Renhua Lu

Kidney-brain crosstalk in the acute and chronic setting

Patients with kidney disease often exhibit multiple organ dysfunction that is caused, in part, by marked connectivity between the kidney and other organs and tissues. Substantial crosstalk occurs between the kidney and the brain, as indicated by the frequent presentation of neurological disorders, such as cerebrovascular disease, cognitive impairment, and neuropathy during the natural history of chronic kidney disease. The underlying pathophysiology of such comorbid neurological disorders in kidney disease is governed by shared anatomic and vasoregulatory systems and humoral and non-humoral bidirectional pathways that affect both the kidney and the brain. During acute kidney injury, the brain and kidney might interact through the amplification of cytokine-induced damage, extravasation of leukocytes, oxidative stress, and dysregulation of sodium, potassium, and water channels. The advent of dialysis and renal transplantation programmes has led to a reduction in the rate of neurological complications associated with uraemia, but a new set of complications have arisen as a consequence of the effects of dialysis on the central nervous system over the short and long term. This Review discusses the clinical complications of acute and chronic renal failure from a neurologic perspective, and highlights current understanding of the underlying pathophysiologies.

Optimizing a kidney stress test to evaluate renal functional reserve.

BACKGROUND Renal function reserve (RFR) describes the capacity of the kidney to increase glomerular filtration rate (GFR) in response to physiological or pathological stimuli. The scope of our study was to evaluate the optimal level of stimulation using different doses of protein load (PL) for a standard renal stress test (RST). METHODS 18 young healthy individuals were given sessions of PL with 1 and 2 g/kg body weight. Endogenous creatinine clearance was calculated. Baseline GFR (bGFR) and stress GFR (sGFR) (post-PL) were obtained; RFR is the difference between stress and baseline GFR. A p-value < 0.05 was considered statistically significant. RESULTS Mean bGFR was 107.97 ± 12.33 mL/min/1.73m2. sGFR with 1 and 2 g PL were significantly higher than bGFR in all subjects. The sGFR after 2 g PL (141.75 ± 19.90 mL/min/1.73m2) was not statistically different from the sGFR after 1 g PL (142.37 ± 22.35 mL/min/1.73m2). sGFR and therefore RFR were independent from the value of bGFR. CONCLUSIONS We found no difference between 1 and 2 g/kg body weight PL to elicit sGFR. RST may be useful to predict susceptibility and risk of developing acute kidney injury and/or progression to chronic kidney disease. RST uncovers the possible loss of renal functional mass when this condition is not manifested clinically. Further studies are needed to set this hypothesis.

Peritoneal Dialysis in Patients with Refractory Congestive Heart Failure: A Systematic Review

Background: Refractory congestive heart failure (RCHF) is associated with a high mortality rate and is a major contributor to hospital admissions. Peritoneal dialysis (PD) is an option to control volume overload and perhaps improve outcomes in this challenging patient population. The aim of this systematic review is to describe the relative risk-benefit ratio based on data reported regarding the use of PD in RCHF. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. An electronic search of PubMed, Embase, and the Cochrane Library was performed to identify relevant studies published from January 1951 to February 2014. Eligible studies selected were prospective or retrospective adult population studies on PD in the setting of RCHF. The following clinical outcomes were used to assess PD therapy: (1) hospitalization rates; (2) heart function; (3) renal function; (4) fluid overload, and (5) adverse clinical outcomes. Summary: Of 864 citations, we excluded 843 citations and included 21 studies (n = 673 patients). After PD, hospitalization days declined significantly (p = 0.0001), and heart function improved significantly (left ventricular ejection fraction: p = 0.0013; New York Heart Association classification: p = 0.0000). There were no statistically significant differences in glomerular filtration rate after PD treatment in non-chronic kidney disease stage 5D patients (p = 0.1065). Among patients treated with PD, body weight decreased significantly (p = 0.0006). The yearly average peritonitis rate was 14.5%, and the average yearly mortality was 20.3%. Key Messages: This systematic review suggests that PD may be an effective and safe therapeutic tool for patients with RCHF.

