Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: The usefulness of measures of neutrophil gelatinase-associated lipocalin (NGAL) in urine or plasma obtained on clinical laboratory platforms for predicting acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) has not been fully evaluated. We sought to quantitatively summarize published data to evaluate the value of urinary and plasma NGAL for kidney risk prediction. STUDY DESIGN: Literature-based meta-analysis and individual-study-data meta-analysis of diagnostic studies following PRISMA-IPD guidelines. SETTING & STUDY POPULATIONS: Studies of adults investigating AKI, severe AKI, and AKI-D in the setting of cardiac surgery, intensive care, or emergency department care using either urinary or plasma NGAL measured on clinical laboratory platforms. SELECTION CRITERIA FOR STUDIES: PubMed, Web of Science, Cochrane Library, Scopus, and congress abstracts ever published through February 2020 reporting diagnostic test studies of NGAL measured on clinical laboratory platforms to predict AKI. DATA EXTRACTION: Individual-study-data meta-analysis was accomplished by giving authors data specifications tailored to their studies and requesting standardized patient-level data analysis. ANALYTICAL APPROACH: Individual-study-data meta-analysis used a bivariate time-to-event model for interval-censored data from which discriminative ability (AUC) was characterized. NGAL cutoff concentrations at 95% sensitivity, 95% specificity, and optimal sensitivity and specificity were also estimated. Models incorporated as confounders the clinical setting and use versus nonuse of urine output as a criterion for AKI. A literature-based meta-analysis was also performed for all published studies including those for which the authors were unable to provide individual-study data analyses. RESULTS: We included 52 observational studies involving 13,040 patients. We analyzed 30 data sets for the individual-study-data meta-analysis. For AKI, severe AKI, and AKI-D, numbers of events were 837, 304, and 103 for analyses of urinary NGAL, respectively; these values were 705, 271, and 178 for analyses of plasma NGAL. Discriminative performance was similar in both meta-analyses. Individual-study-data meta-analysis AUCs for urinary NGAL were 0.75 (95% CI, 0.73-0.76) and 0.80 (95% CI, 0.79-0.81) for severe AKI and AKI-D, respectively; for plasma NGAL, the corresponding AUCs were 0.80 (95% CI, 0.79-0.81) and 0.86 (95% CI, 0.84-0.86). Cutoff concentrations at 95% specificity for urinary NGAL were>580ng/mL with 27% sensitivity for severe AKI and>589ng/mL with 24% sensitivity for AKI-D. Corresponding cutoffs for plasma NGAL were>364ng/mL with 44% sensitivity and>546ng/mL with 26% sensitivity, respectively. LIMITATIONS: Practice variability in initiation of dialysis. Imperfect harmonization of data across studies. CONCLUSIONS: Urinary and plasma NGAL concentrations may identify patients at high risk for AKI in clinical research and practice. The cutoff concentrations reported in this study require prospective evaluation.

Relative Adrenal Insufficiency is Associated with the Clinical Outcome in Patients with Stable Decompensated Cirrhosis.

