Anja Bienholz

From the nephrologist's point of view: diversity of causes and clinical features of acute kidney injury

Acute kidney injury (AKI) is a clinical syndrome with multiple entities. Although AKI implies renal damage, functional impairment or both, diagnosis is solely based on the functional parameters of serum creatinine and urine output. The latest definition was provided by the Kidney Disease Improving Global Outcomes (KDIGO) working group in 2012. Independent of the underlying disease, and even in the case of full recovery, AKI is associated with an increased morbidity and mortality. Awareness of the patients individual risk profile and the diversity of causes and clinical features of AKI is pivotal for optimization of prophylaxes, diagnosis and therapy of each form of AKI. A differentiated and individualized approach is required to improve patient mortality, morbidity, long-term kidney function and eventually the quality of life. In this review, we provide an overview of the different clinical settings in which specific forms of AKI may occur and point out possible diagnostic as well as therapeutic approaches. Secifically AKI is discussed in the context of non-kidney organ failure, organ transplantation, sepsis, malignancy and autoimmune disease.

Successful treatment of chronic hepatitis C virus infection with sofosbuvir and ledipasvir in renal transplant recipients

Background Treatment of chronic hepatitis C virus (HCV) infection after renal allograft transplantation has been an obstacle because of contraindications associated with IFN-based therapies. Direct-acting antiviral agents are highly efficient treatment options that do not require IFN and may not require ribavirin. Therefore, we assessed the efficacy and safety of sofosbuvir and ledipasvir in renal transplant patients with chronic HCV infection. Methods Fifteen renal allograft recipients with therapy-naive HCV genotype (GT) 1a, 1b, or 4 were treated with the combination of sofosbuvir and ledipasvir without ribavirin for 8 or 12 weeks. Clinical data were retrospectively analyzed for viral kinetics and for renal and liver function parameters. Patients were closely monitored for trough levels of immunosuppressive agents, laboratory values, and potential adverse effects. Results Ten patients (66%) exhibited a rapid virologic response within 4 weeks (HCV GT1a, n = 4; HCV GT1b, n = 6). The other 5 patients exhibited a virologic response within 8 (HCV GT 1b, n = 4) or 12 weeks (HCV GT4, n = 1). One hundred percent of patients exhibited sustained virologic response at week 12 after the end of treatment. Clinical measures of liver function improved substantially for all patients. Adverse events were scarce; renal transplant function and proteinuria remained stable. Importantly, dose adjustments for tacrolimus were necessary for maintaining sufficient trough levels. Conclusions The described regimen appears to be safe and effective for patients after renal transplant and is a promising treatment regimen for eradicating HCV in this patient population.

Urinary neutrophil gelatinase-associated lipocalin (NGAL) for the detection of acute kidney injury after orthotopic liver transplantation

