Metabolic Syndrome but Not Fatty Liver-Associated Genetic Variants Correlates with Glomerular Renal Function Decline in Patients with Non-Alcoholic Fatty Liver Disease.

The association between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) has been extensively demonstrated. Recent studies have focused attention on the role of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism in the association between NAFLD and CKD in non-metabolic adults and children, but the genetic impact on NAFLD-CKD association is still a matter of debate. The aim of the study was to investigate the impact of PNPLA3, transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and glucokinase regulatory protein (GCKR) gene variants rather than metabolic syndrome features on renal function in a large population of NAFLD patients. The present study is a post hoc analysis of the Plinio Study (ClinicalTrials.gov: NCT04036357). PNPLA3, TM6SF2, MBOAT7 and GCKR genes were analyzed by using real-time PCR with TaqMan probes. Glomerular filtration rate (GFR) was estimated with CKD-EPI. We analyzed 538 NAFLD; 47.2% had GFR < 90 mL/min/1.73 m2 while 5.9% had GFR < 60 mL/min/1.73 m2. The distribution of genotypes was superimposable according to GFR cut-offs. Results from the multivariable regression model did not show any correlation between genotypes and renal function. Conversely, metabolic syndrome was highly associated with GFR < 90 mL/min/1.73 m2 (odds ratio (OR): 1.58 [1.10−2.28]) and arterial hypertension with GFR < 60 mL/min/1.73 m2 (OR: 1.50 [1.05−2.14]). In conclusion, the association between NAFLD and CKD might be related to the shared metabolic risk factors rather than the genetic NAFLD background.

Gender Disparities in Vascular Access and One-Year Mortality among Incident Hemodialysis Patients: An Epidemiological Study in Lazio Region, Italy.

(1) Background: Interest in gender disparities in epidemiology, clinical features, prognosis and health care in chronic kidney disease patients is increasing. Aims of the study were to evaluate the association between gender and vascular access (arteriovenous fistula (AVF) or central venous catheter (CVC)) used at the start of hemodialysis (HD) and to investigate the association between gender and 1-year mortality. (2) Methods: The study includes 9068 adult chronic HD patients (64.7% males) registered in the Lazio Regional Dialysis Register (January 2008-December 2018). Multivariable logistic regression models were used to investigate the associations between gender and type of vascular access (AVF vs. CVC) and between gender and 1-year mortality. Interactions between gender and socio-demographic and clinical variables were tested adding the interaction terms in the final model. (3) Results: Females were older, had lower educational level and lower rate of self-sufficiency compared to males. Overall, CVC was used in 51.2% of patients. Females were less likely to use AVF for HD initiation than males. 1354 out of 8215 (16.5%) individuals died at the end of the follow-up period. Interaction term between gender and vascular access was significant in the adjusted model. From stratified analyses by vascular access, OR female vs. male (AVF) = 0.65; 95% CI 0.48-0.87 and OR female vs. male (CVC) = 0.88; 95% CI 0.75-1.04 were found. (4) Conclusions: This prospective population-based cohort study in a large Italian Region showed that in females starting chronic HD AVF was less common respect to men. The better 1-year survival of females is more evident among those women with AVF. Reducing gender disparity in access to AVF represents a key point in the management of HD patients.

Cholemic Nephropathy as Cause of Acute and Chronic Kidney Disease. Update on an Under-Diagnosed Disease.

Cholemic nephropathy (CN) is a recognized cause of acute kidney injury (AKI) in patients with severe hyperbilirubinemia (sHyb) and jaundice. Pathophysiological mechanisms of CN are not completely understood, but it seems caused both by direct toxicity of cholephiles and bile casts formation in nephrons enhanced by prolonged exposure to sHyb, particularly in the presence of promoting factors, as highlighted by a literature reviewed and by personal experience. The aim of our update is to retrace CN in its pathophysiology, risk factors, diagnosis and treatment, underlining the role of sHyb, promoting factors, and CN-AKI diagnostic criteria in the different clinical settings associated with this often-concealed disease. Our purpose is to focus on clinical manifestation of CN, exploring the possible transition to CKD. Cholemic nephropathy is an overlooked clinical entity that enters differential diagnosis with other causes of AKI. Early diagnosis and treatment are essential because renal injury could be fully reversible as rapidly as bilirubin levels are reduced. In conclusion, our proposal is to introduce an alert for considering CN in diagnostic and prognostic scores that include bilirubin and/or creatinine with acute renal involvement, with the aim of early diagnosis and treatment of sHyb to reduce the burden on renal outcome.

