Background: Survivors of severe acute kidney injury remain at high risk of death well-after apparent recovery from the initial event. Methods: We conducted a cohort study of hospitalized adults in Ontario from 1996 to 2008 with acute kidney injury who received temporary dialysis and survived for 90 days following discharge independent from dialysis. The exposure was nephrology follow-up. We used propensity scores to match individuals with early nephrology follow-up to those without. The primary outcome was time to mortality. Results : We identified 3877 patients with acute kidney injury who met the eligibility criteria. A total of 1583 patients had nephrology follow. The incidence of all-cause mortality was lower in those with early nephrology follow-up as compared to those without early follow-up (8.4 vs. 10.6 per 100 person-years, HR 0.76 (95% CI 0.62-0.93)). Conclusions: Nephrology follow-up after hospitalization with acute kidney injury and temporary dialysis was associated with improved survival.

Background: Survivors of severe acute kidney injury remain at high risk of death well-after apparent recovery from the initial event. Methods: We conducted a cohort study of hospitalized adults in Ontario from 1996 to 2008 with acute kidney injury who received temporary dialysis and survived for 90 days following discharge independent from dialysis. The exposure was nephrology follow-up. We used propensity scores to match individuals with early nephrology follow-up to those without. The primary outcome was time to mortality. Results : We identified 3877 patients with acute kidney injury who met the eligibility criteria. A total of 1583 patients had nephrology follow. The incidence of all-cause mortality was lower in those with early nephrology follow-up as compared to those without early follow-up (8.4 vs. 10.6 per 100 person-years, HR 0.76 (95% CI 0.62-0.93)). Conclusions: Nephrology follow-up after hospitalization with acute kidney injury and temporary dialysis was associated with improved survival.

A research report submitted to the Faculty of Health Sciences, University of Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Medicine in the branch of Internal Medicine Johannesburg, 2017 / Objective: There is limited data describing acute kidney injury (AKI) in HIV-infected adult patients in resource-limited settings where increasingly, tenofovir (TDF), which is potentially nephrotoxic, is prescribed. We describe risk factors for, and prognosis of AKI in HIV-infected individuals receiving and naïve to TDF. Methods: This was a prospective case cohort study of hospitalized HIV-infected adults with AKI (as defined by the 2012 KDIGO Clinical Practice Guideline for AKI) stratified by TDF exposure. Adults (≥18 years) were recruited: clinical and biochemical data was collected at admission; their renal recovery, discharge or mortality was ascertained as an in-patient and, subsequently, to a scheduled 3-month follow-up. Results: Amongst this predominantly female (61%), almost exclusively black African cohort of 175 patients with AKI, 93 (53%) were TDF exposed; median age was 41 years (IQR 35-50). Median CD4 count and VL and creatinine at baseline was 116 cells/mm3 and 110159 copies/ml, respectively. A greater proportion of the TDF group had severe AKI on admission (61% v 43% p=0.014); however, both groups had similar rates of newly diagnosed tuberculosis (TB) (52%) and NSAID (32%) use. Intravenous fluid was the therapeutic mainstay; only 7 were dialyzed. Discharge median serum creatinine (SCr) was higher in the TDF group (p=0.032) and fewer in the TDF group recovered renal function after 3-months (p=0.043). 3-month mortality was 27% in both groups but 55% of deaths occurred in hospital. Those that died had a higher SCr and more severe AKI than survivors; TB was diagnosed in 33 (70%) of those who died. Conclusions: AKI was more severe and renal recovery slower in the TDF group; comorbidities, risk factors and prognosis were similar regardless of TDF exposure. Because TB is linked to higher mortality, TB co-infection in HIV-infected patients with AKI warrants more intensive monitoring. In all those with poor renal recovery, our data suggests that a lower threshold for dialysis is needed. / MT2017

The Slit family of secreted proteins act as axonal repellents during embryogenesis. Slit2 via its receptor, Roundabout-1, also inhibits chemotaxis of multiple leukocyte subsets. Using static and microfluidic shear assays, we found that Slit2 inhibited multiple steps required to recruit circulating neutrophils. Slit2 blocked capture and firm adhesion of human neutrophils to and transmigration across inflamed primary vascular endothelial cells. To determine the response of Slit2 in renal ischemia reperfsuion injury, Slit2 was administered prior to bilateral renal pedicle clamping in mice. This led to significant decreases in both renal tubular necrosis score and neutrophil infiltration. Administration of Slit2 also prevented elevation of plasma creatinine following injury in a dose-dependent manner. Furthermore, administration of Slit2 did not increase hepatic bacterial load in mice infected with L.monocytogenes infection. Collectively, these data demonstrate Slit2 as an exciting therapeutic molecule to combat renal ischemia reperfusion injury without compromising protective host innate immune functions.

