Comprehensive analysis of HPV infection, EGFR exon 20 mutations and LINE1 hypomethylation as risk factors for malignant transformation of sinonasal-inverted papilloma to squamous cell carcinoma.

Different risk factors are suspected to be involved in malignant transformation of sinonasal papillomas and include HPV infection, tobacco smoking, occupational exposure, EGFR/KRAS mutations and DNA methylation alterations. In our study, 25 inverted sinonasal papillomas (ISPs), 5 oncocytic sinonasal papillomas (OSP) and 35 squamous cell carcinomas (SCCs) from 54 patients were genotyped for 10 genes involved in EGFR signalling. HPV-DNA detection was performed by in-situ hybridisation and LINE-1 methylation was quantitatively determined by bisulphite-pyrosequencing. High-risk HPV was observed only in 13% of ISP-associated SCC and in 8% of de novo-SCC patients. EGFR mutations occurred in 72% of ISPs, 30% of ISP-associated SCCs and 17% of de novo-SCCs. At 5-year follow-up, SCC arose in only 30% (6/20) of patients with EGFR-mutated ISPs compared to 76% (13/17) of patients with EGFR-wild-type ISP (p = 0.0044). LINE-1 hypomethylation significantly increased from papilloma/early stage SCC to advanced stage SCC (p = 0.03) and was associated with occupational exposure (p = 0.01) and worse prognosis (p = 0.09). In conclusion, our results suggest that a small subset of these tumours could be related to HPV infection; EGFR mutations characterise those ISPs with a lower risk of developing into SCC; LINE-1 hypomethylation is associated with occupational exposure and could identify more aggressive nasal SCC.

Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial.

BACKGROUND: Autosomal dominant polycystic kidney disease slowly progresses to end-stage renal disease and has no effective therapy. A pilot study suggested that the somatostatin analogue octreotide longacting release (LAR) could be nephroprotective in this context. We aimed to assess the effect of 3 years of octreotide-LAR treatment on kidney and cyst growth and renal function decline in participants with this disorder. METHODS: We did an academic, multicentre, randomised, single-blind, placebo-controlled, parallel-group trial in five hospitals in Italy. Adult (>18 years) patients with estimated glomerular filtration rate (GFR) of 40 mL/min per 1·73 m(2) or higher were randomly assigned (central allocation by phone with a computerised list, 1:1 ratio, stratified by centre, block size four and eight) to 3 year treatment with two 20 mg intramuscular injections of octreotide-LAR (n=40) or 0·9% sodium chloride solution (n=39) every 28 days. Study physicians and nurses were aware of the allocated group; participants and outcome assessors were masked to allocation. The primary endpoint was change in total kidney volume (TKV), measured by MRI, at 1 year and 3 year follow-up. Analyses were by modified intention to treat. This study is registered with ClinicalTrials.gov, NCT00309283. FINDINGS: Recruitment was between April 27, 2006, and May 12, 2008. 38 patients in the octreotide-LAR group and 37 patients in the placebo group had evaluable MRI scans at 1 year follow-up, at this timepoint, mean TKV increased significantly less in the octreotide-LAR group (46·2 mL, SE 18·2) compared with the placebo group (143·7 mL, 26·0; p=0·032). 35 patients in each group had evaluable MRI scans at 3 year follow-up, at this timepoint, mean TKV increase in the octreotide-LAR group (220·1 mL, 49·1) was numerically smaller than in the placebo group (454·3 mL, 80·8), but the difference was not significant (p=0·25). 37 (92·5%) participants in the octreotide-LAR group and 32 (82·1%) in the placebo group had at least one adverse event (p=0·16). Participants with serious adverse events were similarly distributed in the two treatment groups. However, four cases of cholelithiasis or acute cholecystitis occurred in the octreotide-LAR group and were probably treatment-related. INTERPRETATION: These findings provide the background for large randomised controlled trials to test the protective effect of somatostatin analogues against renal function loss and progression to end-stage kidney disease. FUNDING: Polycystic Kidney Disease Foundation.

Identification of MGMT Downregulation Induced by miRNA in Glioblastoma and Possible Effect on Temozolomide Sensitivity.