BACKGROUND: The clinical impact of relative adrenal insufficiency (AI) on patients with stable decompensated cirrhosis (DeCi) has not been yet elucidated. AIM: Explore the association between AI and outcome [death or liver transplantation (LT)] in patients with DeCi. MATERIAL AND METHODS: Patients with DeCi presenting no active complication have been included. Clinical and laboratory data, including serum levels of corticosteroid-binding globulin (CBG), interleukin (IL)-1b, IL-6 and tumor necrosis factor (TNFα) were recorded in each participant. Salivary cortisol (SC) and serum total cortisol (STC) were assessed at (T0) and 1 h (T60) after intravenous injection of 250 µg corticotropin. RESULTS: 113 consecutive patients were totally tested. Median SC was 3.9 ng/mL and 15.5 ng/mL and median STC was 10.7 µg/dL and 22.7 µg/dL at T0 and T60 respectively. The patients with AI [group 1, n = 34 (30%)] had significantly lower systolic blood pressure (106 ± 12 vs. 113 ± 13 mmHg, p = 0.05), serum sodium (133 ± 7 vs. 137 ± 12 mEq/ L, p = 0.04), HDL (29.9 ± 14 vs. 38.6 ± 18 mg/dL, p = 0.034) and albumin (2.7 ± 0.5 vs. 3.1 ± 0.5 g/dL, p = 0.002), but higher direct bilirubin (median: 1.6 vs. 0.8 mg/dL, p = 0.029) compared to those without AI [group 2, n = 79 (70%)]. Moreover, group 1 patients presented more frequently past history of spontaneous bacterial peritonitis (SBP) [10/34 (29.4%) vs. 6/79 (7.5%), p = 0.002]. AI was significantly associated with death [HR = 2.65, 95% C.I.: 1.55 - 4.52, p = 0.003 over a follow up period of 12 (6-48) months.] Conclusions. The presence of AI in patients with stable DeCi predispose to obvious clinical implications since it is associated with circulatory dysfunction, previous history of SBP and worse survival.

Microcirculatory alterations during continuous renal replacement therapy in ICU: A novel view on the 'dialysis trauma' concept.

OBJECTIVE: The purpose of this study was to evaluate microcirculation over 24 h renal replacement therapy (CRRT) in critically ill patients. METHODS: We conducted a single-center, prospective, observational study, measuring microcirculation parameters, monitored by near infrared spectroscopy (NIRS) before hemodiafiltration onset (H0), and at six (H6) and 24 h (H24) during CRRT in critically ill patients. Serum Cystatin C (sCysC) and soluble (s)E-selectin levels were measured at the same time points. Twenty-eight patients [19 men (68%)] were included in the study. RESULTS: Tissue oxygen saturation (StO2, %) [76.5 ± 12.5 (H0) vs 75 ± 11 (H6) vs 70 ± 16 (H24), p = 0.04], reperfusion rate, indicating endothelial function (EF, %/sec) [2.25 ± 1.44 (H0) vs 2.1 ± 1.8 (H6) vs 1.6 ± 1.4 (H24), p = 0.02] and sCysC (mg/L) [2.7 ± 0.8 (H0) vs 2.2 ± 0.6 (H6) vs 1.8 ± 0.8 (H24), p < 0.0001] significantly decreased within the 24 h CRRT. Change of EF positively correlated with changes of sCysC within 24 h CRRT (r = 0.464, p = 0.013) while in patients with diabetes the change of StO2 correlated with dose (r = − 0.8, p = 0.01). No correlation existed between hemoglobin and temperature changes with the deteriorated microcirculation indices. sE-Selectin levels in serum were elevated; no difference was established over the 24 h CRRT period. A strong correlation existed between the sE-Selectin concentration change at H6 and H24 and the mean arterial pressure change in the same period (r = 0.77, p < 0.001). CONCLUSIONS: During the first 24 h of CRRT implementation in critically ill patients, deterioration of microcirculation parameters was noted. Microcirculatory alterations correlated with sCysC changes and with dose in patients with diabetes.

Caregivers' experience in patients with chronic diseases.

The aim of this study was to describe the characteristics of caregivers of patients with chronic diseases, assess their perceived burden, and investigate factors influencing this burden. Seventy-three patient-attendants (43 men and 30 women) participated in the pilot-research conducted by two clinics. Of them, 68% attended patients with a malignant disease and 32% attended patients in the end stage of renal disease. Based on questionnaire data, the influence of the social support was studied, in particular that of family members or through state programmers. Family members are the primary caregivers (spouses 51%, children 29%, and others 20%). Psychological support is the main important help that they need and there are a small number of caregivers who have access to a network of medical and social support. It is found that the family still remains the main supporting mechanism for attendants and patients in our population.

Treatment of hepatitis B in patients with chronic kidney disease.