Nonalcoholic Fatty Liver Disease and the Kidney: A Review.

Nonalcoholic fatty liver disease (NAFLD) is associated with several extrahepatic manifestations such as cardiovascular disease and sleep apnea. Furthermore, NAFLD is reported to be associated with an increased risk of incident chronic kidney disease (CKD). Inflammation and oxidative stress are suggested to be the key factors involved in the inflammatory mechanisms and pathways linking NAFLD to CKD and are responsible for both the pathogenesis and the progression of CKD in NAFLD patients. This review aims to provide a more comprehensive overview of the association between CKD and NAFLD, also considering the effect of increasing severity of NAFLD. A PubMed search was conducted using the terms "non-alcoholic fatty liver disease AND kidney". In total, 537 articles were retrieved in the last five years and 12 articles were included in the qualitative analysis. Our results showed that CKD developed more frequently in NAFLD patients compared to those without NAFLD. This association persisted after adjustment for traditional risk factors and according to the severity of NAFLD. Therefore, patients with NAFLD should be considered at high risk of CKD. Intensive multidisciplinary surveillance over time is needed, where hepatologists and nephrologists must act together for better and earlier treatment of NAFLD patients.

HCV cirrhotic patients treated with direct-acting antivirals: Detection of tubular dysfunction and resolution after viral clearance.

BACKGROUND/AIMS: Hepatitis C virus (HCV) has been identified in tubular epithelial cells of infected patients; however, the presence of tubular dysfunction, which is a risk factor for chronic kidney disease (CKD), has never been examined in vivo. The present prospective longitudinal study aimed to estimate the prevalence of tubular dysfunction alone or with glomerular damage and its evolution after HCV clearance in cirrhotic patients. METHODS: One hundred and thirty-five consecutive Child-Pugh A cirrhotic patients were evaluated before antiviral treatment and 6 months after the end of therapy. Tubular dysfunction was evaluated by urinary alpha1-microglobulin to creatinine ratio (α1-MCR), and glomerular damage was assessed by urinary albumin to creatinine ratio (ACR). RESULTS: Almost all the patients (93.3%) showed a normal or mildly decreased e-GFR (KDIGO-G1/G2-categories). Tubular dysfunction was found in 23.7% (32/135) of patients, co-occurring with glomerular damage in 37.5% (12/32) of cases, while glomerular damage was found in 16.3% (22/135) of patients. In multiple logistic regression, glomerular damage and the concomitant presence of diabetes and hypertension were the only predictors significantly associated with tubular dysfunction. After HCV clearance, patients experienced a significant reduction of α1-MCR levels (21.0 vs 10.5 µg/mg, P = .009) and tubular dysfunction resolved in 57.1% of subjects. CONCLUSIONS: Tubular dysfunction is an unrecognized feature of HCV-related kidney disease in cirrhotic patients and its presence should be primarily investigated in subjects with glomerular damage, diabetes and hypertension, despite normal e-GFR. Tubular dysfunction resolves in the majority of cases after HCV clearance; however, it may persist after antiviral treatment and further studies should evaluate its long-term impact on kidney function.

A systematic review on the association between obstructive sleep apnea and chronic kidney disease.

This systematic review aims to provide a more comprehensive overview of the association between obstructive sleep apnea (OSA) and chronic kidney disease (CKD). A PubMed search was conducted using the terms "(obstructive sleep disorders OR obstructive sleep apnea OR obstructive sleep apnea syndrome) AND (kidney function OR renal outcome OR chronic kidney disease OR end stage renal disease)". Four hundred seventy four articles were initially retrieved, 227 in the last five years. We included articles with similar definitions of OSA, in particular only diagnosed by polysomnography, in order to exclude bias related to different diagnostic clinical tools, prediction algorithms and questionnaires that affected previous studies. Six cross-sectional and two retrospective studies were analyzed. There were a total of 8795 participants across all the studies with a mean age between 51 and 63 years. One study included only males but the proportion of males in the other studies ranged from 58 to 85.6%. The mean body mass index ranged from 25.2 to 32 kg/m2. The majority of studies considered indicate that OSA and CKD are significantly associated, in particular in their more severe categories. It is of great importance to set up a strong clinical collaboration between sleep medicine and nephrology.