Glioblastoma multiforme (GBM) remains one of the tumors with the worst prognosis. In recent years, a better overall survival (OS) has been described in cases subjected to Gross Total Resection (GTR) that were presenting hypermethylation of Methylguanine-DNA methyltransferase (MGMT) promoter. Recently, also the expression of specific miRNAs involved in MGMT silencing has been related to survival. In this study, we evaluate MGMT expression by immunohistochemistry (IHC), MGMT promoter methylation and miRNA expression in 112 GBMs and correlate the data to patients' clinical outcomes. Statistical analyses demonstrate a significant association between positive MGMT IHC and the expression of miR-181c, miR-195, miR-648 and miR-767.3p between unmethylated cases and the low expression of miR-181d and miR-648 and between methylated cases and the low expression of miR-196b. Addressing the concerns of clinical associations, a better OS has been described in presence of negative MGMT IHC, in methylated patients and in the cases with miR-21, miR-196b overexpression or miR-767.3 downregulation. In addition, a better progression-free survival (PFS) is associated with MGMT methylation and GTR but not with MGMT IHC and miRNA expression. In conclusion, our data reinforce the clinical relevance of miRNA expression as an additional marker to predict efficacy of chemoradiation in GBM.

Recent Information on Pan-Genotypic Direct-Acting Antiviral Agents for HCV in Chronic Kidney Disease.

BACKGROUND: Hepatitis C virus (HCV) is still common in patients with chronic kidney disease. It has been recently discovered that chronic HCV is a risk factor for increased incidence of CKD in the adult general population. According to a systematic review with a meta-analysis of clinical studies, pooling results of longitudinal studies (n = 2,299,134 unique patients) demonstrated an association between positive anti-HCV serologic status and increased incidence of CKD; the summary estimate for adjusted HR across the surveys was 1.54 (95% CI, 1.26; 1.87), (p < 0.0001). The introduction of direct-acting antiviral drugs (DAAs) has caused a paradigm shift in the management of HCV infection; recent guidelines recommend pan-genotypic drugs (i.e., drugs effective on all HCV genotypes) as the first-choice therapy for HCV, and these promise to be effective and safe even in the context of chronic kidney disease. AIM: The purpose of this narrative review is to show the most important data on pan-genotypic DAAs in advanced CKD (CKD stage 4/5). METHODS: We recruited studies by electronic databases and grey literature. Numerous key-words ('Hepatitis C' AND 'Chronic kidney disease' AND 'Pan-genotypic agents', among others) were adopted. RESULTS: The most important pan-genotypic combinations for HCV in advanced CKD are glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL). Two clinical trials (EXPEDITION-4 and EXPEDITION-5) and some 'real-world' studies (n = 6) reported that GLE/PIB combinations in CKD stage 4/5 gave SVR12 rates ranging between 86 and 99%. We retrieved clinical trials (n = 1) and 'real life' studies (n = 6) showing the performance of SOF/VEL; according to our pooled analysis, the summary estimate of SVR rate was 100% in studies adopting SOF/VEL antiviral combinations. The drop-out rate (due to AEs) in patients on SOF/VEL ranged between 0 and 4.8%. CONCLUSIONS: Pan-genotypic combinations, such as GLE/PIB and SOF/VEL, appear effective and safe for HCV in advanced CKD, even if a limited number of studies with small sample sizes currently exist on this issue. Studies are under way to assess whether successful antiviral therapy with DAAs will translate into better survival in patients with advanced CKD.

Acute kidney injury and chronic kidney disease after liver transplant: A retrospective observational study.

BACKGROUND AND RATIONALE: Chronic kidney disease remains an important risk factor for morbidity and mortality among LT recipients, but its exact incidence and risk factors are still unclear. MATERIAL AND METHODS: We carried out a retrospective cohort study of consecutive adults who underwent liver transplant (January 2009-December 2018) and were followed (at least 6 months) at our institution. CKD was defined following the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guidelines. Long-term kidney function was classified into 4 groups: no CKD (eGFR, ≥60mL/min/1.73m2), mild CKD (eGFR, 30-59mL/min/1.73m2), severe CKD (eGFR, 15-29mL/min/1.73m2), and end-stage renal disease (ESRD). RESULTS: We enrolled 410 patients followed for 53.2±32.6 months. 39 had CKD at baseline, and 95 developed de novo CKD over the observation period. There were 184 (44.9%) anti-HCV positive, 47 (11.5%) HBsAg positive, and 33 (8.1%) HBV/HDV positive recipients. Recipient risk factors for baseline CKD were advanced age (P=0.044), raised levels of serum uric acid (P<0.0001), and insulin dependent DM (P=0.0034). Early post-transplant AKI was common (n=95); logistic regression analysis found that baseline serum creatinine was an independent predictor of early post-LT AKI (P=0.0154). According to our Cox proportional hazards model, recipient risk factors for de novo CKD included aging (P<0.0001), early post-transplant AKI (P=0.007), and baseline serum creatinine (P=0.0002). At the end of follow-up, there were 116 LT recipients with CKD - 109 (93.9%) and 7 (6.1%) had stage 3 and advanced CKD, respectively. Only two of them are undergoing long-term dialysis. CONCLUSION: The incidence of CKD was high in our cohort of LT recipients, but only a slight decline in kidney function over time was recorded. Prevention of post-transplant AKI will improve kidney function in the long run. We need more studies to analyze the function of kidneys among LT recipients over extended follow-ups and their impact on mortality.

