1.65; tumor necrosis factor-α levels, 8.75, 5.8, 5.4, and 3.6. Interleukin 1, IL-6, and tumor necrosis factor-α were significantly higher in the patients with SLE than in the healthy controls; IL-1 was significantly higher in group A than in group C. Interleukin 10 showed positive correlation with C-reactive protein, whereas it showed negative correlation with C3. Conclusions Data from our cohort, one of the largest so far reported, add to the evidence that proinflammatory cytokines such as Interleukin-1, Interleukin-6, Interleukin-10 and tumor necrosis factor-α are important in SLE pathogenesis.

Background. Alport syndrome (AS) is a hereditary disease of the glomerular basement membrane in the kidney characterized by progressive renal failure, sensorineural deafness, anduor ocular abnormalities. In contrast to the well-known X-linked phenotype, very little is known about the autosomal dominant form. Rare autosomal forms of AS have been described with mutations in COL4A3 and COL4A4 at chromosome region 2q35-q37, but there have been no descriptions of dominant forms due to a mutation in COL4A4. Methods. We describe a Sardinian family with a classical AS-phenotype plus hypercholesterolaemia, a clinical feature also present in Fechtner syndrome (FS), a disease that segregates as an autosomal dominant trait. Results. A suggestive linkage (LODs2.7) between AS and the COL4A3uA4 locus at 2q35-q37 was identified. Other candidate collagen genes encoding basement membrane collagen (COL4A1uA2 and COL4A5uA6) were excluded by linkage analysis (13q33-q34 and Xq22), or by sequence (COL4A3). DNA sequence analysis of the COL4A4 gene revealed that the Lys325Asn mutation was present in all affected family members, but was absent in all unaffected members and in a random sample of the Sardinian population. A clear indication of a gene-dosage effect was seen in the most severely affected family member, since she carried the mutation in the homozygous form. Conclusions. These data confirm the importance of collagen 4A4 as a component in the structural integrity of the glomerular basement membrane and confirm the phenotypic and genetic heterogeneity of collagen disorders.

In a healthy human being, the extracellular volume is kept constant by homeostatic systems. One of these is represented by the antidiuretic hormone (ADH). ADH release is modulated by osmoreceptors and baroreceptors which respond to an increase in osmolality of extracellular fluid and a decrease in blood volume, respectively. In previous studies we investigated the existence of additional structures sensitive to plasma volume modifications. We found evidence of the presence of such receptors in the inner ear, with nervous connections to supraoptic and paraventricular nuclei. However, the possibility that the cerebral ventricle wall contained stretch sensors could not be excluded. To test our hypothesis, we studied 19 rats divided into three groups: Group 1 (n =7), Group 2 (n =7) and Group 3 (control group n =5). In each rat, under total anaesthesia, a femoral cannula was inserted into the left artery and a 22 gauge stainless steel cannula was implanted into the left cerebral ventricle. In the first group an isotonic fluid, similar to the animal's cerebrospinal fluid (CSF), was infused intracerebroventricularly (ICV) at a rate of 0.6 microl min-1 continuously for 6 h. In the second group, under the same conditions, CSF was aspirated; the third group was used as the control. In all animals, plasma modifications of ADH (pADH), osmolality (pOSM), Na+(pNa+) and K+(pK+) were evaluated before and after the experimental procedures. Mean arterial pressure (MAP) and heart rate (HR) were recorded throughout the experiment. At the end of the experiment no significant changes in pNa+, pK+, MAP and HR were observed. Plasma osmolality was significantly lower in Group 2 before and during the experimental procedure, since we deliberately expanded the volume in animals of Group 2 to partially suppress ADH, in order to evaluate its modifications. Plasma ADH fell in the first experimental group (-37.4%+/-6.3 sem) after the ventricular pressure had been increased, and rose in the second (+47.3%+/-14.7 sem) after ventricular decompression. These changes were statistically significant in comparison with those occurring in control subjects (-0.9+/-18.9 sem;P =0.07 and P =0.03, respectively). These results suggest the presence of additional volume receptors probably located in the cerebral ventricles, capable of controlling ADH. The importance of these receptors in physiological situations of plasma volume contraction or expansion remains to be established.

We report the results of a combined immunosuppressive schedule for the treatment of patients with idiopathic nephrotic syndrome, in which prednisone and cyclophosphamide were given in four phases: induction, maintenance, tapering and discontinuation.Sixty-seven patients with nephrotic syndrome, followed for an average of 7.1 +/- 4.5 years, were studied. Treatment outcomes were remission, progression, end-stage renal disease and death.At the end of the follow-up, 72% of patients maintained a complete remission. Stepwise logistic regression showed that the cumulative dose of cyclophosphamide was the only independent predictor of a favourable outcome, being associated both with complete remission of the nephrotic syndrome and with lack of progression to chronic renal failure.We suggest that the combination treatment may be indicated in all histological subgroups of nephrotic syndrome, provided that prednisone is given at high doses on alternate days, cyclophosphamide is given for 6 months, and relapses are treated with the same schedule. The adverse effects of treatment, however, require the adoption of a programme to prevent bone loss, infertility, bladder cancer and infections.