The Slit family of secreted proteins act as axonal repellents during embryogenesis. Slit2 via its receptor, Roundabout-1, also inhibits chemotaxis of multiple leukocyte subsets. Using static and microfluidic shear assays, we found that Slit2 inhibited multiple steps required to recruit circulating neutrophils. Slit2 blocked capture and firm adhesion of human neutrophils to and transmigration across inflamed primary vascular endothelial cells. To determine the response of Slit2 in renal ischemia reperfsuion injury, Slit2 was administered prior to bilateral renal pedicle clamping in mice. This led to significant decreases in both renal tubular necrosis score and neutrophil infiltration. Administration of Slit2 also prevented elevation of plasma creatinine following injury in a dose-dependent manner. Furthermore, administration of Slit2 did not increase hepatic bacterial load in mice infected with L.monocytogenes infection. Collectively, these data demonstrate Slit2 as an exciting therapeutic molecule to combat renal ischemia reperfusion injury without compromising protective host innate immune functions.

Kidney disease remains a public health problem worldwide, where there is an increase in the number of incidence of Acute Kidney Injury (AKI) in hospitalized patients. The AKI is characterized by an abrupt decrease in renal function, resulting in the inability of the kidneys to perform itÂs basics functions. The Ischemia/Reperfusion (I/R) injury can be defined as all changes resulting from the deprivation and the re-establishment of the oxygen supply to tissues and organs. It is a complex process that results in the production of reactive oxygen species (ROS) and oxidative stress damage. The Brazilian Red Propolis is a complex mixture collected and produced by Apis mellifera bees, and seems to be promising in this context, attenuating the oxidative and nephrotoxic effect in the kidney. This experimental study aims to replicate and standardize a framework of AKI by Ischemia/reperfusion (I/R) in rats, and analyze the possible protective renal effects of Red Propolis Alcohol Extract (RPAE) at a dose of 150mg/kg on markers and pathological variables. Wistar rats, adult males, were divided into 4 groups, using an induction and treatment regimen. We evaluated biochemical parameters indicative of renal function (creatinine, urea, creatinine clearance) tubular function (FENa+ and FEK+), oxidative profile through MDA (malondialdehyde) and activity of antioxidant enzyme GSH, in addition to histological analysis and immunohistochemistry. The RPAE significantly altered almost all parameters investigated. The results demonstrated the protective effect of the extract in the dose used against the nephrotoxicity: decreased serum levels of creatinine (1.8  0.5 vs 2,7Â0,9) and urea (181.1  65.6 vs 274,3Â91,81), reversed the increase in FENa+ (0,58Â0,30 vs 1,03Â0,39) and FEK+ (64,74Â52,44 vs 134,4Â54,94), reversed the decrease of creatinine clearance (0,41Â0,14 vs 