Association between non-alcoholic fatty liver disease and obstructive sleep apnea.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is an emerging liver disease and currently the most common cause of incidental abnormal liver tests. The pathogenesis of NAFLD is multifactorial and many mechanisms that cause fatty liver infiltration, inflammation, oxidative stress and progressive fibrosis have been proposed. Obstructive sleep apnea (OSA) may be linked with the pathogenesis and the severity of NAFLD. AIM: To study the association between NAFLD and OSA considering also the efficacy of continuous positive airway pressure (CPAP) treatment. METHODS: A PubMed search was conducted using the terms "non-alcoholic fatty liver disease AND (obstructive sleep apnea OR obstructive sleep disorders OR sleep apnea)". Research was limited to title/abstract of articles published in English in the last 5 years; animal and child studies, case reports, commentaries, letters, editorials and meeting abstracts were not considered. Data were extracted on a standardized data collection table which included: First author, publication year, country, study design, number of patients involved, diagnosis and severity of OSA, diagnosis of NAFLD, patient characteristics, results of the study. RESULTS: In total, 132 articles were initially retrieved on PubMed search and 77 in the last five years. After removal of irrelevant studies, 13 articles were included in the qualitative analysis. There was a total of 2753 participants across all the studies with a mean age between 42 and 58 years. The proportion of males ranged from 21% to 87.9% and the mean body mass index ranged from 24.0 to 49.9 kg/m2. The results of this review showed an increased prevalence of NAFLD in patients with diagnosis of OSA, even in the absence of coexisting comorbidities such as obesity or metabolic syndrome. Furthermore, the severity of NAFLD is associated with the increase in OSA severity. Effective CPAP treatment, although not always decisive, may stabilize or slow NAFLD progression with benefits on metabolic and cardiovascular functions. CONCLUSION: In NAFLD patients, although asymptomatic, it is recommended to systematically perform polysomnography in order to early and better treat them before the development of potentially life threatening systemic dysfunctions.

Expected and Observed Glomerular Filtration Rates in Kidney Transplant Patients Converted to Once Daily Tacrolimus: 10 Years of Follow-up.

The decline of allograft kidney function in the long term remains a significant issue in renal transplantation, with drug nephrotoxicity and cardiovascular complications as important risk factors. Our study aimed to evaluate the estimated glomerular filtration rate (eGFR) trend and metabolic cardiovascular risk factors over 10 years in a cohort of kidney transplant (KT) recipients converted from twice-daily (TD) tacrolimus (Tac) to once-daily (OD)-Tac. We enrolled 55 consecutive KT recipients who had been at the outpatient clinic between 2009 and 2011. Thirty-seven reached the 10-year follow-up. We compared the observed eGFR with the expected eGFR trend described in KT-recipients and monitored blood pressure and metabolic cardiovascular risk factors. The observed eGFR remained stable throughout the complete follow-up (P = .188). The observed decline of eGFR was significantly lower compared with the expected decline for KT patients (P < .001). The blood pressure was maintained within target values. The monitoring of plasma glucose levels demonstrated the stability of median values (P = .686), as well as cholesterol level (P = .250), high-density lipoprotein (HDL) cholesterol (P = .294), and triglycerides (P = .592) throughout the follow-up. The monitoring of tacrolimus plasma level demonstrated that median trough levels remained constant (median values 4.4-5.5 ng/mL) throughout the entire follow-up period (P = .149). We suggest that the reasonable control of metabolic risk factors for cardiovascular disease over long-term follow-up may significantly contribute to the preservation of eGFR compared with the decline expected in KT recipients.

Female gender and overestimation of glomerular filtration rate: Independent predictors of acute kidney injury after liver transplantation
.