Data about clinical-laboratory features and outcome of antiphospholipid syndrome nephropathy (APSN) in the course of lupus nephritis (LN) are scarce. To determine prevalence, clinical correlations and outcome of APSN in patients with LN, retrospective analysis of renal specimens and review of medical records from 48 LN patients were performed. APSN was found in 12/48 (25 %) of LN. Positivity for lupus anticoagulant (LAC) and double antiphospholipids positivity [LAC plus anticardiolipin (aCL)] were significantly more frequent in APSN-LN (p = 0.02 and p = 0.01, respectively) than in LN, while single aCL positivity was not. Overt antiphospholipid syndrome appeared more frequent in patients with APSN-LN (p = 0.05). There were no statistically significant differences between APSN-LN and LN in the proportion of each World Health Organization class of LN (with the exception of a trend toward fewer Class III LN in APS-LN) and in the systemic lupus erythematosus (SLE) disease duration and severity. At the time of renal biopsy, patients with APSN-LN had median serum creatinine levels significantly higher than patients with LN [1.45 (0.6–6.6) vs. 1.00 (0.7–3.0), p = 0.02]. Double antiphospholipid positivity was the only variable significantly associated with APSN-LN at multivariate regression analysis (OR 8, 95 % CI 1.7–37, p = 0,008). APSN-LN and LN did not differ significantly as regards the rate of complete (25 vs. 19.4 %, p = 0.72) and partial treatment response (25 vs. 29 %, p = 0.82) at 6 months and the progression to end-stage renal disease after a median follow-up of 8.1 ± 3.6 years (16.6 vs. 13.8 %, p = 0.82). APSN was demonstrated in a quart of LN, appeared to be independent from underlying LN class and SLE severity, and did not seem to confer a worse prognosis to LN. The findings of higher creatinine and more interstitial fibrosis in APSN should be confirmed in future prospective larger studies.

The treatment of membranoproliferative glomerulonephritis (MPGN) is considered by most authors as unrewarding, and the disease progresses to end-stage renal disease (ESRD). We studied the effectiveness of a new immunosuppressive (IS) regimen by analyzing the rates of remission, relapse and progression to ESRD in 19 patients with MPGN. The treatment consisted of 4 phases: (1) induction with intravenous boluses of methylprednisolone plus cyclophosphamide (CPM) orally; (2) maintenance with oral prednisone (PDN) in an alternate-day regimen and CPM in a daily oral dose; (3) tapering during which PDN alone was slowly decreased; (4) discontinuation when CPM was omitted and PDN slowly withdrawn according to the steroid withdrawal schedule. At the end of the treatment that lasted on average 10 +/- 1 months, 15 patients remitted, 3 improved and 1 progressed. There were 8 relapses in 6 patients: 4 in 3 patients were treated with repeat cycles and remitted completely. Four patients who had relapsed after 4, 8, 11 and 13 years of remission refused retreatment and progressed rapidly to ESRD. All patients treated and retreated after relapsing had remissions, while renal failure and disease progression occurred in 1 patient only. Plasma creatinine averaged, in the whole group, 165 +/- 26 before, 156 +/- 30 after treatment and 224 +/- 57 microM/l at the end of 7.4 +/- 0.8 years of follow-up. An intensive IS regimen combining steroids and alkylating agents in high doses and for a prolonged time is effective in inducing remission and halting progression to ESRD in patients with MPGN.

Allograft rejection during the first year after renal transplantation can lead to persistent allograft dysfunction and reduced long-term graft survival. Thus, it is important to define early predictors of kidney damage, less invasive than allograft biopsy. Urinary glycosaminoglycan/proteoglycan concentration and distribution, N-acetyl-β-(d)-glucosaminidase (NAG), and monokine induced by IFN-γ (MIG) levels were evaluated in the immediate post-transplant and during a 1-year follow-up. We observed increased urinary levels of MIG, urinary trypsin inhibitor and its degradation products, the lack of urinary heparan sulfate excretion, and the decreased chondroitin sulfate relative content at day 1 post-transplant in most patients who developed complications in the postoperative period. Moreover, urinary MIG levels showed significant correlations with NAG, C-reactive protein, and GFR at day 1 post-transplant. The monitoring of glycosaminoglycan/proteoglycan urinary pattern and the levels of urine MIG could serve as useful markers for predicting possible complications of transplantation, unraveling an early inflammatory state, on whose basis the immunosuppressive therapy could be appropriately modified.

