Renal Histology in CKD Stages: Match or Mismatch with Glomerular Filtration Rate?

A reliable assessment of renal function is of paramount importance in several clinical assets in order to tailor a personalized medical approach. CKD classification system, created in 2002 by the National Kidney Foundation-sponsored Kidney Disease Outcomes Quality Initiative and then implemented in the following years by the K-DIGO guidelines, offered clinicians a new strategy to better identify nephrological patients at low or high risk to develop renal insufficiency, in order to avoid the progression to end-stage renal disease. However, the criteria used to create this classification did not consider some important aspects related to renal histology and glomerular filtration rate measurement, resulting in a possible over- or underestimation of the real established renal damage. In this mini-review, we will summarize the most relevant shortcomings in the CKD classifications, which can create misleading diagnosis in daily clinical practice.

Radiomic and gEnomic approaches for the enhanced DIagnosis of clear cell REnal Cancer (REDIRECt): a translational pilot methodological study.

Background: The combination of radiomic and transcriptomic approaches for patients diagnosed with small clear-cell renal cell carcinoma (ccRCC) might improve decision making. In this pilot and methodological study, we investigate whether imaging features obtained from computed tomography (CT) may correlate with gene expression patterns in ccRCC patients. Methods: Samples from 6 patients who underwent partial nephrectomy for unilateral non-metastatic ccRCC were included in this pilot cohort. Transcriptomic analysis was conducted through RNA-sequencing on tumor samples, while radiologic features were obtained from pre-operative 4-phase contrast-enhanced CT. To evaluate the heterogeneity of the transcriptome, after a 1,000 re-sampling via bootstrapping, a first Principal Component Analyses (PCA) were fitted with all transcripts and a second ones with transcripts deriving from a list of 369 genes known to be associated with ccRCC from The Cancer Genome Atlas (TCGA). Significant pathways in each Principal Components for the 50 genes with the highest loadings absolute values were assessed with pathways enrichment analysis. In addition, Pearson's correlation coefficients among radiomic features themselves and between radiomic features and transcripts expression values were computed. Results: The transcriptomes of the analysed samples showed a high grade of heterogeneity. However, we found four radiogenomic patterns, in which the correlation between radiomic features and transcripts were statistically significant. Conclusions: We showed that radiogenomic approach is feasible, however its clinical meaning should be further investigated.

Renal dysfunction and podocyturia in pre-eclampsia may be explained by increased urinary VEGF.

BACKGROUND: Pre-eclampsia has a major impact on renal function as shown by the development of proteinuria and podocyturia. How the systemic, soluble Fms-like tyrosine kinase-1 (sFlt-1)-driven inhibition of vascular endothelial growth factor (VEGF) activity detected in pre-eclampsia directly affects renal function remains unknown. The aim of the study was to clarify whether a non-canonical, renal-centred escape from VEGF inhibition in the case of pre-eclamptic pregnancy might have a direct impact on renal function. METHODS: We evaluated plasma and urinary VEGF and placental growth factor (PlGF), plasma sFlt-1 and carbonic anhydrase IX (CAIX), albuminuria and podocyturia in 18 women with uncomplicated pregnancy, 21 with pre-eclampsia and 18 non-pregnant. The three groups were matched for age and the pregnant groups also for gestational age at enrolment. RESULTS: Plasma VEGF was reduced in uncomplicated (P = 0.001) and pre-eclamptic (P = 0.0003) pregnancies when compared with controls. In uncomplicated pregnancy, the dysfunction was balanced by an increase (P = 0.009) of plasma PlGF. Increased (P = 0.0001) plasma CAIX in pre-eclampsia was in line with hypoxia. Pre-eclampsia resulted in a paradoxical increase (P = 0.0004) of urinary excretion of VEGF. Urinary concentrations of VEGF and podocytes were correlated to each other (r2 = 0.48, P < 0.0005) but also to plasma sFlt-1 (r2 = 0.56, P < 0.0001 and r2 = 0.23, P = 0.03, respectively). CONCLUSIONS: In the case of pre-eclampsia, the systemic VEGF inhibition leads the kidney, possibly the podocyte, to increase the VEGF synthesis. The mechanisms leading to local VEGF overproduction or the overproduced VEGF itself are reasonably involved in the pathogenesis of podocyturia and, as a consequence, renal dysfunction in pre-eclampsia.