Acute kidney injury (AKI) in liver transplant (LT) setting is a recognized complication and is related to increased morbidity and mortality. Pre-LT renal function is difficult to estimate, in particular for the female gender. The aim of the study was to evaluate the incidence of post-LT AKI, its relationship with survival, and related risk factors. In a single-center retrospective study of consecutive LT patients (2008 - 2015), we assessed patient characteristics and intra-LT events, and post-operative data were collected. The occurrence of AKI post-LT was also evaluated (KDIGO guidelines). Data of 145 LT patients were analyzed. 45 (31.0%) patients showed an overestimation of glomerular filtration rate (over-GFR), defined as GFR > 120 mL/min/1.73m2; 83 patients (57.2%) developed post-LT AKI. The patients (n = 145) were divided into two groups: 123 (84.8%) patients with no-AKI & AKI stage 1 and 22 (15.2%) patients with AKI stages 2 and 3. Patients with AKI stages 2 and 3 were characterized by a significantly decreased 5-year survival (p < 0.001). On the multivariable analysis, female gender and over-GFR were significantly predictive for development of AKI stages 2 and 3. Female gender has already been reported as a discriminant factor for LT candidates. Altered estimation of renal function also needs to be considered in this setting, as this could mask the presence of an unknown compromised renal function.

The AKI Prediction Score: a new prediction model for acute kidney injury after liver transplantation.

BACKGROUND: Acute kidney injury (AKI) is a frequent complication after liver transplantation. Although numerous risk factors for AKI have been identified, their cumulative impact remains unclear. Our aim was therefore to design a new model to predict post-transplant AKI. METHODS: Risk analysis was performed in patients undergoing liver transplantation in two centres (n = 1230). A model to predict severe AKI was calculated, based on weight of donor and recipient risk factors in a multivariable regression analysis according to the Framingham risk-scheme. RESULTS: Overall, 34% developed severe AKI, including 18% requiring postoperative renal replacement therapy (RRT). Five factors were identified as strongest predictors: donor and recipient BMI, DCD grafts, FFP requirements, and recipient warm ischemia time, leading to a range of 0-25 score points with an AUC of 0.70. Three risk classes were identified: low, intermediate and high-risk. Severe AKI was less frequently observed if recipients with an intermediate or high-risk were treated with a renal-sparing immunosuppression regimen (29 vs. 45%; p = 0.007). CONCLUSION: The AKI Prediction Score is a new instrument to identify recipients at risk for severe post-transplant AKI. This score is readily available at end of the transplant procedure, as a tool to timely decide on the use of kidney-sparing immunosuppression and early RRT.

Peribiliary gland damage due to liver transplantation involves peribiliary vascular plexus and vascular endothelial growth factor.

Extrahepatic bile ducts are characterized by the presence of peribiliary glands (PBGs), which represent stem cell niches implicated in biliary regeneration. Orthotopic liver transplantation may be complicated by non-anastomotic strictures (NAS) of the bile ducts, which have been associated with ischemic injury of PBGs and occur more frequently in livers obtained from donors after circulatory death than in those from brain-dead donors. The aims of the present study were to investigate the PBG phenotype in bile ducts after transplantation, the integrity of the peribiliary vascular plexus (PVP) around PBGs, and the expression of vascular endothelial growth factor-A (VEGF-A) by PBGs. Transplanted ducts obtained from patients who underwent liver transplantation were studied (N=62). Controls included explanted bile duct samples not used for transplantation (N=10) with normal histology. Samples were processed for histology, immunohistochemistry and immunofluorescence. Surface epithelium is severely injured in transplanted ducts; PBGs are diffusely damaged, particularly in ducts obtained from circulatory-dead compared to brain-dead donors. PVP is reduced in transplanted compared to controls. PBGs in transplanted ducts contain more numerous progenitor and proliferating cells compared to controls, show higher positivity for VEGF-A compared to controls, and express VEGF receptor-2. In conclusion, PBGs and associated PVP are damaged in transplanted extrahepatic bile ducts; however, an activation of the PBG niche takes place and is characterized by proliferation and VEGF-A expression. This response could have a relevant role in reconstituting biliary epithelium and vascular plexus and could be implicated in the genesis of non-anastomotic strictures.