Acute kidney injury (AKI) is a frequent complication after orthotopic liver transplantation (OLT). The incidence of post-operative AKI according to acute kidney injury network criteria can be estimated to be as high as 60% of all patients after liver transplantation [1–3]. Besides increasing morbidity and length of hospitalization, graft survival is significantly reduced, even with only modest increase of serum creatinine (> 0.5 mg/dL, AKIN Stage 1) [3, 4]. Postoperative AKI is also an independent risk factor for mortality during the first year after transplantation [1]. The development of AKI following liver transplantation is multifactorial and influenced by numerous pre-, intraand post-operative factors. During the preoperative period, conditions predisposing for post-operative AKI can be present. The most commonly observed preoperative renal dysfunction is due to the hepato-renal syndrome characterized by arterial vasodilatation mainly in the splanchnic vessel area and severe renal vasoconstriction. Intraoperative factors include long periods of vascular crossclamping, hypotension, high doses of vasopressors and large volume load. Post-operative hypotension and calcineurin inhibitors such as cyclosporine and tacrolimus also support conditions potentially culminating in AKI [4]. Currently, there are no effective measures or treatment strategies available for the prevention or treatment of AKI. The development of effective interventions is hampered by the limited ability of early detection of AKI [5, 6]. In order to develop and evaluate strategies for the prevention and treatment of AKI, there is a great need for early biomarkers. In this issue of Nephrology Dialysis Transplantation, Wagener et al. [7] propose increased urinary neutrophil gelatinase-associated lipocalin (NGAL)/creatinine ratio as an early predictor of AKI following OLT. The data source is a prospective cohort study of 92 patients undergoing OLT at a single centre between 2008 and 2010 (18 living related, 74 deceased). Patients underwent OLT for different reasons (hepatitis C, hepatitis B, nutritive toxic liver cirrhosis, primary sclerosing cholangitis) and showed a modified end stage liver disease score of 21.9 7.4 prior to surgery. Patients did not require renal replacement therapy preoperatively and apparently had intact kidney function according to the serum creatinine (0.99 0.64 mg/dL). Urine samples were collected after induction of anaesthesia prior to incision, immediately after portal reperfusion of the liver graft and then 3, 18 and 24 h later. To compensate for possible urinary dilution or concentration, the results of the NGAL measurements are given as urinary NGAL/creatinine ratio. AKI was defined according to the RIFLE criteria by an increased serum creatinine of >150% after OLT compared to preoperative values. Thirty-seven patients (40.2%) developed AKI during the post-operative period. In those patients, serum creatinine concentration significantly increased at Day 2 after transplantation, whereas urinary NGAL/creatinine ratio already showed a significant increase after 3 h. According to the study, there is a diagnostic benefit of ~2 days using urinary NGAL compared to serum creatinine for the diagnosis of AKI after OLT. Interestingly, in patients with AKI, NGAL already declined between 3 and 18 h after OLT and there was no significant difference between the AKI and nonAKI group after 24 h. This time course suggests that the increase in urinary NGAL/creatinine is specific for the kidney injury during OLT. Just before transplantation, and immediately after reperfusion, there were no differences in urinary NGAL/creatinine concentration between patients with AKI and those without AKI. The investigators conclude that urinary NGAL/creatinine ratio is an early marker of AKI after liver transplantation, which, because of its high sensitivity and specificity, might be a useful surrogate end point of AKI in clinical trials. Urinary NGAL might be a more sensitive marker for AKI, especially in patients after liver transplantation, than serum creatinine because unlike serum creatinine, it is not dependent on drugs, muscle mass or liver metabolism [8]. Urinary NGAL is mainly produced by the distal nephron after injury and is immediately secreted into the urine. In contrast, plasma NGAL is a product of multiple sources. Nevertheless, AKI also triggers increasing amounts of messenger RNA in other tissues than the distal nephron including liver and lung [9]. This might explain why both urinary and plasma NGAL proved to be reliable markers for AKI in children after cardiac surgery with an AUC–ROC of >0.9 [14]. But also in patients with AKI after liver transplantation, it was shown to be of benefit. In a prospective study of

Adverse effects of α-ketoglutarate/malate in a rat model of acute kidney injury

Acute kidney injury (AKI) is the most common kidney disease in hospitalized patients with high mortality. Ischemia and reperfusion (I/R) is one of the major causes of AKI. The combination of α-ketoglutarate+malate (αKG/MAL) showed the ability to reduce hypoxia-induced damage to isolated proximal tubules. The present study utilizes a rat model of I/R-induced AKI accompanied by intensive biomonitoring to examine whether αKG/MAL provides protection in vivo. AKI was induced in male Sprague-Dawley rats by bilateral renal clamping (40 min) followed by reperfusion (240 min). αKG/MAL was infused continuously for 60 min before and 45 min after ischemia. Normoxic and I/R control groups received 0.9% NaCl solution. The effect of αKG/MAL was evaluated by biomonitoring, blood and plasma parameters, histopathology, and immunohistochemical staining for kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), as well as by determination of tissue ATP and nonesterified fatty acid concentrations. Intravenous infusion of αKG/MAL at a cumulative dose of 1 mmol/kg each (146 mg/kg αKG and 134 mg/kg MAL) did not prevent I/R-induced increases in plasma creatinine, histopathological alterations, or cortical ATP depletion. On the contrary, the most notable adverse affect in animals receiving αKG/MAL was the decrease in mean arterial blood pressure, which was also accompanied by a reduction in heart rate. Supplementation with αKG/MAL, which is very protective against hypoxia-induced injury in isolated proximal tubules, does not protect against I/R-induced renal injury in vivo, possibly due to cardiovascular depressive effects.

