Urinary Biomarkers of Acute Kidney Injury in Patients with Liver Cirrhosis

Acute kidney injury (AKI) is a common complication in cirrhotic patients. Serum creatinine is a poor biomarker for detection of renal impairment in cirrhotic patients. This study aimed to evaluate urinary neutrophil gelatinase-associated lipocalin (NGAL) and urinary interleukin-18 (IL-18) as early biomarkers of acute kidney injury in cirrhotic patients. 160 patients with cirrhosis admitted to the Liver Units at Zagazig University Hospitals were classified into three groups: (I) nonascitic patients, (II) ascitic patients without renal impairment, and (III) ascitic patients with renal impairment. Patients with renal impairment were further divided into four subgroups: [A] prerenal azotemia, [B] chronic kidney disease (CKD), [C] hepatorenal syndrome (HRS), and [D] acute tubular necrosis (ATN). Significant elevation of both urinary NGAL and urinary IL-18 in cirrhotic patients with renal impairment especially in patients with ATN was observed. Urinary NGAL and urinary IL-18 have the ability to differentiate between AKI types in patients with cirrhosis. This could improve risk stratification for patients admitted to the hospital with cirrhosis, perhaps leading to early ICU admission, transplant evaluation, and prompt initiation of HRS therapy and early management of AKI.

Angiotensin Type-1 Receptor Blockade May Not Protect Kidney against Cisplatin-Induced Nephrotoxicity in Rats

Background. Cisplatin (CDDP) is an anticancer drug, which is accompanied with major side effects including nephrotoxicity. We tested two doses of losartan (10 and 20 mg/kg/day) against nephrotoxicity in a rat model treated with daily administration of CDDP (2.5 mg/kg/day). Methods. Five groups of rats were examined. Groups 1 and 2 received losartan 10 and 20 mg/kg/day, i.p, for a period of 10 days. Group 3 received saline for 10 days, but from day 3 the animals received CDDP (2.5 mg/kg/day, i.p) for the next seven days. Groups 4 and 5 received treatment regimen the same as groups 1 and 2, but from day 3 they also received CDDP for the next seven days. At the end of the experiment, blood samples were obtained and the kidneys were removed to undergo pathological investigation and to obtain supernatant from homogenized tissue. Results. CDDP induced nephrotoxicity, but the serum levels of creatinine and blood urea nitrogen were not attenuated by losartan. The pathological findings confirmed that losartan did not have nephroprotective effect in this experimental model. Conclusion. According to the findings, losartan could not improve renal function impaired by toxicity induced by continuous doses of CDDP, and also it worsened the renal failure.

The Utility of Serial Allograft Biopsies during Delayed Graft Function in Renal Transplantation under Current Immunosuppressive Regimens

Delayed graft function (DGF) of kidney transplants increases risk of rejection. We aimed to assess the utility of weekly biopsies during DGF in the setting of currently used immunosuppression and identify variables associated with rejection during DGF. We reviewed all kidney transplants at our institution between January 2008 and December 2011. All patients received rabbit antithymocyte globulin/Thymoglobulin (ATG) or Basiliximab/Simulect induction with maintenance tacrolimus + mycophenolate + corticosteroid therapy. Patients undergoing at least one weekly biopsy during DGF comprised the study group. Eighty-three/420 (19.8%) recipients during this period experienced DGF lasting ≥1 week and underwent weekly biopsies until DGF resolved. Biopsy revealed significant rejection only in 4/83 patients (4.8%) (one Banff 1-A and two Banff 2-A cellular rejections, and one acute humoral rejection). Six other/83 patients (7.2%) had Banff-borderline rejection of uncertain clinical significance. Four variables (ATG versus Basiliximab induction, patient age, panel reactive anti-HLA antibody level at transplantation, and living versus deceased donor transplants) were statistically significantly different between patients with and without rejection, though the clinical significance of these differences is questionable given the low incidence of rejection. Conclusions. Under current immunosuppression regimens, rejection during DGF is uncommon and the utility of serial biopsies during DGF is limited.