Combined liver-kidney transplantation versus liver transplant alone based on KDIGO stratification of estimated glomerular filtration rate: data from the United Kingdom Transplant registry - a retrospective cohort study.

Patient selection for combined liver-kidney transplantation (CLKT) is a current issue on the background of organ shortage. This study aimed to compare outcomes and post-transplant renal function for patients receiving CLKT and liver transplantation alone (LTA) based on native renal function using estimated glomerular filtration rate (eGFR) stratification. Using the UK National transplant database (NHSBT) 6035 patients receiving a LTA (N = 5912; 98%) or CLKT (N = 123; 2%) [2001-2013] were analysed, and stratified by KDIGO stages of eGFR at transplant (eGFR group-strata). There was no difference in patient/graft survival between LTA and CLKT in eGFR group-strata (P > 0.05). Of 377 patients undergoing renal replacement therapy (RRT) at time of transplantation, 305 (81%) and 72 (19%) patients received LTA and CLKT respectively. A significantly greater proportion of CLKT patients had severe end-stage renal disease (eGFR < 30 ml/min/1.73 m2 ) at 1 year post-transplant compared to LTA (9.5% vs. 5.7%, P = 0.001). Patient and graft survival benefit for patients on RRT at transplantation was favouring CLKT versus LTA (P = 0.038 and P = 0.018, respectively) but the renal function of the long-term survivors was not superior following CLKT. The data does not support CLKT approach based on eGFR alone, and the advantage of CLKT appear to benefit only those who are on established RRT at the time of transplant.

Fluctuations of Estimated Glomerular Filtration Rate Outside Kidney Disease Improving Global Outcomes Diagnostic Criteria for Acute Kidney Injury in End-Stage Liver Disease Outpatients and Outcome Postliver Transplantation.

BACKGROUND: Renal dysfunction in end-stage liver disease (ESLD) results from systemic conditions that affect both liver and kidney with activation of vasoconstrictor systems. In this setting, estimated glomerular filtration rate (eGFR) may undergo variations often outside Kidney Disease Improving Global Outcomes criteria for acute kidney injury (AKI) diagnosis, whose meaning is not clear. The aim of this study was to evaluate eGFR variations in ESLD outpatients listed for liver transplant (liver Tx) and the association with post-Tx outcome. METHODS: Fifty-one patients with ESLD were retrospectively evaluated from listing to transplant (L-Tx time), intraoperatively (Tx time), and up to 5 years post-Tx time. Variations between the highest and the lowest eGFR occurring in more than 48 hours, not satisfying Kidney Disease Improving Global Outcomes guideline, were considered as fluctuations (eGFR-F). Fluctuations of eGFR greater than 50% were defined as eGFR drops (DeGFR). Early graft dysfunction, AKI within 7 days, chronic kidney disease, and short- and long-term patient survivals were considered as outcomes. RESULTS: All patients presented eGFR-F, whereas DeGFR were observed in 18 (35.3%) of 51 (DeGFR+ group). These patients presented higher levels of Model for End-stage Liver Disease score, pre-Tx bilirubin and significantly greater incidence of post-Tx AKI stages 2 to 3 compared with patients without drops (DeGFR-). DeGFR was the only independent predictive factor of the occurrence of post-Tx AKI. The occurrence of AKI post-Tx was associated with the development of chronic kidney disease at 3 months and 5 years post-Tx. CONCLUSIONS: Drops of eGFR are more frequently observed in patients with a worse degree of ESLD and are associated with a worse post-Tx kidney outcome.

The Impact of Combined Warm Ischemia Time on Development of Acute Kidney Injury in Donation After Circulatory Death Liver Transplantation: Stay Within the Golden Hour.