Hierarchical clustering analysis of pathologic and molecular data identifies prognostically and biologically distinct groups of colorectal carcinomas.

This work has evaluated the potential superiority of a morphomolecular classification based on the combination of clinicopathologic and molecular features of colorectal cancers. A cohort of 126 colorectal carcinomas was investigated by unsupervised hierarchical clustering analysis to combine 13 routinely assessed clinicopathologic features and all five molecular markers recently suggested by Jass' classification to distinguish four molecular subtypes of sporadic colorectal carcinomas. Survival analysis was assessed by a Cox proportional hazards model. A clear separation into three prognostically significant groups was identified: cluster A and cluster C were associated with good prognosis and cluster B with poor prognosis (P=0.006). Clinicopathologic and molecular features of cluster A and cluster B tumors were strongly concordant with colorectal cancer profiles characterized by microsatellite instability or by chromosomal instability, respectively. The clinicopathologic features of cluster C tumors were suggestive of a less aggressive disease than cluster B tumors. Genetically, they appeared intermediate between cluster A and cluster B tumors, as they were mainly microsatellite stable tumors showing high levels of both MGMT methylation and loss of heterozygosity. Chromosomal instability was significantly lower in cluster C than in cluster B tumors. A more accurate tumor classification should combine the prognostic power of clinicopathologic parameters with molecular biomarkers that provide information regarding the natural history of the cancer. Hierarchical clustering seems to be a useful, promising and powerful tool for further translational studies and should lead us to define a diagnostic and prognostic signature for different carcinomas.

Sofosbuvir-based regimens for HCV in stage 4-stage 5 chronic kidney disease. A systematic review with meta-analysis.

BACKGROUND: Hepatitis C is an important agent of liver damage in patients with chronic kidney disease and the advent of DAAs has dramatically changed the management of HCV positive patients, including those with advanced CKD. Sofosbuvir is the backbone of many anti-HCV regimens based on DAAs but it remains unclear whether it is appropriate for HCV-infected patients with stage 4-5 CKD. STUDY AIMS AND DESIGN: We performed a systematic review of the literature with a meta-analysis of clinical studies in order to evaluate the efficacy and safety of SOF-based DAA regimens in patients with stage 4-5 CKD. The primary outcome was sustained viral response (as a measure of efficacy); the secondary outcomes were the frequency of SAEs and drop-outs due to AEs (as measures of tolerability). The random-effects model of DerSimonian and Laird was adopted, with heterogeneity and stratified analyses. RESULTS: Thirty clinical studies (n=1537 unique patients) were retrieved. The pooled SVR12 and SAEs rate was 0.99 (95% confidence intervals, 0.97; 1.0, I2=99.8%) and 0.09 (95% CI, 0.05; 0.13, I2=84.3%), respectively. The pooled SVR12 rate in studies with high HCV RNA levels at baseline was lower, 0.87 (95% CI, 0.75; 1.0, I2=73.3%) (P<0.001). The pooled drop-out rate due to AEs was 0.02 (95% CI, -0.01; 0.04, I2=16.1%). Common serious adverse events were anemia (n=26, 38%) and reduced eGFR (n=14, 19%). SAEs were more common in studies adopting full-dose sofosbuvir (pooled rate of SAEs 0.15, 95% CI, 0.06; 0.25; I2=80.1%) and in those based on ribavirin (0.15, 95% CI, 0.07; 0.23, I2=95.8%). Six studies (n=69 patients) reported eGFR levels at baseline/post- antiviral therapy; no consistent changes were found. CONCLUSIONS: SOF-based regimens appear safe and effective in patients with stage 4-5 CKD. Serum creatinine should be carefully monitored during therapy with SOF in patients with CKD. Randomized controlled studies in order to expand our knowledge on this point are under way.

Hepatitis B virus vaccine and chronic kidney disease. The advances.