Although the prevalence of chronic hepatitis B virus (HBV) infection in patients with chronic kidney disease remains low in developed countries, clinicians should be aware of the rationale for treatment in this setting. This patient population presents particular features and various complicating conditions requiring special treatment strategies. Interferon, the standard treatment for HBV infection, has been poorly tolerated by patients with chronic kidney disease, has presented relatively low efficacy, and has posed renal transplant recipients under the risk of acute rejection. The advent of effective nucleos(t)ide analogs (NAs) has offered the opportunity to minimize the consequences of HBV infection in HBV-positive patients with chronic kidney disease. Combination with immunosuppressive agents might be considered in cases of rapid renal function deterioration and/or severe proteinuria. Among the newer NAs, entecavir may be preferred, because of its high potency, high genetic barrier to resistance, and favorable renal safety profile. However, entecavir presented low efficacy in case of lamivudine or telbivudine resistance, and thus tenofovir may be a better option in that setting. All HBsAg-positive candidates should be treated with NAs before renal transplantation in order to maintain undetectable HBV DNA, reduce liver fibrosis, and prevent hepatic decompensation after renal transplantation. This review summarizes updated issues related to treatment of chronic HBV infection in all categories of population with chronic kidney disease (those exhibiting HBV-associated glomerular disease, those treated with hemodialysis, as well as renal transplant candidates, donors, and recipients).

Novel biomarkers of acute kidney injury in the general adult ICU: a review.

Acute kidney injury is one of the most frequent problems occurring in the critically ill patients of the intensive care units and it is well established that it increases both morbidity and mortality in these patients. Moreover, despite technological and pharmaceutical advances during the last decades, the incidence as well as the mortality associated with acute kidney injury in these patients remains unchanged. Creatinine, the most common renal dysfunction biomarker in use, has many disadvantages, such as time delay in its increase and the influence by other factors on its serum concentration, such as age, gender, muscle mass, etc. Hence, the need for better renal biomarkers in order to timely intervene for acute kidney injury prevention is imperative. The lack of an early biomarker is an obstacle for the development of new acute kidney injury prevention strategies. With the incidence of acute kidney injury reaching epidemic dimensions, the need for novel markers is urgent. During the last years, the research for finding such biomarkers has been intense. The purpose of the present article is to review the studies which have tested the predictive ability of those markers (in urine and/or plasma) for early detection of acute kidney injury in the mixed adult intensive care unit population and underline the potential limitations encountered in the various studies.

Intensification of peritoneal dialysis improves valacyclovir neurotoxicity.

Valacyclovir induced neurotoxicity is a life-threatening complication, usually starting 24-48 h after drug-peak serum concentrations. The elderly with impaired renal function seem to be the most susceptible group to valacyclovir neurotoxicity. Although hemodialysis is considered the best method for rapid drug removal, our case showed that intensive peritoneal dialysis regimen leads to the recovery of neurotoxicity after 3 days.

Vitamin D status in patients with recurrent kidney stones.

Data regarding the prevalence of 25-hydroxyvitamin D (25(OH)D) insufficiency in patients with nephrolithiasis, and the effects of vitamin D supplementation on parathyroid hormone (PTH) are few and conflicting. In this article, we examined the prevalence of vitamin D insufficiency and deficiency in 236 recurrent kidney stone formers and the correlation of vitamin D levels with other parameters of stone formation. The prevalent stone composition was calcium oxalate (80.4%) and uric acid (16.45%). One third of stone formers had vitamin D insufficiency and a quarter of them high PTH levels (PTH >7.5 pmol/l) with normal serum (total and ionized) calcium values. Predictor of high PTH was low 25(OH)D level (r = 0.989, r(2) = 0.977, p < 0.001). Stone formers with hypercalciuria had higher 25(OH)D values (72.26 ± 4.21 vs. 59.29 ± 1.76, p = 0.0013) compared to stone formers with urine calcium within normal ranges. Further studies are needed in order to better define the consequences of vitamin D insufficiency and to evaluate the impact of the therapeutic interventions in this cohort.

Normocalcemic hyperparathyroidism in patients with recurrent kidney stones: a disease entity or vitamin D deficiency?