Unexpected Outcomes of Renal Function after Radical Nephrectomy: Histology Relevance along with Clinical Aspects.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are common events after radical nephrectomy (RN). In this study we aimed to predict AKI and CKD after RN relying on specific histological aspects. We collected data from a cohort of 144 patients who underwent radical nephrectomy. A histopathological review of the healthy part of the removed kidney was performed using an established chronicity score (CS). Logistic regression analyses were performed to predict AKI after RN, while linear regression analysis was adopted for estimated glomerular filtration rate (eGFR) variation at 1 year. The outcomes of the study were to determine variables correlated with AKI onset, and with eGFR decay at 1 year. The proportion of AKI was 64%. Logistic analyses showed that baseline eGFR independently predicted AKI (odds ratio 1.04, 95%CI 1.02:1.06). Moreover, AKI (Beta -16, 95%CI -21:-11), baseline eGFR (Beta -0.42, 95%CI -0.52:-0.33), and the presence of arterial narrowing (Beta 10, 95%CI 4:15) were independently associated with eGFR decline. Our findings showed that AKI onset and eGFR decline were more likely to occur with higher baseline eGFR and lower CS, highlighting that RN in normal renal function patients represents a more traumatic event than its CKD counterpart.

Renal histology across the stages of chronic kidney disease.

BACKGROUND: The chronic kidney disease (CKD) classification represents a simple tool to evaluate kidney disease. However, it is not based on kidney histology and this might limit the correlation between renal function and histological damage. The aim of this study was to examine the presence and magnitude of the discordance between CKD classification and kidney histology. MATERIALS AND METHODS: We retrospectively analyzed kidney parenchyma histology in a cohort of 200 patients who underwent radical nephrectomy for a kidney mass to observe its correlation with CKD classification. Kidney tissue of the unaffected part of the removed kidney was analyzed and classified with a chronicity score as described by Sethi et al. Then, all patients were classified according to the respective CKD stage using different equations: CKD-EPI, MDRD, FAS and MCQ. RESULTS: Median age was 67 (57-75). Diabetes, hypertension and overweight were observed in 23%, 60% and 61%, respectively. The CKD-EPI equation stratified 30.5% (n = 61) of the subjects into CKD stage 1, 41.5% (n = 83) into CKD stage 2, 25.5% into CKD stage 3 (n = 51) and 2.5% into CKD stage 4-5 (n = 5). About 30-40% of the patients with CKD stage 3 had mild or no lesions in the histological evaluation (Chronicity Score = 0-1), whereas 7-10% of those with CKD stage 1 had moderate or severe histological lesions (Chronicity Score ≥ 3). Different patients with the same value of estimated glomerular filtration rate (eGFR) had either severe or no histological damage. CONCLUSIONS: The variability of kidney histology observed within each CKD stage is not negligible. This may limit the reliability of the current CKD classification. More research is needed to clarify the relationship between CKD stages and kidney damage.

Parenchymal biopsy in the management of patients with renal cancer.

PURPOSE: The role of non-tumour renal biopsy in predicting renal function after surgery for renal cell carcinoma (RCC) is poorly investigated. The aim of the study was to assess the impact of renal parenchymal histology on renal function after radical nephrectomy in a cohort of patients with RCC. METHODS: This cohort study included 171 patients with RCC submitted to radical nephrectomy between 2006 and 2018. Two biopsy samples from normal parenchyma were collected at nephrectomy and renal parenchyma damage (RPD) was scored on histologic samples according to validated methodology. The outcomes were eGFR after surgery and its reduction > 25% relative to baseline at maximum 12 months' follow-up. Linear and logistic multivariable regression were used, adjusting for age at surgery, presence of hypertension, diabetes, clinical tumour size, time from surgery and basal eGFR. RESULTS: 171 patients were enrolled and RPD was demonstrated in 64 (37%). Patients with RPD had more comorbidities (CCI > 2 in 25 vs. 9%, p < 0.001), in particular hypertension (70 vs. 53%; p = 0.03), diabetes with (5% vs. 0%, p = 0.007) or without (31 vs. 18%; p = 0.007) organ damage, cerebrovascular disease (19 vs. 5%; p = 0.006) and nephropathy (20 vs. 3%; p = 0.0004). At multivariable analyses, RPD was associated with lower eGFR (Est. - 5.48; 95% CI - 9.27: - 1.7; p = 0.005) and with clinically significant reduction of eGFR after surgery (OR 3.06; 95% CI 1.17: 8.49; p = 0.026). CONCLUSIONS: Presence of RPD in non-tumour renal tissue is an independent predictor of functional impairment in patients with RCC. Such preliminary finding supports the use of parenchyma biopsy during clinical decision making.