0,073Â0,048), decreased MDA levels (90,22Â20,82 vs 133,9Â23,36) and increased GSH (1784Â297,4 vs 1267Â229,5), decreased the rate of acute tubular necrosis (2,0Â0,7 vs 3,6Â0,5), increased the expression of eNOS (2,20,4 vs 0,60,5) and Heme-oxygenase (2,60,5 vs 1,40,5). Therefore, occurred protection of renal function, protection of the tubular damage and oxidative stress. These results describe for the first time the effect of Red Propolis on a model of AKI induced by I/R, suggesting the protective effect of the extract against this type of injury. / As doenÃas renais apresentam um problema de saÃde pÃblica mundial, aonde hà um aumento nos nÃmeros de incidÃncia de LesÃo Renal Aguda (LRA) em pacientes hospitalizados. A LRA caracteriza-se por uma reduÃÃo abrupta da funÃÃo renal, resultando na incapacidade dos rins em exercer suas funÃÃes bÃsicas. A lesÃo por isquemia/reperfusÃo (I/R) pode ser definida como as alteraÃÃes resultantes da privaÃÃo seguida do re-estabelecimento do fornecimento de oxigÃnio para tecidos e ÃrgÃos. à um processo complexo, que resulta na produÃÃo espÃcies reativas de oxigÃnio (EROs) e dano por estresse oxidativo. A PrÃpolis Vermelha brasileira à uma mistura complexa coletada e produzida pelas abelhas Apis mellifera, e parece ser promissor nesse contexto, atenuando assim o efeito oxidativo e nefrotÃxico no rim. Este estudo experimental tem como objetivo reproduzir e padronizar um quadro de LRA por Isquemia/ReperfusÃo (I/R) em ratos, e analisar os possÃveis efeitos protetores renais do Extrato AlcoÃlico de PrÃpolis Vermelha (EAPV) na dose de 150mg/kg, sobre os marcadores e variÃveis desse quadro patolÃgico. Foram utilizados ratos Wistar, adultos machos, divididos em 4 grupos, utilizado um esquema de induÃÃo e de tratamento. Foram avaliados os parÃmetros bioquÃmicos indicativos da funÃÃo renal (creatinina, ureia, Clearence de creatinina) funÃÃo tubular (FENa+ e FEK+), o perfil oxidativo atravÃs do MDA (Malonaldeido) e atividade da enzima antioxidante GSH, alÃm da anÃlise histolÃgica e imunohistoquÃmica. O EAPV alterou significativamente quase todos os parÃmetros investigados. Os resultados demonstraram efeito protetor do extrato na dose de utilizada diante dos parÃmetros de nefrotoxicidade: diminuiu os nÃveis sÃricos creatinina (1,8Â0,5 vs 2,7Â0,9) e urÃia (181,1Â65,6 vs 274,3Â91,81), reverteu o aumento da FENa+ (0,58Â0,30 vs 1,03Â0,39) e da FEK+(64,74Â52,44 vs 134,4Â54,94), reverteu a diminuiÃÃo do clearence de creatinina (0,41Â0,14 vs 0,073Â0,048), diminuiu os nÃveis de MDA (90,22Â20,82 vs 133,9Â23,36) e aumentou o de GSH (1784Â297,4 vs 1267Â229,5), diminuiu o Ãndice de necrose tubular aguda (2,0Â0,7 vs 3,6Â0,5) a aumentou a expressÃo de eNOS (2,20,4 vs 0,60,5) e Heme-oxigenase (2,60,5 vs 1,40,5). Portanto, ocorreu proteÃÃo da funÃÃo renal, do dano tubular e do estresse oxidativo. Estes resultados relatam pela primeira vez o efeito da PrÃpolis Vermelha sobre um modelo de LRA induzido por I/R, demonstrando o efeito protetor do extrato na LRA.