This retrospective data analysis was undertaken to examine the biochemical differences between renal stone formers with normocalcemic hyperparathyroidism (NHPT) and those with normal parathyroid hormone (PTH) levels. Our goal was to ascertain whether 25-hydroxyvitamin D (25(OH)D) status related to PTH levels in this patient cohort. Our findings among 74 patients with NHPT indicate that stone formers with NHPT had significantly lower 25(OH)D levels compared to 192 controls (p = 0.0001) and that 25(OH)D is positively correlated with 1,25-dihydroxyvitamin D values (R = 0.736, p = 0.015). Sequential measurements (after 3 - 5 years), among 11 patients with NHPT who did not receive vitamin D (VitD) preparations, showed a significant increase in urinary calcium (3.43 ± 1.96 vs. 5.72 ± 3.95, p = 0.0426) without a significant change in PTH levels. VitD supplementation, to 3 patients resulted in significant PTH decrease (11.8 ± 1.8 vs. 9.8 ± 1.3, p = 0.003). Prospective studies are needed to confirm the role of vitamin supplementation in renal stone formers with NHPT.

Hemolytic-uremic syndrome, malignant hypertension and IgA nephropathy: successful treatment with plasma exchange therapy.

A young patient with hemolytic-uremic syndrome and malignant hypertension with serious deterioration of renal function is described whose biopsy specimen showed additional IgA mesangial deposits. The patient responded to steroid treatment and to plasma exchange therapy without the need of hemodialysis sessions. In the following years, he achieved clinical remission and his blood pressure was in normal ranges without any further complications. IgA glomerulonephritis is rarely associated to hemolytic-uremic syndrome and malignant hypertension, with only a few previously described cases. We present an overview of potential pathophysiological connections between these diseases.

Successful non-surgical treatment of perirenal haematoma after percutaneous renal artery angioplasty in a solitary kidney.

Renal artery angioplasty with stent placement represents an effective choice for correcting renal artery stenosis. However, if iatrogenic renal artery injury occurs, as in the case of solitary kidney, the risk of requiring chronic dialysis increases. This article reports the case of a patient with a solitary kidney, who underwent renal stenting and developed a retroperitoneal haematoma. The patient was managed conservatively and the perirenal haematoma resolved. Within the period of follow-up, the patient had maintained stable renal function with adequate blood pressure control.

Is there any association between IgA nephropathy, Crohn's disease and Helicobacter pylori infection?

A case of IgA nephropathy (IgAN) associated with Crohn's disease (CD) and preceded Helicobacter pylori (Hp) infection is described. Therapy with corticosteroids and azathioprine resulted in clinical improvement. The connection between IgAN and CD is well established, while tonsillar Hp is a potential antigen causative of IgAN. The three entities may reflect a common immunopathogenetic mechanism involving an IgA response to mucosal challenge.

Combination of renal biomarkers predicts acute kidney injury in critically ill adults.

OBJECTIVE: Most studies so far have focused on the performance of individual biomarkers to detect early acute kidney injury (AKI) in the adult intensive care unit (ICU) patients; however, they have not determined the predictive ability of their combinations. The aim of this study was to compare the predictive abilities of plasma neutrophil gelatinase-associated lipocalin (pNGAL), urine neutrophil gelatinase-associated lipocalin (uNGAL), plasma cystatin C (pCysC), serum creatinine (sCr), and their combinations in detecting AKI in an adult general ICU population. METHODS: A total of 100 consecutive ICU patients were included in the analysis. AKI was defined according to RIFLE criteria. Biomarker predictive abilities were evaluated by area under the curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: AKI occurred in 36% of patients 7 days post-admission. All three novel biomarkers as well as sCr had moderate predictive abilities for AKI occurrence. The most efficient combinations (pNGAL + sCr and pNGAL + uNGAL + sCr) were selected to participate in the subsequent analyses. Both combinations, when added to a reference clinical model, increased its AUC significantly (0.858, p = 0.04). Their NRI (0.78, p = 0.0002) was equal to that of pNGAL, but higher than that of the other three biomarkers, whereas their IDI was higher than that of any individual biomarker (0.23, p = 0.0001). Both combinations had better specificities, positive likelihood ratios, and positive predictive values than those of any individual biomarker. CONCLUSION: The biomarker combinations had better predictive characteristics compared with those of each biomarker alone.