Survey of Acute Kidney Injury and Related Risk Factors of Mortality in Hospitalized Patients in a Third-Level Urban Hospital of Shanghai

Objective: The main aim of this study is to investigate the incidence and prognosis of acute kidney injury (AKI) and to clarify the risk factors associated with the prognosis of AKI in hospitalized patients. Method: All patients hospitalized from January 1st to December 31st 2012 in Ren Ji Hospital, School of Medicine Shanghai Jiao Tong University were screened by the Lab Administration Network. All the patients with an intact medical history of AKI according to the Acute Kidney Injury Network (AKIN) were enrolled in the study cohort. AKIs incidence and etiology, as well as the patients characteristics and prognosis, were retrospectively analyzed. Logistic regression analysis was used to investigate the risk factors on the patient prognosis and renal outcome. Results: 934 AKI patients were enrolled. The incidence of AKI in hospitalized patients was 2.41%. The ratio of males to females of patients was 1.88:1 and the mean age was 60.82 w 16.94. The incidence of AKI increased with increase in age. Among hospitalized patients, 63.4% were from the surgical department, 35.4% from the internal medicine department, and 1.2% from the obstetric and gynecologic department. Regarding the cause of AKI, pre-renal AKI, acute tubular necrosis (ATN), acute glomerulonephritis and vasculitis (AGV), acute interstitial nephritis (AIN), and post-renal AKI contributed with 51.7, 37.7, 3.8, 3.5, and 3.3%, respectively. The survival rate on the day 28 after AKI was 71.8%. In addition, 65.7% patients got complete renal recovery, while 16.9% got partial renal recovery and 17.4% got renal loss. The mortality of AKI in hospitalized patients at Stage I, Stage II and Stage III was 24.8, 31.2 and 43.7%, respectively. Multivariate Logistic regression analysis showed that use of nephrotoxic drugs, [Odds Ratio (OR) = 2.313], hypotension in the previous week (OR = 4.482), oliguria (OR = 5.267), the number of extra-renal organ failures (OR = 1.376), and need for renal replacement therapy (RRT) (OR = 4.221) were independent risk factors for mortality. The number of extra-renal organ failures (OR = 1.529) and RRT (OR = 2.117) were independent risk factors for renal loss. Conclusion: AKI is one of the most common complications in hospitalized patients. The mortality is high and renal prognosis is poor after AKI. The prognosis is closely associated with the severity of AKI. Nephrotoxic drugs, hypotension within the last week, oliguria, the number of extra-renal organ failures, and RRT are independent risk factors for mortality, while the number of extra-renal organ failures and RRT are independent risk factors for renal loss. i 2014 S. Karger AG, Basel

Initiation of Renal Replacement Therapy in the Intensive Care Unit in Vicenza (IRRIV) Score

Introduction: One of the top research priorities in acute kidney injury is related to the timing of renal replacement therapy (RRT) initiation. The purpose was to develop an index that might serve as a standardized concept of timing of initiation of RRT. Methods: A previously described database was used. We applied a multivariable Cox regression model with backward selection to characterize parameters present in those patients who received RRT compared with those who did not receive RRT. Results: We studied 590 patients. We identified independent risk factors for RRT and a risk score was devised. The Area Under the Curve of the receiver operating characteristic curve was 0.81 (95% CI 0.74-0.86) for predicting the need for RRT. Conclusions: We have developed a simple Score (IRRIV Score) to identify patients at high risk of requiring RRT. This score may serve as a standardized definition of the timing of initiation of RRT.