INTRODUCTION : Acute kidney injury (AKI) is a disorder that is defined by rising serum creatinine and reduced urine output. It occurs in approximately 1-7% of hospitalized patients and is a major predictor of morbidity and mortality. It increases the costs and duration of hospital stay. AKI has been extensively studied post cardiac surgery, but there has been little attention on AKI occurring after non cardiac surgery . There have been few studies on AKI from developing countries and a paucity of data of post non cardiac surgery AKI. OBJECTIVE : To identify which known risk factors for AKI are commonly encountered at Groote Schuur Hospital, to document 30 and 90 day mortality, length of hospital stay, recovery of renal function at 90 days and identify factors associated with outcome post non-cardiac surgery. DESIGN: Prospective observational study. SETTING: Surgical Wards and ICU. PARTICIPANTS: Patients with AKI post non-cardiac surgery admitted between July 2012 and July 2013, who were 18 years and above without underlying stage 5 chronic kidney disease. OUTCOME MEASURES: Mortality, identification of risk factors, length of hospital stay and recovery of renal function. RESULTS: Of 367 patients referred to renal unit with AKI, 60 patients met inclusion criteria. Patients had an average age of 52.8 years (standard deviation 16.6) and 70% (42/60) were male. 61.7% (37 /60) were Coloured, 20% (12/60) were White and 18.3% (11/60) were Black. These patients were exposed to the following risk factors: 80%(48/60) had emergency surgery, 66. 7%(40/60) had sepsis, 65%(39/60) had perioperative contrast exposure, 53.3%(32/60) had hypotension that required inotropic support in 50%(30/60). Mortality was 33.3% (20/60) at 30 days and 45% (27/60) at 90 days. Of the 33 patients who did not die, 81.8% (27 /33) recovered their renal function to normal baseline creatinine at 90 days. Of the 6 patients, whose renal function did not return to baseline, none required long term dialysis. Perioperative contrast exposure was associated with a longer median length of hospital stay compared to patients not exposed to contrast (21 vs 16 days respectively, p<0.05). Sepsis and age > 60 years was associated with poor recovery of renal function (p=0.005, p=0.01 respectively). No risk factor was identified to be associated with mortality. CONCLUSION: Risk factors for post non cardiac surgery AKI commonly encountered at Groote Schuur Hospital were emergency surgery, sepsis, hypotension, perioperative use of inotropes and perioperative contrast exposure. The latter was identified as a modifiable risk factor which significantly prolonged hospital stay. Sepsis and age > 60 years were associated with poorer recovery of renal function.

Indiana University-Purdue University Indianapolis (IUPUI) / Hydrodynamic delivery is a powerful tool that allows delivery of macromolecules to the kidney culminating in gene expression. This finding is important in the fight against kidney disease. Current therapy for kidney injury, specifically acute kidney injury, is lacking. Supportive care in the form of IV fluids and medications aimed at restoring Glomerular Filtration Rate (GFR) and urine output are currently used. However, even with these treatments, prognoses of patients diagnosed with this disease remains poor. We believe that hydrodynamic delivery provides a mechanism that can be used to reverse and prevent AKI. Hydrodynamic delivery following ischemic injuries leads to reductions in serum creatinine and infiltrating mononuclear cells, as well as increased renal blood flow and survival. These changes are due to reductions in vascular congestion and inflammation typically seen following injury. To determine the underlying mechanisms of gene delivery preventing AKI, we used candidate genes identified in a proteomic screen on kidneys that recovered from AKI. We selected Isocitrate Dehydrogenase II (IDH2) and Sulfotransferase 1C2 (SULT1C2) for study and found that delivery prior to injury prevents serum creatinine increase and reduces cell death. We found that gene delivery of IDH2 prevents a glycolytic shift typically seen following ischemic injuries. The mechanism underlying the prevention of this shift are seen in increased ATP stores and spare respiratory capacity allowing the cell to remain in an oxidative state. Additionally, we show that SULT1C2 post-translationally modifies the mitochondria membrane, increasing oxidative phosphorylation providing the cell with additional energy needed in times of oxidative stress. These candidate genes allow cells to remain in an oxidative state preventing the activation of cell death pathways typically activated following injury, thereby preserving normal kidney function.