Malassezia folliculitis presented as acneiform eruption after cetuximab administration.

Cetuximab, a new recombinant monoclonal antibody that inhibits the epidermal growth factor receptor (EGFR), is frequently associated with cutaneous reaction. A 85-year-old male with a diagnosis of adenocarcinoma of the right parotid gland referred to our department for persistent acneiform eruption on the face and trunk induced after cetuximab administration. Despite cetuximab discontinuation and administration of antibiotics as well as topical steroids, the skin lesions were persisted for several months. Interestingly, the pustules and the acneiform eruption showed significant improvement after a course of oral itraconazole. The latter was given when the microscopic examination of the pus obtained from the lesions revealed the presence of Malassezia folliculitis.

Is everolimus linked to metabolic syndrome in liver transplant recipients?

BACKGROUND: As the mortality rates after liver transplantation (LT) have been reduced, the attention has shifted to additional conditions which still compromise the quality of life and the survival of these patients, such as the post-LT metabolic syndrome (MS). In order to determine the prevalence and the factors associated with the post-LT MS, we carried out the present study. METHODS: One hundred and six LT recipients, after completing at least 1 year follow up after LT, were included in the study. Data on clinical, laboratory parameters and immunosuppressive therapy before and after LT were recorded. MS was defined as per current diagnostic criteria. RESULTS: MS was prevalent in 47.2% (50 of 106 patients) and was not associated with the LT indications and the time period after LT. Univariate analysis showed that history of diabetes mellitus before (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.046-9.918, p = 0.042) and after LT (OR 6.03, 95% CI 2.18-16.67, p = 0.001), the age at the time of baseline visit (OR 1.077, 95% CI 1.033-1.124, p = 0.001) and the everolimus-based immunosuppression (OR 1.23, 95% CI 1.003-1.33, p = 0.019) were significantly associated with MS. Notably, everolimus administration was the only factor independently associated with the presence of post-LT MS (OR 1.026, 95% CI 1.004-1.047, p = 0.019). More specifically, everolimus was linked to the presence of arterial hypertension (OR 1.02, 95% CI 1.0-1.03, p = 0.05) and hyperlipidemia (OR 2.87, 95% CI 1.28-6.56, p = 0.011). CONCLUSIONS: Our study demonstrated for the first time that everolimus was independently associated with post-LT MS. Nevertheless, more robust studies are required to confirm these findings.

Interferon-free regimens in patients with hepatitis C infection and renal dysfunction or kidney transplantation.

Treatment of patients with chronic kidney disease (CKD) and chronic hepatitis C (CHC) differs from that used in the general CHC population mostly when glomerular filtration rate (GFR) is below 30 mL/min, as sofosbuvir, the backbone of several current regimens, is officially contraindicated. Given that ribavirin free regimens are preferable in CKD, elbasvir/grazoprevir is offered in CHC patients with genotype 1 or 4 and ombitasvir/paritaprevir and dasabuvir in genotype 1b for 12 wk. Although regimens containing peginterferon with or without ribavirin are officially recommended for patients with CKD and genotype 2, 3, 5, 6, such regimens are rarely used because of their low efficacy and the poor safety and tolerance profile. In this setting, especially in the presence of advanced liver disease, sofosbuvir-based regimens are often used, despite sofosbuvir contraindication. It seems to have good overall safety with only 6% or 3.4% of CKD patients to discontinue therapy or develop serious adverse events without drug discontinuation. In addition, sustained virological response (SVR) rates with sofosbuvir based regimens in CKD patients appear to be comparable with SVR rates in patients with normal renal function. Treatment recommendations for kidney transplant recipients are the same with those for patients with CHC, taking into consideration potential drug-drug interactions and baseline GFR before treatment initiation. This review summarizes recent data on the current management of CHC in CKD patients highlighting their strengths and weaknesses and determining their usefulness in clinical practice.