BACKGROUND: Acute kidney injury (AKI) is a common complication after liver transplantation and more frequently observed when high-risk grafts, such as donation after circulatory death (DCD) grafts are used. Our aim was to investigate the impact of the ischemia periods on development of AKI in DCD liver transplantation. METHODS: We performed a 2-center retrospective study with 368 DCD graft-recipients. Donor warm ischemia time (DWIT) was divided into agonal phase (withdrawal of life support-cardiac arrest) and asystolic phase (cardiac arrest-start cold perfusion). We introduced a new period of warm ischemia: the combined warm ischemia time (combined WIT), which was defined as the sum of DWIT and recipient WIT. RESULTS: AKI was observed in 65% of the recipients and severe AKI in 41% (KDIGO stage 2/3). The length of combined WIT increased significantly with AKI severity: 61 minutes in recipients without AKI up to 69 minutes in recipients with the most severe form of AKI (P < 0.001). On multivariable analysis, increasing duration of the combined WIT was associated with an increased risk of developing severe AKI (odds ratio, 1.032 per every extra minute; 95% confidence interval, 1.014-1.051; P < 0.001). No relation was observed between length of cold ischemia time and severe AKI. CONCLUSIONS: Combined WIT is a newly defined period of warm ischemia in DCD liver transplantation. Length of combined WIT is associated with severity of postoperative AKI and should ideally not exceed 60 minutes.

Acute kidney injury and post-reperfusion syndrome in liver transplantation.

In the past decades liver transplantation (LT) has become the treatment of choice for patients with end stage liver disease (ESLD). The chronic shortage of cadaveric organs for transplantation led to the utilization of a greater number of marginal donors such as older donors or donors after circulatory death (DCD). The improved survival of transplanted patients has increased the frequency of long-term complications, in particular chronic kidney disease (CKD). Acute kidney injury (AKI) post-LT has been recently recognized as an important risk factor for the occurrence of de novo CKD in the long-term outcome. The onset of AKI post-LT is multifactorial, with pre-LT risk factors involved, including higher Model for End-stage Liver Disease score, more sever ESLD and pre-existing renal dysfunction, either with intra-operative conditions, in particular ischaemia reperfusion injury responsible for post-reperfusion syndrome (PRS) that can influence recipient's morbidity and mortality. Post-reperfusion syndrome-induced AKI is an important complication post-LT that characterizes kidney involvement caused by PRS with mechanisms not clearly understood and implication on graft and patient survival. Since pre-LT risk factors may influence intra-operative events responsible for PRS-induced AKI, we aim to consider all the relevant aspects involved in PRS-induced AKI in the setting of LT and to identify all studies that better clarified the specific mechanisms linking PRS and AKI. A PubMed search was conducted using the terms liver transplantation AND acute kidney injury; liver transplantation AND post-reperfusion syndrome; acute kidney injury AND post-reperfusion syndrome; acute kidney injury AND DCD AND liver transplantation. Five hundred seventy four articles were retrieved on PubMed search. Results were limited to title/abstract of English-language articles published between 2000 and 2015. Twenty-three studies were identified that specifically evaluated incidence, risk factors and outcome for patients developing PRS-induced AKI in liver transplantation. In order to identify intra-operative risk factors/mechanisms specifically involved in PRS-induced AKI, avoiding confounding factors, we have limited our study to "acute kidney injury AND DCD AND liver transplantation". Accordingly, three out of five studies were selected for our purpose.

Different behaviour of BK-virus infection in liver transplant recipients.

Polyomavirus BK (BKV) infects up to 90% of the general population. After primary infection, occurring early during childhood, a state of non-replicative infection is established in the reno-urinary tract, without complications for immunocompetent hosts. In immunocompromised individuals, particularly transplanted patients, asymptomatic BKV viremia and/or viruria can be observed. Renal grafts may also be sources of infection as BKV prefers kidneys rather than other solid organs for transplantation such as the liver. The mechanism behind the higher incidence of BKV infection in kidney transplant patients, compared to liver or heart transplantation, is unclear and the prevalence of BKV infection in non-renal solid organ transplants has not been yet thoroughly investigated. We evaluated the prevalence of Polyomavirus BK infection among liver transplant recipients. A PubMed search was conducted using the terms BKV infection AND liver transplant recipients; BKV AND non-renal solid organ transplant*; BKV infection AND immunosuppression; the search was limited to title/abstract and English-language articles published from 2000, to March 2015. Eleven relevant studies suggest that the prevalence of BKV viruria and/or viremia among liver transplant recipients is less than that reported in kidney or heart transplant recipients, except when chronic kidney disease (CKD) is present at the same time. Data also suggest that viruric and viremic patients have higher levels of serum creatinine than BKV negative patients. Moreover, no specific immunosuppressive drugs are associated with the onset of BKV nephropathy. The comorbidity of transplantation and CKD could play a major role in promoting BKV replication.