Effect of α-Lipoic Acid on Oxidative Stress in End-Stage Renal Disease Patients Receiving Intravenous Iron

Oxidative stress is associated with increased risk of cardiovascular disease in end-stage renal disease (ESRD) patients. Intravenous (IV) iron has been shown to increase oxidative stress. The aim of the study was to evaluate changes in oxidative stress markers following administration of IV sodium ferric gluconate (SFG) to ESRD patients with and without administration of the antioxidant, α-lipoic acid. This is an open-label, crossover study. 125 mg of IV SFG was administered during control (C) and intervention (I) visits. During the I visit, 600 mg of α-lipoic acid was given orally prior to IV SFG. Blood samples were collected at defined time periods for F2-isoprostane (FIP), lipid hydroperoxide (LHP), malondialdehyde (MDA), and iron indices. We recruited ten African-American ESRD subjects: 50% male; mean age 45±9 years; mean hemoglobin 13±1 g/dL; ferritin 449±145 ng/mL; transferrin saturation 27±4%. There were no significant differences in iron indices between the two visits after IV SFG. MDA, FIP, and LHP increased significantly for both C and I visits with a greater increase in the I group. Administration of IV SFG results in an acute rise in oxidative stress in ESRD patients. In contrast to previous studies, administration of α-lipoic acid was associated with a greater increase in oxidative stress.

Proteinuria, 99mTc-DTPA Scintigraphy, Creatinine-, Cystatin- and Combined-Based Equations in the Assessment of Chronic Kidney Disease

Background. Precise estimation of the glomerular filtration rate (GFR) and the identification of markers of progression are important. We compared creatinine, cystatin, and combined CKD-EPI equations with Tc-DTPA99m scintigraphy to measure GFR and proteinuria as markers of progression. Methods. Cross-sectional, observational study including 300 subjects. CKD was classified by Tc-DTPA99m scintigraphy. Determinations. Creatinine, 24-hour creatinine clearance, cystatin, Hoek formula, and creatinine, cystatin, and combined CKD-EPI equations. Results. In the global assessment, creatinine CKD-EPI and combined CKD-EPI equations yielded the highest correlations with Tc-DTPA99m: ρ = 0.839, P<0.0001 and ρ = 0.831, P<0.0001. Intergroup analysis versus Tc-DTPA99m: control G, creatinine clearance ρ = 0.414, P = 0.013; G3, combined CKD-EPI ρ = 0.5317, P<0.0001; G4, Hoek ρ = 0.618, P<0.0001, combined CKD-EPI ρ = 0.4638, P<0.0001; and G5, creatinine clearance ρ = 0.5414, P<0.0001, combined CKD-EPI ρ = 0.5288, P<0.0001. In the global assessment, proteinuria displayed the highest significant correlations with cystatin (ρ = 0.5433, P<0.0001) and cystatin-based equations (Hoek: ρ=-0.5309, P<0.0001). When GFR < 60 mL/min: in stage 3, proteinuria-cystatin (ρ = 0.4341, P<0.0001); proteinuria-Hoek (ρ = −0.4105, P<0.0001); in stage 4, proteinuria-cystatin (ρ = 0.4877, P<0.0001); proteinuria-Hoek (ρ = −0.4877, P = 0.0026). Conclusions. At every stage of GFR < 60 mL/min, cystatin-based equations displayed better correlations with Tc-DTPA99m. Proteinuria and cystatin-based equations showed strong associations and high degrees of correlation.

Long Term Prospective Assessment of Living Kidney Donors: Single Center Experience

Virtually, all studies reporting the outcomes of living kidney donation beyond the first year from donation were retrospective. In this prospective study, the outcome of 81 consecutive living kidney donors was thoroughly evaluated. Clinical, laboratory, and radiological assessments were carried out at predonation (basal), 3, 6, 12, and 24 months after donation. The mean age at time of donation was 37.8 ± 9.8 years and the majority was females (75.3%). The mean BMI increased significantly after donation (P<0.04). The mean serum creatinine levels (mg/dl) were 0.75 ± 0.14, 1.01 ± 0.22, 0.99 ± 0.21, 0.98 ± 0.20, and 0.94 ± 0.20 (P<0.0001). Likewise, the mean levels of measured creatinine clearance (mL/min) were 148.8 ± 35.7, 94.7 ± 26.6, 95.5 ± 24.6, 96.7 ± 20.2, and 101.6 ± 26.2 (P<0.0001). The mean 24 hours urinary protein excretion (gm/dL) were 0.09 ± 0.03, 0.19 ± 0.18, 0.16 ± 0.09, 0.18 ± 0.25, and 0.17 ± 0.12 (P<0.0001). There were significant increases in the means of the longitudinal and transverse diameters of the remaining kidney over time (P<0.001). Out of 42 female donors, eleven female donors have got successful postdonation pregnancies. There were no reported surgical complications, either intra- or postoperative. Long-term follow-up is necessary for all living kidney donors through local institutional and world registries. This trial is registered with ClinicalTrials.gov NCT00813579.