Background: Angiotensin II (AII) is the well-known determinant of kidney damage increasing intraglomerular pressure, matrix expansion and fibroblast proliferation. Renin-angiotensin system (RAS) inhibition, limiting the hemodynamic effects of AII, reduces proteinuria and is renoprotective in the long term. Methods: We studied 15 chronic proteinuric patients by Doppler ultrasonography to clarify the intrarenal hemodynamic changes during RAS blockade by Benazepril (10–20 mg/day) alone and combined with Valsartan (80–160 mg/day). We also investigated the correlation between hemodynamic indices, RAS components and antiproteinuric effect. Results: After 1 month of Benazepril proteinuria, resistive index (RI) and pulsatility index (PI) significantly decreased and proteinuria reduction was directly correlated to decrease in RI (r = 0.55, p = 0.03). Contrarily, after 1 month of combined therapy, RI and PI restored to baseline and progressively increased in the following 3 months, while proteinuria decreased. Increase in RI was directly correlated to concomitant increase in plasma renin activity (r = 0.65, p = 0.01) suggesting a direct role of renin in restoring intrarenal resistances. Conclusion: The hemodynamic changes caused by RAS inhibitors partially contribute to the antiproteinuric effect. Other RAS components, such as renin, may contribute to renal vasoconstriction and could be a further determinant of kidney damage besides a promising target for renoprotection.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by a hypercoagulable state related to persistently elevated levels of antiphospholipid antibodies (aPL). Current treatment for APS is only partially effective and new therapies are strongly needed. We report on a case of a 50 years old man with APS who suffered from recurrent thromboembolic episodes despite conventional anticoagulant treatment. Eight years after the first thrombotic manifestation he was diagnosed with a large B cell non-Hodgkin lymphoma. Treatment with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) plus rituximab was started with partial clinical remission of lymphoma and normalization of aPL levels with a three years follow-up period free of thrombotic episodes. A review of the literature revealed that only 12 case reports on the use of rituximab in patients with primary, secondary and catastrophic APS have been published. Current knowledge clearly suggests the need for clinical trials to evaluate the effect of rituximab in the treatment of resistant APS. Lupus (2008) 17, 50—55.

The phenotypic heterogeneity of Alport's syndrome (AS) is well explained by the genetic heterogeneity. Therefore, the application of genetic techniques, such as linkage analysis (LA), could be helpful in the correct diagnosis of this disease. We performed LA in a family who manifested X-linked inheritance. We used 10 fluorescent microsatellite markers to cover the q-arms of chromosome X. The poly chain reaction (PCR) products were separated on an ABI 377 Sequencer and genotypes were identified using the ABI Genescan/Genotyper software. We confirm in this family an X-linked dominant transmission of AS. All affected individuals shared the same haplotype for the region Xq22. The genetic diagnosis of AS was confirmed in individuals aged one month and 4 years before any clinical manifestation of AS. We conclude that LA is a powerful and approachable tool, which could be used in the diagnosis of AS. An accurate genetic family study using LA may be helpful for correct classification, genetic counseling, prognosis evaluation, the assessment of the risk for kidney transplantation, and for the follow-up and therapy of AS.

A 2-year follow-up study was carried out in patients with IgA nephropathy (IgAN) in order to verify the possible use of quali-quantitative analysis of urinary glycosaminoglycans (GAGs) as a prognostic index of disease and for drug treatment monitoring.Ten patients with IgAN were evaluated at four time points: baseline, and 6, 9 and 24 months later. GAGs were isolated from 24-h urine using ion-exchange chromatography on diethylaminoethyl-Sephacel, and concentrations were expressed as milligrams of hexuronate per gram of creatinine. GAG composition was determined by cellulose acetate electrophoresis and expressed as relative percentages by means of densitometric scanning of Alcian Blue-stained strips.The relative content of total low-sulphated chondroitin sulphate species decreased significantly during the study period compared to baseline, whereas the relative percentages of heparan sulphate and chondroitin sulphate increased significantly. Moreover, a significant correlation was noted between the relative contents of urinary GAGs, renal function and inflammation indexes.It is likely that the excretion of various types of GAGs may be related to different glomerular pathophysiological conditions. Therefore, the determination of urinary GAG composition may represent a reliable indicator of disease activity.

Type 2 diabetic patients often die because of end-stage renal failure, but no definitive reliable factor predicting long-term renal outcome has been identified. We tested whether a renal arterial resistance index (R/I) ≥80, using Doppler ultrasound technique, was predictive of worsening renal function. The primary end points of the study were 1) the course of glomerular filtration rate (GFR) and 2) the albumin excretion rate in 157 microalbuminuric, hypertensive, type 2 diabetic patients after a 7.8-year follow-up period (range 7.1–9.2). Kaplan-Meier curves for the primary end point (decrease of GFR ≥−3.0 ml/min per 1.73 m2 per year) was two to three times more frequently observed in patients with R/I ≥80. Four- to fivefold fewer patients showed a regression to normoalbuminuria during the follow-up period from baseline microalbuminuria in the cohort with R/I ≥80. Overt proteinuria did develop in 24% of patients with R/I ≥80 and in 5% of patients with R/I

Glycosaminoglycans (GAG) play an important role in regulating glomerular permeability, and a reduction in their plasmatic concentration or urinary loss has been implicated in the pathogenesis of diseases associated with increased albumin permeability. The purpose of this study was to evaluate GAG excretion in renal pathology by analyzing the composition of urinary GAG in antibody mediated glomerular injury, such as mesangial glomerulonephritis (IgAGN) and primitive membranous glomerulonephritis (MGN), to verify the effects of glomerular capillary wall lesion with and without mesangial cell injury.Urinary GAG excretion was analyzed in 20 patients with IgAGN, 18 patients with MGN, and in 18 healthy subjects (controls). GAG were isolated from 24-hr urine using ion-exchange chromatography on DEAE-Sephacel, and the results are expressed as mg hexuronate/g creatinine (Cr). GAG composition was determined by cellulose acetate electrophoresis and expressed as relative percentages by densitometric scanning of Alcian Blue stained strips.We found total GAG levels significantly higher in the urine of patients with MGN in comparison with controls and patients with IgAGN. The electrophoretic pattern analysis demonstrated low sulfated chondroitin sulfate proteoglycan (LSC-PG) in all patients compared to 44% in controls (8/18), but also low sulfated chondroitin sulfate (LSC) in 18.4% of patients (7/38) and slow migrating LSC (SM-LSC) in 8% of patients (3/38), only in the MGN group. Moreover, in patients with MGN, the LSC-PG relative content was significantly higher when compared to that observed in controls. Finally, in IgAGN and MGN patients, a significant reduction in chondroitin sulfate (CS) relative content was observed.It seems likely that an increase in total GAG levels takes place when a reduction in renal function occurs, but the alteration of CS and herapan sulfate (HS) relative contents, and the presence of LSC-PG and free LSC also in the urine of IgAGN patients, allows us to suggest that the GAG distribution pattern becomes abnormal before an increase in total urine GAG excretion. In addition, the quali-quantitative determination of urinary GAG and GAGprotein complex could constitute an additional non-invasive marker to appraise the metabolism of renal connective tissue in some renal diseases.