Screening for cervical cancer in Africa: A proposal of a different combination of VIA test and cervical smear in Uganda.

OBJECTIVE: To evaluate the efficacy of visual inspection with acetic acid (VIA) screening combined with a cervical smear in Uganda. METHODS: Nine screening campaigns were held in Uganda between January 2011 and October 2019. In the last three campaigns, a new approach was used: the cervical smear was performed before the VIA test and, in case of a positive VIA test, the slide was sent for examination. The data collected were divided into two groups: the first six campaigns and the last three campaigns. RESULTS: During the study period, 10 520 women were screened, of whom 911 had a positive VIA test. The VIA test showed 84.2% false positives. In the first group, the VIA test was positive in 516 women, of whom 93% were referred for further examinations. In the second group, the VIA test was positive in 395 women, but the cervical smear was positive in only 65 women. Thus, only 16.5% women were referred for further examinations. CONCLUSION: Combining cervical smear, VIA test, and slide analysis in positive VIA tests may allow women who need treatment to be selected more effectively, while waiting for other more expensive solutions to become more affordable for this setting.

Lanosterol Synthase Genetic Variants, Endogenous Ouabain, and Both Acute and Chronic Kidney Injury.

RATIONALE & OBJECTIVE: Studies of humans and animals have suggested that endogenous ouabain (EO) and related genes are mediators of acute (AKI) and chronic kidney injury. We sought to examine the relationship among EO levels, genetic variants in lanosterol synthase (LSS; an enzyme that catalyzes synthesis of cholesterol, a precursor of EO), and both AKI and chronic kidney injury. STUDY DESIGN: 2 prospective observational cohort studies and a cross-sectional study of kidney tissue. SETTING & PARTICIPANTS: (1) A prospective cohort study of patients undergoing cardiovascular surgery, (2) measurement of EO concentration in kidney tissue removed because of an adjacent tumor, and (3) a prospective cohort study of patients with newly diagnosed essential hypertension. EXPOSURE: Missense variant in LSS (A instead of C allele at rs2254524), which leads to a valine to leucine substitution at amino acid 642. OUTCOMES: Development of postoperative AKI in the cardiovascular surgery cohort, EO concentration in kidney tissue, and estimated glomerular filtration rate (eGFR) reductions in the essential hypertension cohort. ANALYTICAL APPROACH: Logistic regression for analysis of postoperative AKI, analysis of variance for EO concentration in kidney tissue, and generalized linear models for changes in eGFR over time. RESULTS: AKI incidence following cardiovascular surgery was greater among those with the LSS rs2254524 AA genotype (30.7%) than in those with the CC genotype (17.4%; P=0.001). LSS rs2254524 AA kidneys had higher EO concentrations than CC kidneys (2.14±0.29 vs 1.25±0.08ng/g; P<0.001). In the longitudinal study of patients with essential hypertension (median follow-up, 4 years; range, 1-15 years), eGFR decline was greater among the LSS rs2254524 AA genotype group (-4.39±1.18mL/min/1.73m2 per year) than in the AC or CC genotype groups (-1.07±0.55 and -2.00±0.45mL/min/1.73m2 per year respectively; P = 0.03). LIMITATIONS: These associations do not necessarily represent causal relationships; LSS rs2254524 variants may have effects on other steroid hormones. CONCLUSIONS: These findings support the potential value of LSS rs2254524 genotype-based risk stratification to identify patients at high risk for AKI before cardiovascular surgery, as well as predict accelerated eGFR in the setting of hypertension. These findings also suggest that LSS may in part drive EO-mediated kidney damage. EO may represent a new potential therapeutic target for the prevention of AKI and slowing of kidney damage in the setting of hypertension.