Comparison of creatinine clearance estimates in subgroups based on Body Mass Index and albumin.

BACKGROUND: The establishment of accurate equations for glomerular filtration rate (GFR) estimations is still far from the realization. Factors such as age, diabetes, stage of CKD, pregnancy, muscle mass and ethic nation are associated with less reliance upon commonly utilized estimation equations. We aimed to compare the routine use of 24-hour creatinine clearance (CrCl) and GFR estimates calculated by Crockoft-Gault (CG) and modification of diet in renal disease (MDRD) formulas in patients with different levels of renal dysfunction in subgroups, based on Body Mass Index (BMI) and serum albumin (Alb) levels. METHODS: Two hundred and seventy-nine non diabetic patients (172 men and 107 women), aged 54±23 years, with BMI 27.3±4.4 were enrolled in the study. All patients presented creatinine 1.8±1.2 (mg/dL) and Alb 3.5±1.3g/dL. The comparison of CrCl versus CG had bias 3.1 while the comparison of CrCl versus MDRD had a bias of 6.6. RESULTS: Univariate analysis showed that age, sex and BMI were not significant biases related to the CG, MDRD and CrCl. Indeed, the bias related to the CG was significantly lower than that related to MDRD in patients with either low or high serum albumin. Interestingly, the bias associated with CG was 1.3 in non-diabetic patients with Alb ≤3.5 mg /dL suggesting that CG equation could be used interchangeable to CrCl in these patients. CONCLUSION: CG gave a better prediction of measured CrCl than MDRD in Mediterranean, non-diabetic, non-hospitalized patients although misclassification of patients with regard to renal impairment stage was not present.

Pharmaceutical management of hepatitis B and C in liver and kidney transplant recipients.

The combination of hepatitis B immune globulin with entecavir or tenofovir (at least for a certain period of time) seems to be the most reasonable prophylaxis against recurrent hepatitis B after liver transplantation. Entecavir represents an attractive option for treatment of naïve kidney transplant recipients, because of its high efficacy and the low rates of resistance. However antiviral treatment should be individualized in the view of kidney function and the previous resistance. To date, new captivating therapeutic strategies could make interferon-free regimens viable for treatment of hepatitis C virus positive liver transplant recipients. The recent combinations of sofosbuvir with simeprevir or daclatasvir or ledipasvir plus/minus ribavirin have boosted the on treatment and sustained virological response to rates approaching 100% within liver transplant recipients with recurrent chronic hepatitis C (CHC). Preliminary data showed that the second generation direct oral antivirals could result to high treatment rates of recurrent CHC in kidney transplant recipients as well. Ongoing studies will clarify the optimal treatment of recurrent CHC in kidney transplant recipients.

Treatment of chronic hepatitis C in liver transplant candidates and recipients: Where do we stand?

The first generation direct antiviral agents (DAAs) highlighted substantial prognosis improvement among liver transplant (LT) candidates and recipients with recurrent hepatitis C virus (HCV) infection. During 2014, second generation DAAs are associated with high sustained virological response rates (> 95%), shortened duration courses and relatively few toxicities. In keeping with the currently available data, patients with decompensated cirrhosis awaiting LT is preferable to be treated with interferon-free, new generation DAAs, with or without ribavirin combinations. Although data about the safety of new DAAs combinations in this patient population are limited, sofosbuvir and daclatasvir pharmacokinetics do not appear to change significantly in moderate or severe liver impairment, while other new DAAs (simeprevir, asunaprevir) seem to be contraindicated in patients with severe liver impairment (Child-Pugh class C). On the other hand, sofosbuvir should not be given in patients with glomerular filtration rate ≤ 30 mL/min, but ongoing trials will clarify better this issue. With the objective that newer antiviral combinations will yield safer and more efficient manipulation of HCV recurrence post-transplant, the European Association for the Study of the Liver has recently updated its recommendations towards this direction. Nevertheless the new antivirals' high cost may be the biggest challenge to their implementation worldwide.