Susceptibility of HLA-E*01:03 Allele Carriers to Develop Cytomegalovirus Replication After Living-Donor Kidney Transplantation

Cytomegalovirus (CMV) causes serious complications among solid organ transplant recipients. We report the positive correlation between the presence of the HLA-E*01:03 allele in living-donor kidney recipients and CMV reactivation during the first year after transplantation. Thus, HLA-E genotyping may help identify CMV replication-prone patients who require individualized patient-based CMV management.

Association of high HLA-E expression during acute cellular rejection and numbers of HLA class I leader peptide mismatches with reduced renal allograft survival

Non-classical Human Leukocyte Antigen (HLA)-E preferentially presents leader peptides derived from classical HLA-class I molecules. HLA-E can trigger opposed immune responses by interacting with inhibitory NKG2A or by activating NKG2C receptors on NK and T-cells. We studied the impact of HLA-E on renal allograft survival during acute cellular rejection. HLA-E expression was up-regulated in acute cellular rejection (ACR) biopsies (n=12) compared to biopsies from 13 renal allografts with no rejection-signs. HLA-E up-regulation was correlated with numbers of HLA-class I leader peptide mismatches (p=0.04). CD8+ and CD56+ infiltrating cells correlated with HLA-E expression (p<0.0001 and p=0.0009, respectively). Activating NKG2C receptor dominated on effector cells in biopsies and peripheral blood during ACR potentially allowing HLA-E-mediated immune activation. Moreover, HLA-E expression correlated with deterioration in renal allograft function (p<0.008) and reduced allograft survival (p=0.002). Our findings provide evidence that during renal allograft rejection HLA-E along with high numbers of mismatched HLA-class I leader peptides might represent additional targets for immune-activating responses.

Characterization of injury in isolated rat proximal tubules during cold incubation and rewarming

Organ shortage leads to an increased utilization of marginal organs which are particularly sensitive to storage-associated damage. Cold incubation and rewarming-induced injury is iron-dependent in many cell types. In addition, a chloride-dependent component of injury has been described. This work examines the injury induced by cold incubation and rewarming in isolated rat renal proximal tubules. The tissue storage solution TiProtec® and a chloride-poor modification, each with and without iron chelators, were used for cold incubation. Incubation was performed 4°C for up to 168 h, followed by rewarming in an extracellular buffer (3 h at 37°C). After 48, 120 and 168 h of cold incubation LDH release was lower in solutions containing iron chelators. After rewarming, injury increased especially after cold incubation in chelator-free solutions. Without addition of iron chelators LDH release showed a tendency to be higher in chloride-poor solutions. Following rewarming after 48 h of cold incubation lipid peroxidation was significantly decreased and metabolic activity was tendentially better in tubules incubated with iron chelators. Morphological alterations included mitochondrial swelling and fragmentation being partially reversible during rewarming. ATP content was better preserved in chloride-rich solutions. During rewarming, there was a further decline of ATP content in the so far best conditions and minor alterations under the other conditions, while oxygen consumption was not significantly different compared to non-stored control tubules. Results show an iron-dependent component of preservation injury during cold incubation and rewarming in rat proximal renal tubules and reveal a benefit of chloride for the maintenance of tubular energy state during cold incubation.