Inflammatory pseudotumor (IPT) and follicular dendritic reticulum cell tumor (FDRCT) are rare entities of the lymph node characterized by spindle-cell proliferation. We report a case of a 31-year-old woman, who was admitted for biopsy of a lymph node in the left submandibular area. The microscopic examination revealed a proliferation of spindle cells, partially replacing the normal lymph node architecture, suggestive of an IPT. The preserved peripheral portion showed follicular hyperplasia with Castleman-like appearance. Six years later she presented with a new enlargement in the same submandibular area. The nodule was removed, and a diagnosis of a classic FDRCT of the lymph node was made. The present case is remarkable, and clinicopathological data show that IPT-like proliferations could be in some case an early presentation of FDRCT. © 2005 Elsevier Inc. All rights reserved.

Transforming growth factor-beta1 (TGF-beta1) is a potent multifunctional polypeptide that is involved in normal renal function and in the development of glomerular sclerosis. It is also an important mediator of the immune and anti-inflammatory responses. The purpose of this study was to examine whether the measurement of urinary TGF-beta1 excretion in patients with different types of renal diseases and in newly diagnosed type 1 diabetes mellitus represents a non-invasive tool to evaluate disease activity and to monitor response to therapy. We studied the urinary excretion of TGF-beta1 in 57 nephropathic patients divided in different groups according to the underlying disease: 15 had mesangial glomerulonephritis (IgAGN), 9 membranous glomerulonephritis (MGN), 7 rapidly progressive glomerulonephritis (RPGN), 8 systemic lupus erythematosus (SLE), 9 interstitial nephritis (IN), 9 chronic renal failure (CRF). TGF-beta1 was also measured in 38 patients with type 1 (insulin-dependent) diabetes mellitus (12 with newly diagnosed diabetes, 26 long-standing diabetes) and 31 healthy controls. Total urinary TGF-beta1 concentration was assayed by enzyme-linked immunoassay (ELISA), and expressed as a ratio to urinary creatinine concentration. The urinary TGF-beta1 levels were compared with the findings of biopsy and clinical parameters. Urinary TGF-beta1 excretion was significantly increased in all groups except MGN, IN and CRF. In non-diabetic patients, urinary TGF-beta1 levels correlated with crescent formation, floccular adhesion and mesangial proliferation, but not with the degree of tubulo-interstitial fibrosis. Urinary TGF-beta1 levels did not correlate with indices of renal function (serum creatinine, glomerular filtration rate (GFR), albumin excretion rate [AER]). Among diabetic patients, HbA(1C) significantly correlated with TGF-beta1 urinary excretion. Urinary TGF-beta1 levels may represent a valid indicator of acute glomerular flogosis associated with mesangial proliferation in glomerulonephrities. In newly diagnosed diabetic patients, hyperglycaemia seems to represent the principal factor leading to TGF-beta1 overproduction. Follow-up studies of urinary TGF-beta1 levels measured during optimal glycaemic control are necessary to clarify the relationship between hyperglycaemia and TGF-beta1 excretion.

Prepubertal patients receiving chemotherapy are relatively resistant to cyclophosphamide-induced germinal cell alterations.To study the possible protective effect of testosterone used to inhibit germinal cell activity in men who are receiving cyclophosphamide.Randomized, clinical trial.University medical center.15 patients with the nephrotic syndrome who were treated with cyclophosphamide for 6 to 8 months.Five patients received daily oral cyclophosphamide, five received cyclophosphamide in monthly bolus injections, and five received monthly intravenous boluses of cyclophosphamide plus testosterone (100 mg intramuscularly every 15 days).Sperm counts, serum follicle-stimulating hormone levels, and serum luteinizing hormone levels were measured before, during, and after treatment with cyclophosphamide alone or cyclophosphamide plus testosterone.The 10 patients who did not receive testosterone became azoospermic during cyclophosphamide therapy. In only 1 of the 10 patients did the sperm count return to normal 6 months after discontinuation of therapy. Follicle-stimulating hormone levels were elevated in these patients (mean +/- SE, 19.20 +/- 1.28 IU/L in patients receiving oral cyclophosphamide and 16.04 +/- 2.22 IU/L in patients receiving intravenous cyclophosphamide alone). All 5 patients who received testosterone became azoospermic or severely oligospermic during treatment but had a normal sperm count 6 months after the discontinuation of therapy. In these patients, the mean sperm count was 45.78 +/- 3.89 x 10(6)/mL and follicle-stimulating hormone levels were normal (5.08 +/- 0.56 IU/L).Testosterone given to men before and during an 8-month cycle of cyclophosphamide therapy for the nephrotic syndrome may preserve fertility.