BACKGROUND: Hepatitis B is an important agent of liver disease in patients with chronic kidney disease and chronic HBV infection promotes the development of CKD in the adult general population. Patients with CKD have a suboptimal response to various vaccines, and it remains unclear how we boost the immune response of CKD patients to HB vaccine. STUDY AIMS AND DESIGN: We performed a narrative review to assess the mechanisms of lower immunogenicity of HBV vaccine in CKD population; multiple approaches to improve the response rate of CKD patients to HBV vaccine have been reported. This is a very important topic for nephrologists who often serve as primary case providers for patients with CKD. RESULTS: The recommended vaccine schedule for CKD patients including those on maintenance dialysis is based on recombinant vaccine, four doses (month 0,1,2, and 6; 40mcg each) by intramuscular route (deltoid muscle). According to RCTs or observational studies, some recombinant vaccines with adjuvants (i.e., HBV-AS02 and HBV-AS04) look promising. HBV-AS04 showed to give better seroprotection rates and durable immune response over extended follow-ups compared with licensed HBV vaccine in CKD patients. The seroprotection rate was 95% (97/102) and 82% (202/248) in pre-dialysis and dialysis patients, respectively, one month after completing vaccine schedule with HBV-AS04. HBV-AS02 was superior to licensed vaccine in terms of seroprotection rate, 76.9% vs. 37.6%. CONCLUSIONS: We suggest adjuvanted recombinant (HBV-AS04) vaccine (0,1,2 and 3 months; 20 mcg each dose) and post vaccination testing of anti-HBs antibody after vaccination. Booster doses to patients whose anti-HBs titers fall below the seroprotection level (<10IU/mL) during the follow-up are appropriate. The patho-physiologic mechanisms responsible for the poor immunogenicity of HBV vaccine in CKD patients are under active investigation.

Hepatitis B virus vaccine and chronic kidney disease. The advances.

BACKGROUND: Hepatitis B is an important agent of liver disease in patients with chronic kidney disease and chronic HBV infection promotes the development of CKD in the adult general population. Patients with CKD have a suboptimal response to various vaccines, and it remains unclear how we boost the immune response of CKD patients to HB vaccine. STUDY AIMS AND DESIGN: We performed a narrative review to assess the mechanisms of lower immunogenicity of HBV vaccine in CKD population; multiple approaches to improve the response rate of CKD patients to HBV vaccine have been reported. This is a very important topic for nephrologists who often serve as primary case providers for patients with CKD. RESULTS: The recommended vaccine schedule for CKD patients including those on maintenance dialysis is based on recombinant vaccine, four doses (month 0,1,2, and 6; 40mcg each) by intramuscular route (deltoid muscle). According to RCTs or observational studies, some recombinant vaccines with adjuvants (i.e., HBV-AS02 and HBV-AS04) look promising. HBV-AS04 showed to give better seroprotection rates and durable immune response over extended follow-ups compared with licensed HBV vaccine in CKD patients. The seroprotection rate was 95% (97/102) and 82% (202/248) in pre-dialysis and dialysis patients, respectively, one month after completing vaccine schedule with HBV-AS04. HBV-AS02 was superior to licensed vaccine in terms of seroprotection rate, 76.9% vs. 37.6%. CONCLUSIONS: We suggest adjuvanted recombinant (HBV-AS04) vaccine (0,1,2 and 3 months; 20 mcg each dose) and post vaccination testing of anti-HBs antibody after vaccination. Booster doses to patients whose anti-HBs titers fall below the seroprotection level (<10IU/mL) during the follow-up are appropriate. The patho-physiologic mechanisms responsible for the poor immunogenicity of HBV vaccine in CKD patients are under active investigation.

Updated Evidence on the Epidemiology of Hepatitis C Virus in Hemodialysis.

Prevalence rates of HCV infection are decreasing in hemodialysis units of most developed countries; however, nosocomial transmission of HCV continues to occur in the hemodialysis setting, not only in the emerging world. According to the Dialysis Outcomes and Practice Patterns Study (DOPPS, 2012-2015), the prevalence of HCV among patients on regular hemodialysis was 9.9%; in incident patients, the frequency of HCV was approximately 5%. Outbreaks of HCV have been investigated by epidemiologic and phylogenetic data obtained by sequencing of the HCV genome; no single factor was retrieved as being associated with nosocomial transmission of HCV within hemodialysis units. Transmission of HCV within HD units can be prevented successfully by full compliance with infection control practices; also, antiviral treatment and serologic screening for anti-HCV can be useful in achieving this aim. Infection control practices in hemodialysis units include barrier precautions to prevent exposure to blood-borne pathogens and other procedures specific to the hemodialysis environment. Isolating HCV-infected hemodialysis patients or using dedicated dialysis machines for HCV-infected patients are not currently recommended; reuse of dialyzers of HCV-infected patients should be made, according to recent guidelines. Randomized controlled trials regarding the impact of isolation on the risk of transmission of HCV to hemodialysis patients have not been published to date. At least two studies showed complete elimination of de novo HCV within HD units by implementation of strict infection control practices without isolation practices. De novo HCV within hemodialysis units has been independently associated with facility HCV prevalence, dialysis vintage, and low staff-to-patient ratio. Antiviral treatment of HCV-infected patients on hemodialysis should not replace the implementation of barrier precautions and other routine hemodialysis unit procedures.