IL28B rs12979860 genotype as a predictor marker of progression to BKVirus Associated nephropathy, after kidney transplantation.

BK virus (BKV) associated nephropathy (BKVAN) is still an important cause of allograft dysfunction after kidney transplantation (KT). Recent data have shown that the new interferon (IFN)-λ family has been ascribed antiviral properties similar to IFNα, and that the response to IFNλ in kidney is restricted to epithelial cells, suggesting that the IFNλ system evolves as specific protection of the epithelia. We aimed to test the hypothesis of correlation between a single nucleotide polymorphism (C/T dimorphism rs12979860) in the genomic region of IL28B and BKVAN, in patients after KT. Fifty kidney-transplanted patients were included as follow: Group 1 (BKV+/BKVAN+): 11 patients with active BKV- replication and biopsy-proven BKVAN; Group 2 (BKV+/BKVAN-): 22 patients with active BKV- replication but without evidence of BKVAN; Group 3 (BKV-/BKVAN-): 17 patients without evidence of BKV- replication (control group). Here we show that the C/C genotype was statistically higher in group 2 than in group 1 and BKVAN was detected significantly more frequently in patients with C/T and T/T genotypes than in patients with C/C genotype. We therefore propose IL28B polymorphism (rs12979860), as a predictor-marker to differentiate between patients with self-limited, even if persistent, BKV- reactivation and patients with a high risk of progression towards BKVAN, and to modulate the clinical management of these patients accordingly.

MicroRNA 193b-3p as a predictive biomarker of chronic kidney disease in patients undergoing radical nephrectomy for renal cell carcinoma.

BACKGROUND: A significant proportion of patients undergoing radical nephrectomy (RN) for clear-cell renal cell carcinoma (RCC) develop chronic kidney disease (CKD) within a few years following surgery. Chronic kidney disease has important health, social and economic impact and no predictive biomarkers are currently available. MicroRNAs (miRs) are small non-coding RNAs implicated in several pathological processes. METHODS: Primary objective of our study was to define miRs whose deregulation is predictive of CKD in patients treated with RN. Ribonucleic acid from formalin-fixed paraffin embedded renal parenchyma (cortex and medulla isolated separately) situated >3 cm from the matching RCC was tested for miR expression using nCounter NanoString technology in 71 consecutive patients treated with RN for RCC. Validation was performed by RT-PCR and in situ hybridisation. End point was post-RN CKD measured 12 months post-operatively. Multivariable logistic regression and decision curve analysis were used to test the statistical and clinical impact of predictors of CKD. RESULTS: The overexpression of miR-193b-3p was associated with high risk of developing CKD in patients undergoing RN for RCC and emerged as an independent predictor of CKD. The addition of miR-193b-3p to a predictive model based on clinical variables (including sex and estimated glomerular filtration rate) increased the sensitivity of the predictive model from 81 to 88%. In situ hybridisation showed that miR-193b-3p overexpression was associated with tubule-interstitial inflammation and fibrosis in patients with no clinical or biochemical evidence of pre-RN nephropathy. CONCLUSIONS: miR-193b-3p might represent a useful biomarker to tailor and implement surveillance strategies for patients at high risk of developing CKD following RN.

α-1-Antitrypsin detected by MALDI imaging in the study of glomerulonephritis: Its relevance in chronic kidney disease progression.