Hyaluronan Is Not a Ligand but a Regulator of Toll-Like Receptor Signaling in Mesangial Cells: Role of Extracellular Matrix in Innate Immunity

Glomerular mesangial cells (MC), like most cell types secrete hyaluronan (HA), which attached to the cell surface via CD44, is the backbone of a hydrophilic gel matrix around these cells. Reduced extracellular matrix thickness and viscosity result from HA cleavage during inflammation. HA fragments were reported to trigger innate immunity via Toll-like receptor-(TLR-) 2 and/or TLR4 in immune cells. We questioned whether HA fragments also regulate the immunostimulatory capacity of smooth muscle cell-like MC. LPS (TLR4-ligand) and PAM3CysSK4 (TLR2-ligand) induced IL-6 secretion in MC; highly purified endotoxin-free HA < 3000 Da up to 50 μg/mL did not. Bovine-testis-hyaluronidase from was used to digest MC-HA into HA fragments of different size directly in the cell culture. Resultant HA fragments did not activate TLR4-deficient MC, while TLR2-deficient MC responded to LPS-contamination of hyaluronidase, not to produced HA fragments. Hyaluronidase increased the stimulatory effect of TLR2-/-3/-5 ligands on their TLR-receptors in TLR4-deficient MC, excluding any effect by LPS-contamination. Supplemented heparin suppressed every stimulatory effect in a dose-dependent manner. We conclude that the glycosaminoglycan HA creates a pericellular jelly barrier, which covers surface receptors like the TLRs. Barrier-thickness and viscosity balanced by HA-synthesis and degradation and the amount of HA-receptors on the cell surface regulate innate immunity via the accessibility of the receptors.

Residual Renal Function in Hemodialysis Patients: The Role of Angiotensin-Converting Enzyme Inhibitor in Its Preservation

Residual Renal function (RRF) has an important role in the overall morbidity and mortality in hemodialysis patients. The role of angiotensin-converting enzyme inhibitor (ACEi) in preserving renal function in chronic proteinuric nephropathies is well documented. We test the hypothesis that enalapril (an ACEi) slows the rate of decline of RRF in patients starting hemodialysis. A prospective, randomized open-label study was carried out. 42 patients were randomized in two groups either in treatment with enalapril or no treatment at all. Our study has proven that enalapril has a significant effect on preserving residual renal function in patients starting dialysis at least during the first 12 months from the initiation of the hemodialysis. Further studies are necessary in order to investigate the potential long-term effect of ACEi on residual renal function and on morbidity and mortality in patients starting hemodialysis.

Comprehensive and Personalized Care of the Hemodialysis Patient in Tassin, France: A Model for the Patient-Centered Medical Home for Subspecialty Patients

The Centre de Rein Artificiel in Tassin, France, provides comprehensive care to patients with chronic renal disease similar to the model proposed for Patient Center Medical Homes; patients with end-stage renal disease in the Tassin Hemodialysis Center appear to have better outcomes than patients in the United States. These differences likely reflect this center’s approach to patient-centered care, the use of longer dialysis times, and focused vascular access care. Longer dialysis times provide better clearance of small and middle toxic molecules, salt, and water; 85% of patients at the Tassin center have a normal blood pressure without the use of antihypertensive medications. The observed mortality rate in patients at the Tassin Center is approximately 50% of that predicted based on the United States Renal Data system standard mortality tables. Patient outcomes at the Tassin center suggest that longer dialysis times and the use of multidiscipline teams led by nephrologists directing all health care needs probably explain the outcomes in these patients. These approaches can be imported into the U.S healthcare system and form the framework for patient-centered medical practice for ESRD patients.

Dialysis Efficiency of AN69, a Semisynthetic Membrane Not Well Suited for Diffusion

AN69 membrane is not suited for diffusion, with an suggested limit at 25 mL/min dialysate flow rate. When prescribing continuous hemodialysis this threshold must be surpassed to achieve. We designed a study aimed to check if a higher dose of dialysis could be delivered efficiently with this membrane. Ten ICU patients under continuous hemodiafiltration with 1.4 m2 AN69 membrane were included and once a day we set the monitor to exclusively 50 mL/min dialysate flow rate and 250 mL/min blood flow rate and after 15 minutes measured dialysate saturation for urea, creatinine, and -microglobulin. We detected that urea saturation of dialysate was nearly complete () for at least 40 hours, while creatinine saturation showed a large dispersion () and did not detect any relation for these variables with time, blood flow, or anticoagulation regime. Saturation of -microglobulin was low () and decreased discretely with time (, ) and significantly with TMP increases (, ). In our experience AN69 membrane shows a better diffusive capability than previously acknowledged, covering efficiently the range of standard dosage for continuous therapies. Creatinine is not a good marker of the membrane diffusive capability.