Transfemoral transcatheter aortic valve implantation in patients with end-stage renal disease and kidney transplant recipients

Transcatheter aortic valve implantation (TAVI) has evolved to a treatment of choice in high-risk patients and is therefore ideal for patients with advanced chronic kidney disease, as patients with end-stage renal disease and kidney transplant recipients. Especially, outcome of this special patient group is very important. 22 patients with chronic kidney disease stage 5 undergoing intermittent hemodialysis treatment (CKD 5D) and 8 kidney transplant recipients (KT) with severe aortic valve stenosis underwent transfemoral TAVI. TAVI was successfully performed in all patients. Postinterventional acute kidney injury (AKI) occurred in four kidney transplant recipients (KDIGO grade 1: n = 3, grade 3: n = 1) but creatinine/eGFR returned to baseline values in all patients. Short-term (30-day) mortality was 3% (1 patient in CKD 5D group). KT had a higher 2-year mortality than CKD5D patients (31% vs. 53%; p = 0.309), and cause of death was non-cardiac because of sepsis in all cases. The amount of contrast medium during TAVI was not associated with the development of acute kidney injury. TAVI is feasible in patients with CKD5D and in KT. Postinterventional AKI in these patients is often mild and does not impact renal function at day 30, while infection/ sepsis is the leading cause of mid-term mortality.

Acute kidney injury in liver transplant candidates: a position paper on behalf of the LIVER INTENSIVE CARE GROUP of EUROPE.

INTRODUCTION Acute kidney injury is associated with high mortality in the perioperative period of liver transplantation. The aim of this position paper was to provide an up-to-date overview with special emphases on diagnosis, risk factors, and treatment. EVIDENCE ACQUISITION The Liver Intensive Care Group of Europe nominated a panel of recognized international experts who reviewed the available literature published from 1990 to January 2016 and produced clinical recommendations. The level of evidence and strength of recommendation were judged according to the Grading of Recommendations Assessment Development and Evaluation system. EVIDENCE SYNTHESIS Diagnosis of AKI should be based on the KDIGO criteria. The preoperative risk factors are more related to the patients predisposing factors and post-operative risk factors tend to be difficult to control. Therefore, focusing on intra-operative risk factors it would be important to maintain an adequate hemodynamics and to keep inferior vena cava clamping as short as possible. Biomarkers to identify AKI at an early stage are available; however, there is a lack of robust data that indicates their true beneficial effect. Intraoperative renal replacement therapy may be beneficial in some selective cases whereas its postoperative timing is still under debate. CONCLUSIONS Perioperative liver transplant risk factors for acute kidney injury are difficult to control. Therefore, the focus should be on intra-operative hemodynamics and nephrotoxic drugs avoidance. Prospective randomized trials are needed to show the beneficial effect of early replacement therapy. In this context, the new biomarkers would be helpful in identifying kidney injury earlier.

Recipient HLA-G +3142 CC Genotype and Concentrations of Soluble HLA-G Impact on Occurrence of CMV Infection after Living-Donor Kidney Transplantation

The expression modulation of the immunosuppressive non-classical Human leukocyte antigen-G (HLA-G) molecule and its soluble isoforms is an immune evasion strategy being deployed by cytomegalovirus (CMV). The +3142 C>G single nucleotide polymorphism (SNP) located within the 3′ untranslated region (3′UTR) is of crucial importance for the regulation of HLA-G expression. Therefore, we analyzed the influence of the +3142 C>G HLA-G SNP on the occurrence of CMV infection in a cohort of 178 living-donor kidney recipients and their 178 corresponding donors. In addition, soluble HLA-G (sHLA-G) levels were quantified before and after transplantation. The presence of the HLA-G +3142 CC genotype in recipients, but not donors of our cohort as along with elevated sHLA-G levels (≥6.1 ng/mL) were associated with higher susceptibility to CMV infection after transplantation. Our results provided evidence that (i) HLA-G is implicated in the establishment of CMV after living-donor kidney transplantation and (ii) recipient HLA-G +3142 CC genotype and sHLA-G concentration levels could represent important predictive risk markers for CMV infection.