Idiopathic glomerulonephritis (GN), such as membranous glomerulonephritis, focal segmental glomerulosclerosis (FSGS), and IgA nephropathy (IgAN), represent the most frequent primary glomerular kidney diseases (GKDs) worldwide. Although the renal biopsy currently remains the gold standard for the routine diagnosis of idiopathic GN, the invasiveness and diagnostic difficulty related with this procedure highlight the strong need for new diagnostic and prognostic biomarkers to be translated into less invasive diagnostic tools. MALDI-MS imaging MALDI-MSI was applied to fresh-frozen bioptic renal tissue from patients with a histological diagnosis of FSGS (n = 6), IgAN, (n = 6) and membranous glomerulonephritis (n = 7), and from controls (n = 4) in order to detect specific molecular signatures of primary glomerulonephritis. MALDI-MSI was able to generate molecular signatures capable to distinguish between normal kidney and pathological GN, with specific signals (m/z 4025, 4048, and 4963) representing potential indicators of chronic kidney disease development. Moreover, specific disease-related signatures (m/z 4025 and 4048 for FSGS, m/z 4963 and 5072 for IgAN) were detected. Of these signals, m/z 4048 was identified as α-1-antitrypsin and was shown to be localized to the podocytes within sclerotic glomeruli by immunohistochemistry. α-1-Antitrypsin could be one of the markers of podocyte stress that is correlated with the development of FSGS due to both an excessive loss and a hypertrophy of podocytes.

Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression.

Hypertension and chronic kidney disease (CKD) are complex traits representing major global health problems. Multiple genome-wide association studies have identified common variants in the promoter of the UMOD gene, which encodes uromodulin, the major protein secreted in normal urine, that cause independent susceptibility to CKD and hypertension. Despite compelling genetic evidence for the association between UMOD risk variants and disease susceptibility in the general population, the underlying biological mechanism is not understood. Here, we demonstrate that UMOD risk variants increased UMOD expression in vitro and in vivo. Uromodulin overexpression in transgenic mice led to salt-sensitive hypertension and to the presence of age-dependent renal lesions similar to those observed in elderly individuals homozygous for UMOD promoter risk variants. The link between uromodulin and hypertension is due to activation of the renal sodium cotransporter NKCC2. We demonstrated the relevance of this mechanism in humans by showing that pharmacological inhibition of NKCC2 was more effective in lowering blood pressure in hypertensive patients who are homozygous for UMOD promoter risk variants than in other hypertensive patients. Our findings link genetic susceptibility to hypertension and CKD to the level of uromodulin expression and uromodulin's effect on salt reabsorption in the kidney. These findings point to uromodulin as a therapeutic target for lowering blood pressure and preserving renal function.

cGMP-dependent protein kinase 1 polymorphisms underlie renal sodium handling impairment.

Defective pressure-natriuresis related to abnormalities in the natriuretic response has been associated with hypertension development. A major signaling pathway mediating pressure natriuresis involves the cGMP-dependent protein kinase 1 (PRKG1) that, once activated by Src kinase, inhibits renal Na(+) reabsorption via a direct action on basolateral Na-K ATPase and luminal Na-H exchanger type 3, as shown in renal tubuli of animals. Because a clear implication of PRKG1 in humans is still lacking, here we addressed whether PRKG1 polymorphisms affect pressure-natriuresis in patients. Naive hypertensive patients (n = 574), genotyped for PRKG1 rs1904694, rs7897633, and rs7905063 single nucleotide polymorphisms (SNPs), underwent an acute Na(+) loading, and the slope of the pressure-natriuresis relationship between blood pressure and Na(+) excretion was calculated. The underlying molecular mechanism was investigated by immunoblotting protein quantifications in human kidneys. The results demonstrate that the PRKG1 risk haplotype GAT (rs1904694, rs7897633, rs7905063, respectively) associates with a rightward shift of the pressure-natriuresis curve (0.017 ± 0.004 µEq/mm Hg per minute) compared with the ACC (0.0013 ± 0.003 µEq/mm Hg per minute; P = 0.001). In human kidneys, a positive correlation of protein expression levels between PRKG1 and Src (r = 0.83; P<0.001) or α1 Na-K ATPase (r = 0.557; P<0.01) and between α1 Na-K ATPase and Na-H exchanger type 3 (r = 0.584; P<0.01) or Src (r = 0.691; P<0.001) was observed in patients carrying PRKG1 risk GAT (n = 23) but not ACC (n = 14) variants. A functional signaling complex among PRKG1, α1 Na-K ATPase, and Src was shown by immunoprecipitation from human renal caveolae. These findings indicate that PRKG1 risk alleles associate with salt-sensitivity related to a loss of the inhibitory control of renal Na(+) reabsorption, suggestive of a blunt pressure-natriuresis response.