Plasma Pentraxin 3 Is Closely Associated with Peripheral Arterial Disease in Hemodialysis Patients and Predicts Clinical Outcome: A 6-Year Follow-Up

Background: The aim of this study is to investigate the value of plasma PTX3 level for assessing peripheral artery disease (PAD) and clinical outcome in hemodialysis (HD) patients. Methods: The ankle-brachial index (ABI) was measured in HD patients. PTX3 levels in 116 HD patients were measured by ELISA. Results: Overall, 116 HD patients were enrolled; 21 (18%) patients had PAD. Using the ROC curve analysis for PAD, PTX3 (cut-off value 4.06 ng/ml, AUC 0.901, p < 0.0001) showed a significantly better positive predictive value than hsCRP (cut-off value 3.33 ng/ml, AUC 0.640, p < 0.05). During follow-up (mean 57 ± 26 months), 40 deaths (34%) occurred. Kaplan-Meier analysis found that those patients with elevated PTX3 had a significantly poor outcome (p < 0.0001), and Cox analysis further confirmed that PTX3 was an independent predictor of overall mortality (HR, 1.105, p = 0.03). For prediction of overall mortality, the AUC for PTX3 (cut-off value 3.22 ng/ml, AUC 0.690, p < 0.0001) was close to hsCRP (cut-off value 5.84 ng/ml, AUC 0.620, p < 0.001). Conclusions: For the prediction of PAD in HD patients, the diagnostic sensitivity and specificity of PTX3 were higher than those of hsCRP. Furthermore, PTX3 was also a predictor of all-cause mortality in HD patients. PTX3 may be considered a novel biomarker of inflammation in HD patients.

Fabry’s disease: an example of cardiorenal syndrome type 5

Cardiorenal syndrome type 5 (CRS-5) includes conditions where there is a simultaneous involvement of the heart and kidney from a systemic disorder. This is a bilateral organ cross talk. Fabry’s disease (FD) is a devastating progressive inborn error of metabolism with lysosomal glycosphingolipid deposition in variety of cell types, capillary endothelial cells, renal, cardiac and nerve cells. Basic effect is absent or deficient activity of lysosomal exoglycohydrolase a-galactosidase A. Renal involvement consists of proteinuria, isosthenuria, altered tubular function, presenting in second or third decade leading to azotemia and end-stage renal disease in third to fifth decade mainly due to irreversible changes to glomerular, tubular and vascular structures, especially highlighted by podocytes foot process effacement. Cardiac involvement consists of left ventricular hypertrophy, right ventricular hypertrophy, arrhythmias (sinus node and conduction system impairment), diastolic dysfunction, myocardial ischemia, infarction, transmural replacement fibrosis, congestive heart failure and cardiac death. Management of FD is based on enzymatic replacement therapy and control of renal (with anti-proteinuric agents such as angiotensin-converting enzyme inhibitors—and/or angiotensin II receptor blockers), brain (coated aspirin, clopidogrel and statin to prevent strokes) and heart complications (calcium channel blockers for ischemic cardiomyopathy, warfarin and amiodarone or cardioverter device for arrhythmias).

Klotho Reduces Necroptosis by Targeting Oxidative Stress Involved in Renal Ischemic-Reperfusion Injury

Background/Aims: Klotho is a multifunctional protein expressed predominantly in kidney tubular epithelium. Here, we investigated the protective effects of Klotho on necroptosis in renal ischemic-reperfusion injury (IRI) and the role of oxidative stress in this process. Methods: Mice were subjected to bilateral renal pedicle clamping. Mouse renal tubular epithelial (TCMK-1) cells were exposed to hypoxia/reoxygenation (H/R) or H2O2. Kidney samples from acute kidney injury (AKI) patients and controls were examined by immunofluorescence. Klotho protein and N-acetyl-L-cysteine (NAC) were used to define their roles in mediating necroptosis. Necroptosis was assessed by TUNEL staining, immunoblotting, and real-time PCR. Oxidative stress was studied via ELISA, immunoblotting, colorimetric, and thiobarbituric acid reactive substances assays. Results: Renal IRI induced Klotho deficiency in the serum and kidney, but an increase in the urine. The levels of the necroptotic markers receptor-interacting protein kinase (RIP) 1, RIP3, IL-1β, and TUNEL-positive cells increased after IRI; all increases were ameliorated by Klotho. In TCMK-1 cells, Klotho and NAC attenuated the elevation in RIP1, RIP3, and LDH release induced by H/R or H2O2. Moreover, Klotho decreased the levels of oxidative stress biomarkers and elevated superoxide dismutase 2 expression in both in vivo and in vitro experiments. Studies in human samples further confirmed the Klotho deficiency and increased formation of RIP3 puncta in AKI kidneys. Conclusion: Klotho protects tubular epithelial cells from IRI and its anti-necroptotic role may be associated with oxidative stress inhibition.