An Updated View on the Antiviral Therapy of Hepatitis C in Chronic Kidney Disease.

BACKGROUND: Hepatitis C virus infection remains common in patients with chronic kidney disease, including those on maintenance dialysis. The relationship between hepatitis C virus infection and chronic kidney disease is bi-directional; in fact, HCV is both a cause and consequence of chronic kidney disease. According to a systematic review with meta-analysis of observational studies (n = 23 studies) (n = 574,081 patients on long-term dialysis), anti-HCV positive serologic status was an independent and significant risk factor for death in patients with advanced chronic kidney disease on long-term dialysis. The overall estimate for adjusted mortality (all-cause death risk) with HCV was 1.26 (95% CI, 1.18; 1.34) (p < 0.0001). Interferon-based therapies are biased by low efficacy/safety in chronic kidney disease, but the advent of direct-acting antiviral drugs has made a paradigm shift in the treatment of HCV-infection. These medications give interruption of viral replication because they target specific non-structural viral proteins; four classes of DAAs exist-NS3/4A protease inhibitors, NS5A inhibitors, NS5B nucleoside and non-nucleoside polymerase inhibitors. All-oral, interferon-free, ribavirin-free combinations of DAAs are now available. AIM: The goal of this narrative review is to report the available treatment options for HCV in advanced chronic kidney disease. METHODS: We have made an extensive review of the medical literature and various research engines have been adopted. RESULTS: Some combinations of DAAs are currently recommended for HCV in advanced CKD (including patients on maintenance dialysis): elbasvir/grazoprevir; glecaprevir/pibrentasvir; and sofosbuvir-based regimens. Solid evidence, based on registration and "real life" studies supports their efficacy (SVR rates > 90%) and safety even in patients with advanced CKD. No dosage adjustment is necessary and treatment duration is 8-12 weeks. However, recent data highlight that many patients with advanced CKD remain untreated, and numerous barriers to antiviral treatment of HCV still exist. Whether successful antiviral therapy with DAAs will translate into improved survival in the advanced CKD population is another point of future research.

Impact of antiviral therapy with direct acting antiviral agents (DAAs) on kidney disease in patients with chronic hepatitis C.

Hepatitis C virus and chronic kidney disease are major public health issues all over the world and controversy persists regarding the role of Hepatitis C as a risk factor for the development of chronic kidney disease in the adult general population. Numerous studies found a relationship between positive anti-HCV antibody serologic prevalence and increased frequency of incidence, prevalence and accelerated progression of chronic kidney disease (CKD) over time. However, this has not been universally accepted. One method to analyze the relationship between anti-HCV status and CKD is to evaluate the impact of anti-HCV antiviral therapy on the risk of CKD in the general population. The availability of safe and effective drugs (direct-acting antiviral agents) for HCV eradication supports this approach. Novel data support the notion that sustained viral response with anti-HCV regimens leads to improvement of hepatic and extrahepatic outcomes. A systematic review with meta-analysis of clinical observational studies was recently performed on this point. Fifteen studies were retrieved (N.=356, 285 patients); a relationship between sustained viral response and lower rate of kidney disease was noted- the summary estimate for adjusted risk of kidney disease was 2.5 (95% CI: 1.41; 4.41) (P=0.0016). An association between anti-HCV therapy and reduced risk of kidney disease after comparison of treated vs. untreated cohorts was observed, the summary estimate for adjusted HR was 0.44 (95% CI: 0.25; 0.63) (P=0.0001). Several biologic mechanisms have been cited to explain the detrimental role of HCV on kidney disease in the general population, and a direct and indirect activity of HCV on atherogenesis at kidney level has been mentioned. Clinical and experimental studies are under way.

An Update on Hepatocellular Carcinoma in Chronic Kidney Disease.