Objective To assess the results of a new immunosuppressive cycle, which had given favorable results in other immune-mediated glomerulonephritides, in the treatment of Henoch-Schonlein disease. Methods Eight patients (seven male and one female; age range, 13 to 61 years) with biopsy-proved Henoch-Schonlein were treated with the following protocol: (1) induction with 250 to 750 mg intravenous methylprednisolone every day for 3 to 7 days plus 100 to 200 mg oral cyclophosphamide every day, (2) maintenance with 100 to 200 mg oral prednisone on alternate days plus cyclophosphamide, as before, for 30 to 75 days; (3) tapering, with prednisone reduced on average by 25 mg every month while the cyclophosphamide dose remained the same, and (4) discontinuation, after at least 6 months, with abrupt interruption of cyclophosphamide and slow tapering of prednisone. The results were assessed in terms of remission, improvement, progression of disease, kidney failure, and death, unambiguously defined. The follow-up extended up to 12 years. Results Seven of eight patients had a complete remission that was maintained indefinitely thereafter. Plasma creatinine levels decreased on average from 211 ± 81 to 92 ± 27 μmol/L (p < 0.01) and urine protein excretion decreased from 1.9 ± 0.8 to 0.3 ± 0.1 gm/day (p < 0.01). One patient died of intestinal infarction caused by atherosclerotic mesenteric artery thrombosis. Conclusions Our data suggest that an intensive immunosuppressive regimen that combines prednisone and cyclophosphamide at high doses can be effective in healing Henoch-Schonlein disease. Clinical Pharmacology & Therapeutics (1996) 60, 576–581; doi

The aim of our study was to determine whether immunosuppressive treatment is effective in preventing and reversing the evolution of Berger's disease toward chronic renal failure.We studied 20 unselected, consecutive patients with biopsy-proven Berger's disease who met the criteria for disease progression. They had proteinuria, significant histologic changes, persistent hematuria, and red cell casts. The treatment consisted of prednisone in an alternate-day regimen and cyclophosphamide, either in a daily oral administration or in a monthly intravenous pulse injection, both given for a 6-month cycle. Five patients had chronic renal failure (as disclosed by plasma creatinine of 230 +/- 71 mumol/L), hypertension, and proteinuria (2.7 +/- 0.8 gm/day), whereas the remaining 15 patients had normal renal function (plasma creatinine, 97 +/- 18 mumol/L) and less severe proteinuria (1.9 +/- 1.1 gm/day). However, even these 15 patients had a significant number of risk factors heralding progression to chronic renal failure.Over an average follow-up of 8.7 +/- 3.7 years (range, 5 to 15 years), all patients but one had complete disease remission, including five patients with incipient chronic renal failure. Relapse occurred in two patients who were healed after a repeat treatment cycle. Over the entire follow-up period, no patient progressed to chronic renal failure and plasma creatinine concentration remained stable, even in subjects in whom it was high before treatment (257 +/- 79 versus 230 +/- 71 mumol/L; p0.05).The immunosuppressive treatment of patients with Berger's disease with high probability of progression appears to be effective in the prevention of end-stage renal disease.

Volume receptors are situated in many organs and are capable of modulating ADH secretion. We have evaluated the variation of plasma ADH concentration after an experimentally induced increase of cerebrospinal fluid (CSF) pressure (PCSF). The experiment was performed in controlled environmental conditions to avoid pain or stress-related ADH release. In 15 rats (10 experimental, 5 control) a cannula was positioned in the left cerebral ventricle: in the experimental group artificial CSF was infused at a rate of 0.6 (microliter/min for 6h: this manoeuvre, in a separate set of animals obtained an increase from 13.03 +/- 0.8 to 25.4 +/- 2.5 cmH2O of PCSF. The same conditions were reproduced in the control group without infusion into lateral ventricle. At the end of the experiment, plasma ADH had fallen significantly in the experimental group from 18.9 +/- 4.8 to 11.9 +/- 2.3 pg/ml (p0.05), while it was not changed in the control group (from 25.5 +/- 13.7 to 23.7 +/- 16.2 pg/ml). Heart rate, arterial pressure, plasma Na+ and osmolality, did not change significantly. Plasma K+ fell significantly in both groups: from 5.5 +/- 0.6 to 4.3 +/- 0.3 (p0.05) and from 5.4 +/- 0.7 to 4.3 +/- 0.15 mEq/l (p0.05) in the experimental and control group respectively. Plasma creatinine was normal, checked only at the end of the experiment. Our results demonstrate that a relationship exists between PCSF variations and plasma ADH concentration. We believe this relationship is due to the pressure receptors in the cerebral ventricles or in structures connected to it, such as the inner ear, and we hypothesize the existence of a control system of body fluids, more diffused than though to be, up till now.

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The treatment of Glomerulonephritides (GN) is controversial (1). Immunosuppressive (IS) treatment is very effective in controlling GN of systemic diseases, such as SLE (2), but it still yields conflicting results in membranous (M) GN (3,4), and is considered ineffective in Membranoprolipherative GN (MPGN). Therefore we started the present study with a flexible IS regimen combining high doses of Prednisone (PDN) and Cyclophosphamide (CPM) for a prolonged period of time.