Prognostic Value of the Delivery Dialysis Dose on Twice-Weekly Hemodialysis Patients

Background: Few studies have evaluated the prognostic value of dialysis dose in twice-weekly hemodialysis (HD). A single-pool Kt/V (spKt/V) over 1.70 may benefit patients receiving twice-weekly maintenance HD. Methods: This is a multicenter randomized controlled trial performed on 163 patients from 17 dialysis centers in Shanghai who were allocated to high- (n = 98) and standard-dose groups (n = 65) and followed through 96 weeks of study period. Therapeutic approaches were given to increase spKt/V to over 1.70 in the high-dose group. Data were collected every 12-24 weeks. The primary outcomes were all-cause mortality and major adverse cardio-cerebrovascular events (MACEs) occurrence, and secondary outcomes included residual kidney function (RKF) and health-related quality of life (HR-QOL). Results: The spKt/V in high-dose and standard-dose groups were 1.80 ± 0.23 and 1.55 ± 0.19, respectively, after an 8-week intervention (p < 0.001). At the end of the study, SF-36 physical function and total score in high-dose group were 82 (69-90) and 74 (47-84), respectively, both of which were higher than those in the standard-dose group. Decline in urine volume was observed in both groups with no significant difference (p = 0.431). No difference was found in overall survival between the 2 groups (p = 0.580). The 1-year MACE-free survival for high-dose group was 84.49%, better than 76.72% for standard-dose group (p = 0.029). Conclusions: Higher spKt/V is also associated with MACE-free survival and better HR-QOL, especially in physical function aspect for twice-weekly dialysis patients. Increasing spKt/V over 1.70 in twice-weekly HD population does not cause loss of RKF.

Hemodialysis versus peritoneal dialysis: an observational study in two international centers

Introduction: Given that it is difficult to randomize end-stage renal disease (ESRD) patients to either hemodialysis (HD) or peritoneal dialysis (PD), differences between these renal replacement therapy (RRT) modalities are of major interest and remain controversial. Methods: All data on maintenance dialysis patients during 2009 to 2013 in the Renji Hospital in Shanghai, China and in the San Bortolo Hospital in Vicenza, Italy were selected. Patients who changed their therapy from HD to PD or PD to HD during this study were excluded. Results: 919 maintenance dialysis patients were included in the present study, including 509 patients on HD and 410 on PD. During the 5-year follow-up, mean arterial pressure (MAP) was higher in HD patients. The level of serum HCO3- was significantly better in PD patients than in HD patients. Phosphate was significantly higher in HD patients than in PD patients. With respect to lipid metabolism, triglyceride, total cholesterol and LDL were significantly higher in PD patients. Serum protein and albumin were higher in HD patients than in PD patients. Overall, 236 patients died (25.7%); 150 (16.3%) on HD and 86 (9.4%) on PD. The main cause of death in HD and PD patients was cerebral vascular disease and infection, respectively. After adjusting for dialysis vintage, the Kaplan-Meier patient survival was similar between HD and PD patients. Conclusions: Based on 5 years of data, we demonstrate that lipid metabolism and nutritional status were better in HD patients. However, blood pressure control, acid-base balance, phosphate (P) control were better in PD patients. The main cause of death in HD and PD was cerebral vascular disease and infection, respectively. Considering the dialysis vintage, the Kaplan-Meier patient survival was similar between HD and PD patients.