Chronic kidney disease is a major public health issue globally and the risk of cancer (including HCC) is greater in patients on long-term dialysis and kidney transplant compared with the general population. According to an international study on 831,804 patients on long-term dialysis, the standardized incidence ratio for liver cancer was 1.2 (95% CI, 1.0-1.4) and 1.5 (95% CI, 1.3-1.7) in European and USA cohorts, respectively. It appears that important predictors of HCC in dialysis population are hepatotropic viruses (HBV and HCV) and cirrhosis. 1-, 3-, and 5-year survival rates are lower in HCC patients on long-term dialysis than those with HCC and intact kidneys. NAFLD is a metabolic disease with increasing prevalence worldwide and recent evidence shows that it is an important cause of liver-related and extra liver-related diseases (including HCC and CKD, respectively). Some longitudinal studies have shown that patients with chronic hepatitis B are aging and the frequency of comorbidities (such as HCC and CKD) is increasing over time in these patients; it has been suggested to connect these patients to an appropriate care earlier. Antiviral therapy of HBV and HCV plays a pivotal role in the management of HCC in CKD and some combinations of DAAs (elbasvir/grazoprevir, glecaprevir/pibrentasvir, sofosbuvir-based regimens) are now available for HCV positive patients and advanced chronic kidney disease. The interventional management of HCC includes liver resection. Some ablative techniques have been suggested for HCC in CKD patients who are not appropriate candidates to surgery. Transcatheter arterial chemoembolization has been proposed for HCC in patients who are not candidates to liver surgery due to comorbidities. The gold standard for early-stage HCC in patients with chronic liver disease and/or cirrhosis is still liver transplant.

Updated View on Kidney Transplant from HCV-Infected Donors and DAAs.

BACKGROUND: The discrepancy between the number of potential available kidneys and the number of patients listed for kidney transplant continues to widen all over the world. The transplant of kidneys from hepatitis C virus (HCV)-infected donors into HCV naïve recipients has grown recently because of persistent kidney shortage and the availability of direct-acting antiviral agents. This strategy has the potential to reduce both waiting times for transplant and the risk of mortality in dialysis. AIM: We made an extensive review of the scientific literature in order to review the efficacy and safety of kidney transplant from HCV-viremic donors into HCV naïve recipients who received early antiviral therapy with direct-acting antiviral agents (DAAs). RESULTS: Evidence has been rapidly accumulated on this topic and some reports have been published (n = 11 studies, n = 201 patients) over the last three years. Various combinations of DAAs were administered-elbasvir/grazoprevir (n = 38), glecaprevir/pibrentasvir (n = 110), and sofosbuvir-based regimens (n = 53). DAAs were initiated in a range between a few hours before renal transplant (RT) to a median of 76 days after RT. The sustained virological response (SVR) rate was between 97.5% and 100%. A few severe adverse events (SAEs) were noted including fibrosing cholestatic hepatitis (n = 3), raised serum aminotransferase levels (n = 11), and acute rejection (n = 7). It remains unclear whether the AEs were related to the transmission of HCV, the use of DAAs, or kidney transplant per se. It appears that the frequency of AEs was greater in those studies where DAAs were not given in the very early post-kidney transplant phase. CONCLUSIONS: The evidence gathered to date encourages the expansion of the kidney donor pool with the adoption of HCV-infected donor organs. We suggest that kidney transplants from HCV-viremic kidneys into HCV-uninfected recipients should be made in the context of research protocols. Many of the studies reported above were externally funded and we need research generating "real-world" evidence. The recent availability of pangenotypic combinations of DAAs, which can be given even in patients with eGFR < 30/min/1.73 m2, will promote the notion that HCV-viremic donors are a significant resource for kidney transplant.

Urinary mRNA Expression of Glomerular Podocyte Markers in Glomerular Disease and Renal Transplant.

The research of novel markers in urinary samples, for the description of renal damage, is of high interest, and several works demonstrated the value of urinary mRNA quantification for the search of events related to renal disease or affecting the outcome of transplant kidneys. In the present pilot study, a comparison of the urine mRNA expression of specific podocyte markers among patients who had undergone clinical indication to renal transplanted (RTx, n = 20) and native (N, n = 18) renal biopsy was performed. The aim of this work was to identify genes involved in podocytes signaling and cytoskeletal regulation (NPHS1, NPHS2, SYNPO, WT1, TRPC6, GRM1, and NEUROD) in respect to glomerular pathology. We considered some genes relevant for podocytes signaling and for the function of the glomerular filter applying an alternative normalization approach. Our results demonstrate the WT1 urinary mRNA increases in both groups and it is helpful for podocyte normalization. Furthermore, an increase in the expression of TRPC6 after all kinds of normalizations was observed. According to our data, WT1 normalization might be considered an alternative approach to correct the expression of urinary mRNA. In addition, our study underlines the importance of slit diaphragm proteins involved in calcium disequilibrium, such as TRPC6.