Recent advances in pathophysiology and biomarkers of sepsis-induced acute kidney injury.

Sepsis is a complex clinical syndrome characterized by a systemic inflammatory response to an infective insult. This process often leads to widespread tissue injury and multiple organ dysfunction. In particular, the development of acute kidney injury (AKI) is one of the most frequent complications, which increases the complexity and cost of care, and is an independent risk factor for mortality. Previous suggestions highlighting systemic hypotension, renal vasoconstriction and ischaemia-reperfusion injury as the primary pathophysiological mechanisms involved in sepsis-induced AKI have been challenged. Recently it has been shown that sepsis-induced AKI occurs in the setting of microvascular dysfunction with release of microparticles, inflammation and energetic adaptation of highly metabolic organs to cellular stress. The intolerable high mortality rate associated with sepsis-induced AKI is partially explained by an incomplete understanding of its pathophysiology and a delay in diagnosis. The aim of this review is to focus on advances in understanding the sepsis pathophysiology, with particular attention to the fundamental mechanisms of sepsis-induced AKI and the potential diagnostic and prognostic markers involved.

Role of BK virus infection in end-stage renal disease patients waiting for kidney transplantation--viral replication dynamics from pre- to post-transplant.

We report the prevalence of BK virus (BKV) infection before renal transplantation and the dynamics of BKV viremia from pre- to post-transplantation. We assessed 60 kidney transplanted patients from a single cohort in Italy, treated with identical immunosuppressive therapy, for BK viremia at pre-transplantation, 12 h, and three and six months post-transplantation. Polymerase chain reaction showed that the prevalence of plasma BKV replication--considered a marker of infection--was 20% in pre-transplant patients. All pre-transplant-positive patients remained positive post-transplant, whereas the majority of pre-transplant-negative patients remained negative. Viremia dynamics classification revealed three clusters of patients: Cluster A++, pre-transplant-positive patients (20%) who tested positive at least once post-transplant; Cluster B-+, pre-transplant-negative patients (28%) who tested positive at least once post-transplant; and Cluster C- -, pre-transplant-negative patients (52%) who remained negative throughout. These clusters presented significant differences related to the prevalence of substantially positive patients with high plasma viral load (>10(3) copies/mL) in cluster A, but not in donors' or grafts' characteristics. We suggest that pre-transplant viral status should be considered as an additional risk factor for post-transplant BKV replication. Therefore, pre-transplant BKV infection screening in kidney transplant patients should be performed for improving planning of personalized immunosuppressant schemes and specific post-transplant surveillance.

Possible antiviral effect of ciprofloxacin treatment on polyomavirus BK replication and analysis of non-coding control region sequences.

Acute renal dysfunction (ARD) is a common complication in renal transplant recipients. Multiple factors contribute to ARD development, including acute rejection and microbial infections. Many viral infections after kidney transplantation result from reactivation of "latent" viruses in the host or from the graft, such as the human Polyomavirus BK (BKV). We report the case of a 39 year-old recipient of a 2nd kidney graft who experienced BKV reactivation after a second episode of acute humoral rejection. A 10-day treatment with the quinolone antibiotic ciprofloxacin was administered with an increase of immunosuppressive therapy despite the active BKV replication. Real Time PCR analysis performed after treatment with ciprofloxacin, unexpectedly showed clearance of BK viremia and regression of BK viruria. During the follow-up, BK viremia persisted undetectable while viruria decreased further and disappeared after 3 months.BKV non-coding control region sequence analysis from all positive samples always showed the presence of archetypal sequences, with two single-nucleotide substitutions and one nucleotide deletion that, interestingly, were all representative of the subtype/subgroup I/b-1 we identified by the viral protein 1 sequencing analysis.We report the potential effect of the quinolone antibiotic ciprofloxacin in the decrease of the BKV load in both blood and urine.