The authors report a case of tubulointerstitial nephritis and uveitis (TINU syndrome) in a 48-year-old woman. The patient's ocular symptoms (relapsing bilateral uveitis) began 4 months before the renal disease was diagnosed and were treated successfully with local steroid therapy. The main baseline laboratory findings were anemia, a rapid sedimentation rate, and a decreased renal function. Urinalysis results showed mild proteinuria and some hyaline and hyaline-granular casts. Immunoglobulin (Ig) G and IgM antibodies to Epstein-Barr virus (EBV) were present. The renal biopsy showed interstitial lymphocytes and infiltration by rare plasma cells, tubular atrophy without granulomas, and slight expansion of the mesangium; electronic microscopy showed rare electron-dense deposits in the mesangium; no vascular alterations were seen, and immunofluorescent staining was uniformly negative. X-ray of the pelvis showed bilateral sacroileitis, which has been previously described in only 1 case of TINU syndrome; human leukocyte antigen B27 was negative. After 6 months without any therapy, all laboratory findings were normal; after 30 months, renal function was still normal, uveitis had not relapsed, but sacroiliac involvement was still present; EBV-viral capsid antigen (VCA) IgM were still high (28 UA/mL), and the EBV IgG titers were increased (VCA>170, EBV-nuclear antigen 108 UA/mL). This case confirms that this rare entity, originally observed in children, may occur and have a favorable spontaneous renal outcome also in the adult; EBV may play a role, as previously suggested. This is, to the authors' knowledge, the first reported case of TINU syndrome with the association of a well-documented bilateral sacroileitis.

In a previous study, we described a new method [3] to measure Na reabsorption by each segment of the human nephron independently. Reabsorption was expressed as equivalent volumes of solute-free water (CH2O) generated by the loop of Henle (CH2O-HL) and by the distal tubule (CH2O-DT), and dissipated by back diffusion (BD) across collecting ducts (CH2O-BD). These data were obtained during maximal water diuresis (MWD). The present study was undertaken to calculate CH2O-HL by experiments performed during maximal antidiuresis (MA). For this purpose, a new theoretical approach was devised, described by algebraic equations which allowed calculations of segmental transport during MA alone, where only CH2O-HL could be calculated independently. The study was performed on 14 normal volunteers who were studied twice by clearance measurements, firstly during MWD and again during MA. In each experiment, clearance periods were performed during baseline conditions and during the administration of furosemide (0.7 mg/kg bolus injection followed by 0.06 mg/kg/min maintenance infusion). From the values measured during either condition, segmental reabsorption was calculated. During MWD, CH2O-HL averaged 19.4 + 10.4, during MA 20.4 + 8.0 ml/min/GFR X 100; p greater than 0.05. The paired measurements were significantly correlated (r = 0.80; p less than 0.01). These data demonstrate that CH2O-HL obtained with the original theory is a reproducible result that can be confirmed with independent measurements obtained during different experimental conditions. Thus, measurements of segmental Na transport in the human nephron are feasible and can contribute important informations on disease states.

Experiments were performed on humans to study the blunting on the diuretic action of furosemide by prostaglandin synthetase inhibitors. Maximal water diuresis was instituted. At the peak of urine flow, clearance periods were performed during baseline conditions and repeated after the injection of aspirin and, subsequently, of furosemide. Control subjects did not receive aspirin. Urine flow rate (V), Cosm, and Na excretion (UNa) . V were significantly lower when the administration of the diuretic had been preceded by that of aspirin. In the absence of furosemide, however, aspirin did not influence renal hemodynamics nor Na and water reabsorption. Therefore, the same experimental protocol was repeated in paired experiments where each normal subject served as his own control, being studied twice, in the presence and absence of aspirin, respectively. The average changes in water and Na excretion induced by furosemide were not different when the patients were pretreated with aspirin as compared with those measured in the absence of prostaglandin inhibition. Changes occurring in individual experiments were significantly correlated (r = 0.95, P less than 0.01) with those in calculated furosemide clearance. Since aspirin, indomethacin, and meclophenamate are secreted by the organic acid transport system of the proximal tubule, competition for a common secretory mechanism, rather than prostaglandin inhibition, could mediate the blunting of furosemide diuresis.

The authors investigated the effect of a single 75-mg oral dose of pirenzepine, a drug which selectively blocks the muscarinic receptors and does not cross the blood-brain barrier, on the function of the HPA axis. A significant decrease in basal cortisol values following the administration of the drug was observed in comparison with a placebo test. Moreover, the adrenal response to exogenous adrenocorticotropin (ACTH) administration was unchanged following a 5-day course of the drug, ruling out direct action of pirenzepine at the adrenal level. These data suggest that cholinergic muscarinic hypothalamic and/or pituitary systems may be involved in the regulation of ACTH-cortisol secretion.