Acute kidney injury and chronic kidney disease after liver transplant: A retrospective observational study.

BACKGROUND AND RATIONALE: Chronic kidney disease remains an important risk factor for morbidity and mortality among LT recipients, but its exact incidence and risk factors are still unclear. MATERIAL AND METHODS: We carried out a retrospective cohort study of consecutive adults who underwent liver transplant (January 2009-December 2018) and were followed (at least 6 months) at our institution. CKD was defined following the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guidelines. Long-term kidney function was classified into 4 groups: no CKD (eGFR, ≥60mL/min/1.73m2), mild CKD (eGFR, 30-59mL/min/1.73m2), severe CKD (eGFR, 15-29mL/min/1.73m2), and end-stage renal disease (ESRD). RESULTS: We enrolled 410 patients followed for 53.2±32.6 months. 39 had CKD at baseline, and 95 developed de novo CKD over the observation period. There were 184 (44.9%) anti-HCV positive, 47 (11.5%) HBsAg positive, and 33 (8.1%) HBV/HDV positive recipients. Recipient risk factors for baseline CKD were advanced age (P=0.044), raised levels of serum uric acid (P<0.0001), and insulin dependent DM (P=0.0034). Early post-transplant AKI was common (n=95); logistic regression analysis found that baseline serum creatinine was an independent predictor of early post-LT AKI (P=0.0154). According to our Cox proportional hazards model, recipient risk factors for de novo CKD included aging (P<0.0001), early post-transplant AKI (P=0.007), and baseline serum creatinine (P=0.0002). At the end of follow-up, there were 116 LT recipients with CKD - 109 (93.9%) and 7 (6.1%) had stage 3 and advanced CKD, respectively. Only two of them are undergoing long-term dialysis. CONCLUSION: The incidence of CKD was high in our cohort of LT recipients, but only a slight decline in kidney function over time was recorded. Prevention of post-transplant AKI will improve kidney function in the long run. We need more studies to analyze the function of kidneys among LT recipients over extended follow-ups and their impact on mortality.

The impact of antiviral therapy for HCV on kidney disease: a systematic review and meta-analysis.

BACKGROUND: Controversy persists about the role of hepatitis C as a risk factor for developing kidney disease in the general population. Some authors have evaluated the effect of antiviral therapy for HCV on the risk of kidney disease. STUDY AIMS AND DESIGN: A systematic review of the published medical literature was performed to assess whether antiviral therapy for HCV has an independent impact on kidney survival in the adult general population. A random effects model was used to generate an overall estimate of the risk of kidney disease after anti-HCV therapy across the published studies. Meta-regression and stratified analysis were also carried out. RESULTS: Fifteen studies were eligible (n=356, 285 patients) and separate meta-analyses were conducted according to the outcome. Pooling studies based on viral responses (n=7; 34,763 individual patients) demonstrated a relationship between sustained viral response and lower frequency of kidney disease; the overall estimate for adjusted risk of kidney disease was 2.50 (95% CI, 1.41; 4.41) (p=0.0016) and between-study heterogeneity was found (p-value by Q test=0.004). Aggregation of studies comparing treated vs untreated cohorts (n=8, n=333,312 patients) revealed an association between anti-HCV therapy and lower risk of kidney disease. The overall estimate for adjusted risk of kidney disease across the eight studies was 0.39 (95% CI, 0.25; 0.612) (p=0.0001). Meta-regression showed that the effectiveness of antiviral therapy in reducing the frequency of kidney disease diminishes as cirrhosis (p=0.02) and HBV infection (p=0.0001) increase among HCV-infected individuals. CONCLUSIONS: Antiviral therapy for HCV lowers the risk of kidney disease among HCV-infected individuals. Studies to understand the mechanisms underlying this association are ongoing.

HCV-infected solid organ donors, direct-acting antivirals and the current challenges.