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg, 2016 / Background: Despite preventive guidelines, iatrogenic contrast-induced nephropathy (CIN) ranks third as a cause of hospital acquired acute kidney injury (AKI), and impacts significantly on morbidity and mortality and is associated with high hospital costs. In Sub-Saharan Africa, the rates and risk factors for CIN remain unexplored. Despite the positive association of genetic polymorphisms in the TNFα and IL10 genes with CIN in Asian populations, the CIN genetic susceptibility in other races is unknown. Serum creatinine is a sub-optimal biomarker for the early diagnosis of CIN resulting in delayed interventions. This study investigated rates, risk factors and outcomes of CIN, the influence of genetic susceptibility to CIN in the black population and lastly, the accuracy of novel biomarkers in the early diagnosis of CIN and prognosticating patient outcomes. Methods: This was a prospective case-controlled study conducted at Charlotte Maxeke Johannesburg Academic Hospital, in South Africa from January 1, 2014 to December 30, 2015.Hospitalized patients undergoing enhanced computed tomography and angiography were consecutively recruited to the study and followed up for development of CIN. CIN was defined as an increase in serum creatinine >25% or an absolute increase of >44 μmol/l from baseline at 48-72 hours after exposure to contrast media. In the second part of the study, a nested case-controlled cohort that included 30 CIN patients and 60 controls (those undergoing contrast administrations and not meeting CIN criteria) were ethnically matched for gender, and age in a case: control ratio of 1:2 at all-time intervals. Sera for neutrophil gelatinaseassociated lipocalin-2 (NGAL), cystatin C, beta-2 microglobulin (β2M), interleukin 18 (IL18), IL10, and tumor necrosis factor alpha (TNFα) were collected at four time points: baseline (pre-contrast), 24 hours, 48 hours and ≥5-7 days after contrast administration and their concentrations were determined using luminex assays and an enzyme linked immunosorbent assay for β2M as per manufacturer’s instructions. The areas under receiver operating characteristic curves (AUROC) were generated to determine accuracy of novel biomarkers to diagnose CIN and CIN mortality. Genomic DNA was extracted from peripheral blood samples of 208 black South Africans using the Maxwell DNA purification kit (Promega AS1010, USA) and their genotypes for - 308(rs1800629) and -857(rs1799724) in the TNFα gene and -592(rs1800872), - 819(rs1800871), -1082 (rs1800896) and +1582(rs1554286) in the IL10 gene were determined by restriction fragment length polymorphism (RFLP). Results: We recruited 371 hospitalized patients (mean age 49.3±15.9); the rates of CIN were4.6% and 16.4% respectively, using an absolute or relative increase in serum creatinine from baseline. Anaemia was an independent predictor for the development of CIN (RR 1.71, 95% 1.01-2.87; p=0.04). The median serum albumin was 34 g/l (IQR: 29-39.5) vs. 38 g/l (IQR: 31-42), p=0.01 in the CIN and control groups respectively.Mortality was significantly increased in the CIN group (22.4% vs. 6.8%; p<0.001), and CIN together with anaemia predicted mortality with a 2-fold (p=0.01) and a 3-fold (RR p=0.003) riskrespectively. The median cystatin C at 24 hours (p<0.001) and β2M(at all-time points)levels were significantly higher in the CIN group compared to controls. The median cystatin C at 24 hours and β2Mlevels at 48 hours were 856.59 ng/ml (IQR 620.75-1002.96) vs. 617.42 ng/ml (IQR 533.11-805.20); p<0.001 and 5.3 μg/ml (IQR 3.8-6.9) vs. 3.3 μg/ml (IQR 2.7-4.5); p<0.001 with AUROCs of 0.75 and 0.78 respectively for early CIN discrimination.Pre-contrast IL18 (p <0.001), β2M (p=0.04) and TNFα (p<0.001) levels were significantly higher in the nonsurviving group and their AUROC were 0.83, 0.82 and 0.94 for CIN+ mortality. Baseline NGAL was a better marker for excluding patients at higher risk of developing CIN with negative predictive and positive predictive values of 0.81 and 0.50 respectively. The frequency of TNFα -308 AA genotype was significantly increased in the CIN group compared to controls (13.3% vs.1.82%, p=0.016) and the presence of the TNFα-308 AA (high producer) vs. GA genotypes was associated with a 9-fold CIN risk (9.24, 95% CI, 1.88-45, p=0.006). The IL10-1082 AA-allele (low producer) was significantly higher in the non-surviving CIN+ patients compared to controls (p=0.01). Conclusions:CIN occurred at a relatively high rate in our study and predicted poorer clinical outcomes. The presence of CIN and anaemia positively predicted mortality. Caution should be exercised in patients with anaemia and hypoalbuminaemia undergoing contrast studies. Serumcystatin C was the best novel biomarker for the early diagnosis of CIN and while baseline NGAL is superior as a biomarker for excluding patients at higher risk for CIN. IL18, β2M and TNFα are the best novel biomarkers for predicting the prognosis of patients with CIN. Increased frequency of the TNFα-308 AA genotype is a predisposing factor for CIN development. The low producer IL10-1082 AA genotype decreases survival in patient with CIN. / MT2017

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