1 The relative importance of the effect of prostaglandins on renal sodium and water reabsorption was assessed in rats. 2 Clearance experiments were performed on 24 anaesthetized rats divided into 3 groups. Each group was infused throughout either with Ringer solution at 9 ml/h (Protocol I), or at 3 ml/h (Protocol II) or with hypotonic fluid at 5 ml/h (Protocol III). Clearance periods were performed before and after intravenous injection of indomethacin (5 mg/kg) and then of aspirin (20 mg/kg). The natriuretic response to different degrees of volume expansion was not modified during the action of the inhibitors. 3 When baseline urine osmolality (Uosm) was high (Protocol II) no further increase occurred in the presence of prostaglandin inhibition. Conversely, Uosm rose from 771 +/- 134 to 1356 +/- 414 and from 575 +/- 245 to 841 +/- 407 mosm/kg (P less than 0.05) in Protocol I and Protocol III respectively, when antidiuretic hormone secretion was inhibited by the higher degree of volume expansion. 4 There was a significant correlation between the change in urine flow rate induced by cyclooxygenase inhibitors and the attendant variations in Na excretion, r = 0.42, n = 41, P less than 0.01. 5 Thus, prostaglandins affect Na loss during saline load as a side effect of their action on water permeability. They could play an important role in volume depletion by counterbalancing the large secretion rate of renal vasoconstrictors.

The segment of the nephron where carbohydrate deprivation depresses Na transport leading to natriuresis was sought by a new clearance technique designed to measure segmental reabsorption in each portion of the human renal tubule. Experiments were performed during maximal water diuresis before and 4 days after carbohydrate withdrawal. Proximal reabsorption had fallen from 70 ± 4 to 60 + 5 ml ■ min-1 p < 0.05, by the 4th day of sugar deprivation, accounting for the natriuresis and the associated weight loss of 1.8 kg. By the 4th day of fasting, when Na excretion had returned to control levels, GFR had fallen nonsignificantly from 99 ± 6 to 95 ± 5 ml · min-1, while Na reabsorption along distal segments had risen. In fact, Na transport, expressed by the equivalent volumes of solute free-water generated, rose from 17.4 ± 3.4 to 23.6 ± 2.1 along the ascending limb of Henle’s loop, and from 8.1 ± 0.8 to 9.2 ± 1.3 ml · min-1 · GFR-1 · 100 along the distal tubule. Thus, analysis of segmental Na transport by this method discloses that starvation natriuresis is a proximal tubular event, progressively counterbalanced by enhanced Na reclamation in more distal sites. Volume contraction and the attendant fall in GFR concur to curb delivery out of the proximal tubule which is matched by enhanced distal Na reabsorption till a new steady-state excretion is attained.

We have developed (1) and extensively applied (1,4) a new method to measure transport by each segment of the human nephron. We assumed that F, by abolishing NaCl transport of HL, wipes out the osmotic gradient between collecting duct (CD) urine and interstitium, and the abstraction of solute free water (SFW) that occurs in the absence of ADH: therefore, the urine flow during maximal water diuresis (MWD) plus F (Vf) represents a true measurement of delivery from proximal tubule (PT). In addition, the urine will be diluted by the distal tubule (DT) during F: therefore, the SFW excreted during F, CH20f, is that formed by the DT, CH20-DT. Thus, CH20f = CH20-DT (I). The difference between V during F (Vf) and that during MWD alone (V) measures the volume of SFW reabsorbed in the absence of ADH, indicated as CH20-BD. This being the part of SFW which is not excreted, the true SFW generated is that excreted (CH20) plus that reabsorbed (CH20-BD): hence, CH20-T = CH20-BD + CH20 (II), where CH20-T is the total SFW formed. The SFW generated by HL alone can be calculated as CH20-HL = CH20-T - CH20-DT (III). For these concepts to gain a wide acceptance, it is necessary to confirm the measurements by an independent method. We devised the present experiments to compare by an independent method the results obtained by previously published technique based on MWD.

Forty-three patients suffering from hypertension of different origin (chronic renal failure, gout, or idiopathic) were treated with propranolol (121 +/- 12 mg q.d.) plus hydrochlorothiazide (50 mg q.d.) for 75 +/- 9 days. Blood pressure did not return to normal limits in 15 patients, who were continued on the same protocol plus 10 to 50 mg oxdralazine q.d. After an average of 68 +/- 35 days blood pressure fell from 180/110 mm Hg to 145/90 mm Hg without orthostatism, significant side effects, or changes in GFR. This combination seems particularly successful since propranolol will prevent the undesired rise in cardiac output due to oxdralazine as well as the activation of the renin-angiotensin axis due to diuretics. Thus, the antihypertensive properties of each agent will be enhanced by a reduction in side effects by the associated drug, resulting in optimal blood pressure control.

Berger’s disease is an IgA nephropathy characterized by irregular hematuria and variable proteinuria (1). Generally considered as benign, it may neverthless progress towards chronic renal failure (2). Though its pathogenesis is unknown, IgA serum levels are important. This immunoglobulin acts on the mucosal surface protecting towards the antigens. The mechanism leading to deposition of IgA containing immune complexes at renal level and activation of C3 and properdine factors is not known (3). Recently, several authors investigated some aspects of the immune regulation of these patients and discovered a reduced activity of T-suppressor cells, a high activity of the T-helper IgA specific cells, and consequently an altered 0KT4/0KT8 ratio (4,5).These results are controversial because of the different variables involved in immune regulation. To evaluate this aspect, we studied the lymphocyte subsets in patients with IgA nephropathy before, during and after immunosuppressive treatment.