Efficacy and toxicity of treatments for nephritis in a series of consecutive lupus patients.

OBJECTIVE: To study efficacy and toxicity of treatments for nephritis in a series of consecutive lupus patients. METHODS: The case records of 40 patients with lupus nephritis followed up in a single center between 1992 and 2011 (median duration = 8.37 years) were retrieved to determine efficacy and toxicity of the treatments. Patients with class III/IV/V lupus nephritis were included. RESULTS: Sustained responses were 21/40 (52.5%) at six months, 33/40 (82.5%) at 18 months and 30/40 (75.0%) at 36 months. Three deaths were observed after 18, 104 and 164 months of follow-up respectively, with one possibly associated with immunosuppression. Kidney survival was 100% at 18 months and 97.7% at 36 months. Kaplan-Meier's survival algorithm estimated a mean overall survival of 236.05 ± 11.56 months and a kidney survival of 240.77 ± 11.07 months. Kidney and overall survival were not significantly different among patients with different nephritis classes. Complications occurred in 12/40 (30.0%). Amenorrhea occurred in 20.7% of patients and was associated with higher cumulative doses of cyclophosphamide. Patients who achieved remission at 36 months or later had lower levels of proteinuria at 6 months (mean ± SD = 0.93 ± 0.97 g/24 h versus 2.60 ± 2.11 g/24 h, p = 0.002) than non-responder patients. CONCLUSIONS: The data demonstrate that in the overall Caucasian population with lupus nephritis the combination of available therapeutic tools is effective and relatively well tolerated.

Decreased transcriptional activity of calcium-sensing receptor gene promoter 1 is associated with calcium nephrolithiasis.

BACKGROUND: CaSR gene is a candidate for calcium nephrolithiasis. Single-nucleotide polymorphisms (SNPs) encompassing its regulatory region were associated with calcium nephrolithiasis. AIMS: We tested SNPs in the CaSR gene regulatory region associated with calcium nephrolithiasis and their effects in kidney. SUBJECTS AND METHODS: One hundred sixty-seven idiopathic calcium stone formers and 214 healthy controls were genotyped for four CaSR gene SNPs identified by bioinformatics analysis as modifying transcription factor binding sites. Strontium excretion after an oral load was tested in 55 stone formers. Transcriptional activity induced by variant alleles at CaSR gene promoters was compared by luciferase reporter gene assay in HEK-293 and HKC-8 cells. CaSR and claudin-14 mRNA levels were measured by real-time PCR in 107 normal kidney medulla samples and compared in patients with different CaSR genotype. RESULTS: Only rs6776158 (A>G), located in the promoter 1, was associated with nephrolithiasis. Its minor G allele was more frequent in stone formers than controls (37.8% vs 26.4%, P = .001). A reduced strontium excretion was observed in GG homozygous stone formers. Luciferase fluorescent activity was lower in cells transfected with the promoter 1 including G allele at rs6776158 than cells transfected with the A allele. CaSR mRNA levels were lower in kidney medulla samples from homozygous carriers for the G allele at rs6776158 than carriers for the A allele. Claudin-14 mRNA levels were also lower in GG homozygous subjects. CONCLUSIONS: Minor allele at rs6776158 may predispose to calcium stones by decreasing transcriptional activity of the CaSR gene promoter 1 and CaSR expression in kidney tubules.

Prognostic significance of immunohistochemical phenotypes in patients treated for high-grade cervical intraepithelial neoplasia.

Strong evidence exists that the host's immune system plays a crucial role for the development of human papillomavirus-related cervical premalignant and malignant lesions. In particular, effective cell-mediated immunity (CMI) promotes spontaneous infection clearance and cancer precursors regression in healthy subjects, while immunosuppressed individuals are more likely to experience infection persistence, cervical intraepithelial neoplasia (CIN) lesions, and cervical cancer. In this study, the prognostic significance of immunohistochemical profiling of CD4+ T-cells, CD8+ T-cells, dendritic cells (CD11c+), T-bet+, and GATA-3+ transcription factors has been studied in surgical specimens of 34 consecutive women affected by high-grade cervical intraepithelial neoplasia (CIN2-3) submitted to cervical conization. Results have been correlated with the clinical outcomes at 24 months after treatment and statistically analyzed. Higher rates of CD4+ T-cells, CD11c+ dendritic cells, and T-bet+ transcription factor positivity showed a strong statistically significative correlation with favourable clinical outcomes (P ≤ 0.0001). These data reinforce the evidence of the relevance of the host's immune status in the natural history of HPV-related cervical disease and add a prognostic significance of the cervical immunological profile in terms of predicting significant lower recurrence rates.