Introduction: The introduction of direct-acting antiviral therapy has generated tremendous interest in transplanting organs from HCV-infected donors, an option which has the potential to lower waiting times for solid organ transplantation (including kidneys). Safe, effective and pangenotypic direct-acting antiviral agents are currently available.Areas covered: We have identified studies from PubMed, EMBASE, and the Cochrane database to review risks and benefits on solid organ transplantation from HCV-exposed donors in uninfected recipients.Expert opinion: The transmission of HCV with transplantation from anti-HCV positive kidneys without viremia is extremely uncommon whereas recent evidence (five clinical studies, n = 94 patients) shows the absence of HCV infection in HCV-naïve recipients who received kidneys from HCV RNA-positive donors and underwent early DAAs. The evidence regarding non-kidney solid organ transplantation from HCV-infected donors is more limited. One report showed the occurrence of dialysis-dependent kidney failure due to glomerulonephritis induced by acute HCV after liver transplant from a NAT-positive donor into an HCV-naïve recipient. Transplantation of kidneys and other solid organs from HCV-viremic donors into uninfected recipients has the potential to become the standard of care resulting in lower waitlist mortality. Further studies are needed urgently to establish clinical practice guidelines on this topic.

HBV vaccination with Fendrix is effective and safe in pre-dialysis CKD population.

BACKGROUND: Patients with chronic kidney disease have a poor response to hepatitis B vaccine due to the immunodeficiency conferred from chronic uremia. A recombinant HB vaccine containing an improved adjuvant system AS04 (HBV-AS04) has been manufactured but scarce evidence exists on HBV-AS04 use among patients with CKD. AIM: To assess efficacy and safety of an adjuvanted recombinant vaccine (HBV-AS04) in a large cohort of CKD patients at pre-dialysis stage (with susceptibility to HBV infection). METHODS: Patients were prospectively enrolled to receive four 20-mcg doses of HBV-AS04 by intramuscular route (deltoid muscle) at months 1, 2, 3, and 4. Anti-HBs surface antibody concentrations were tested at intervals of 1, 2, 3, 4, and 12months. Multivariate analyses were performed to assess the parameters, which predicted immunologic response to HBV-AS04 vaccine. RESULTS: One hundred and seven patients were included and 102 completed the study. At completion of vaccine schedule, the frequency of responders (anti-HBs titers≥10mIU/mL) was 95% (97/102) (mean anti-HBs antibody titers, 688.9±385mIU/mL), according to per-protocol analysis. Serum haemoglobin levels were greater in responder than non- or low-responder patients to HBV-AS04 (P=0.04) and this was confirmed by multivariate analysis. The seroprotection rate at month 50 was 88% (30/34) with lower anti-HBs antibody titers (218.5±269.6mIU/mL, P=0.001). No major side effects were observed. CONCLUSIONS: Our prospective study performed in a real-world setting showed a high immunogenicity and safety of HBV-AS04 vaccine in patients with CKD not yet on maintenance dialysis. Studies provided with longer follow-ups are under way to assess the durability of seroprotection in responders.

COVID-19 and Acute Kidney Injury: A Systematic Review and Meta-Analysis.

BACKGROUND: coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-is an ongoing pandemic with high morbidity and mortality rates. Preliminary evidence suggests that acute kidney injury (AKI) is uncommon in patients with COVID-19 and associated with poor outcomes. Study aims and design: we performed a systematic review of the literature with a meta-analysis of clinical studies to evaluate the frequency of AKI and dialysis requirement in patients who underwent hospitalization due to COVID-19. The incidence of AKI according to the death risk was calculated in these patients. The random-effects model of DerSimonian and Laird was adopted, with heterogeneity and stratified analyses. RESULTS: thirty-nine clinical studies (n = 25,566 unique patients) were retrieved. The pooled incidence of AKI was 0.154 (95% CI, 0.107; 0.201; p < 0.0001) across the studies. Significant heterogeneity was found (p = 0.0001). The overall frequency of COVID-19-positive patients who underwent renal replacement therapy (RRT) was 0.043 (95% CI, 0.031; 0.055; p < 0.0001); no publication bias was found (Egger's test, p = 0.11). The pooled estimate of AKI incidence in patients with severe COVID-19 was 0.53 (95% CI, 0.427; 0.633) and heterogeneity occurred (Q = 621.08, I2 = 97.26, p = 0.0001). According to our meta-regression, age (p < 0.007) and arterial hypertension (p < 0.001) were associated with AKI occurrence in hospitalized COVID-19 positive patients. The odds ratio (OR) for the incidence of AKI in deceased COVID-19 positive patients was greater than among survivors, 15.4 (95% CI, 20.99; 11.4; p < 0.001). CONCLUSIONS: AKI is a common complication in hospitalized COVID-19 positive patients. Additional studies are under way to assess the risk of AKI in COVID-19 patients and to deepen the mechanisms of kidney injury.