Several factors including hypoxia,lysomal enzymes release, endotoxins and kinins have been involved in the pathogenesis of ARF1. Among these, hypoxia represents the initiating event of a series of biochemical reactions which culminate in the production of oxidative radicals. The most important are the superoxide ions (O2 −) and the free radicals which result from their interactions with other molecules. These substances can injure cells by peroxidating the lipid membranes. The organism however has efficient enzymatic and non enzymatic systems which can oppose and control the production of free radicals and superoxide anion. These systems are represented by superoxide dismutase, catalase and glutathione peroxidase which can detoxicate the SR, the hydrogenperoxide and the lipid peroxides3,4 Among the other physiological scavangers glutathion vitamin E and C, cysteine and probably uric acid have great importance5. The biological sequence occurring during ischemia is schematically represented in Fig.1. During hypoxia there is a rapid consumption of ATP with a rise in intracellular AMP concentration, subsequently metabolized to adenosine, inosine and finally hypoxanthine,which accumulates in the ischemic tissue and represents the substrate of xanthine(X) dehydrogenase and X- oxidase Certain authors postulate that the fundamental biochemical phase during hypoxia, is represented by X-dehydrogenase activity, while in the reoxygenation phase the activity of Xoxidase prevails, producing hydrogen peroxide and SR, responsible for the maintenance of the ischemic damage.

The importance of prostaglandins (PG) in Na and water retention of liver cirrhosis was studied in rats with porta-cava shunt (PCS) compared to control, non-shunted animals. Balance studies were performed in metabolic cages with diets of high, normal and low Na. An experimental phase, during which the animals received either 5 mg X kg-1 of indomethacin daily or placebo, was preceded by a control period and followed by a post-indomethacin period identical to the control phase. In each diet, indomethacin, but non placebo, caused a positive Na balance, correlated with Na intake, which in overall pooled data amounted to -1453 +/- 255 muEq in PCS rats, significantly larger than that measured in controls, of -295 +/- 320 muEq (P less than 0.01). This was attended by a reverse change in K balance of -35.6 +/- 349 muEq versus -1566 +/- 582 muEq (P less than 0.01); glomerular filtration rate (GRF) was unchanged. These data demonstrate that PGs contribute to the control of Na homeostasis in the presence of PCS.

A 59-year-old woman was admitted to the hospital for evaluation of her hypertension. She was treated with hydralazine; two days later a severe acute hepatitis supervened. On discontinuation of the agent, the liver damage disappeared, relapsed during inadvertent rechallenge, and healed following permanent withdrawal from the drug. Histologic study of the liver showed severe acute hepatitis with bridging necrosis (so-called subacute hepatitis). Six months after discontinuation of hydralazine, a second liver biopsy specimen showed a complete remission of the disease. This hydralazine-induced hepatitis appears to be fully reversible and to differ both on clinical and histological grounds from two previous reports documenting a granulomatous liver disease. (Arch Intern Med139:698-699, 1979)

Although different pathogenetic factors are involved in the genesis of ARF (1), the morphological and functional modifications that occur are very similar and usually confined to the proximal tubule. There are modifications in active transport mechanisms, in permeability and a clear reduction of the mithocondrial cellular energy (2,3). The acute tubular damage, confirmed by the decreased activity of the correspondent enzyme markers, can be considered the common denominator of all the experimental models of ischemic ARF. Brush border and necrotic cells form casts that occlude the proximal and then the distal convoluted tubule (4). In these cases it was demonstrated that a large infusion of saline solution can prevent the oliguria, as does pretreatment with mannitol, vascular dilators and furosemide (5,6,7). The latters reduce the vascular resistances and increase the urinary excretion of solutes. Furosemide, on the other hand, inhibits the reabsorption of NaCl in the cells of Henle’s loop, causing a drop in intracellular Na with inactivation of the Na-K-ATPase enzyme. Cells that are not using the residual ATP are therefore less exposed to the effects of the transitory ischemia. Finally a pretreatment with substances which inhibit xantine-oxidase was proposed. These substances block the production of superoxide radicals (7), decrease the vascular permeability, facilitating a quick functional recovery of the ischemic organ.

DiabetologiaDOI 10.1007/s00125-008-1079-8This article has been withdrawn due to copyright infringement viaplagiarism.R. Nosadini (*)Department of Endocrinology and Metabolic Diseases,Internal Medicine Department, University of Sassari,Viale San Pietro 8,07100 Sassari, Italye-mail: noscia@tin.itA. Carboni

There is strong evidence that the determination of autoantibodies against filaggrine is a very useful tool for the diagnosis of rheumatoid arthritis (RA). Anti-cyclic citrullinated peptide antibodies (Anti-CCP)-ELISA appear to be the most efficient test among those available for the detection of antifilaggrine autoantibodies, as it has the best diagnostic accuracy for the diagnosis of RA. Furthermore, the anti-CCP-ELISA determination in early arthritis is a good predictor of disease persistence and radiographic joint damage. The positivity of Anti-CCP some years before the onset of the RA and the high concentration of autoantibodies in synovial fluid suggest a possible pathogenetic role of citrullination. However, at present, it is unclear whether anti-CCP antibodies have a better diagnostic performance than rheumatoid factor in recent onset synovitis and if they confer any additional value to the prognostic evaluation obtained with validated predictors of outcome (FR, joint count, duration of disease).