Selective up-regulation of the soluble pattern-recognition receptor pentraxin 3 and of vascular endothelial growth factor in giant cell arteritis: relevance for recent optic nerve ischemia.

OBJECTIVE: To assess local expression and plasma levels of pentraxin 3 (PTX3) in patients with giant cell arteritis (GCA). METHODS: Plasma and serum samples were obtained from 75 patients with GCA (20 of whom had experienced optic nerve ischemia in the previous 3 weeks and 24 of whom had experienced symptom onset in the previous 6 months and had no history of optic nerve ischemia) and 63 controls (35 age-matched healthy subjects, 15 patients with rheumatoid arthritis, and 13 patients with chronic stable angina). In 9 patients in whom GCA was recently diagnosed, circulating levels of interleukin-1ß (IL-1ß), IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12p70, CCL2/monocyte chemotactic protein 1, CCL3/macrophage inflammatory protein 1α (MIP-1α), CCL4/MIP-1ß, CCL11/eotaxin, CXCL9/monokine induced by interferon-γ, CXCL10/interferon-γ-inducible 10-kd protein, tumor necrosis factor α (TNFα), interferon-γ, vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor, and FasL were measured via a multiplexed cytometric assay. PTX3 and VEGF concentrations were assessed by enzyme-linked immunosorbent assay. PTX3 and CD68 expression were determined by immunohistochemistry and immunofluorescence on temporal artery samples. RESULTS: GCA patients with very recent optic nerve ischemia had significantly higher PTX3 and VEGF levels compared to other GCA patients and controls. GCA patients with a disease duration of <6 months had significantly higher PTX3 levels compared to other GCA patients and controls. Immunohistochemistry revealed selective PTX3 expression in the wall of inflamed arteries. CONCLUSION: Our findings indicate that local expression of PTX3 is a feature of vascular inflammation in GCA; elevated circulating levels of PTX3 identify patients with very recent optic nerve ischemia or a recent diagnosis. Optic nerve ischemia is also associated with increased circulating VEGF levels.

Cervical Human Papillomavirus in transplanted Italian women: a long-term prospective follow-up study.

BACKGROUND: Human Papillomavirus (HPV) is the leading cause of cervical cancer among women. Immunosuppression is recognized as one of the major risk factors for HPV infection and persistence. OBJECTIVES: Aim of this study was to determine if solid organs (24 kidney and 24 kidney/pancreas) transplanted Italian women undergoing immunosuppressive therapies were at higher risk of HPV genital infection and cervical precancerous lesions in a ten-year follow-up. STUDY DESIGN: Forty-eight women that underwent transplant from 1990 to 2000, receiving multi-drug immunosuppressive therapy, were enrolled prospectively in a long-term follow-up protocol. Patients were cytologically (Pap smear) and virologically (HPV-DNA test) tested each year for 10 years. Incidence of HPV-DNA positivity and of cervical cytological/histological abnormalities was collected. Results were statistically analyzed and compared to a matching control group of 200 healthy women. RESULTS: HPV-DNA positivity and cytological High-Grade (HG-SIL) cervical lesions did not show statistically significant differences in cases compared to controls, while statistical significance was observed in Low-Grade (LG-SIL) cytological diagnoses. No statistically significant difference was observed in histology-proven cervical lesions. CONCLUSIONS: Women receiving immunosuppression therapy following transplant do not seem to require intensive follow-up, and should not be considered a high-risk subgroup, as they do not show a statistically significant higher incidence of HPV infections or high-grade cervical dysplasia compared to healthy immunocompetent matching controls.