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    Nephrotoxicity associated with preeclampsia in an Arginine Vasopressin induced rat pregnancy model
    (2023-05) Ramdin, Sapna; Naicker, Thajasvarie; Govender, Nalini
    Introduction: Globally, preeclampsia (PE) complicates an estimated 2-8% of pregnancies and is a leading cause of maternal and fetal morbidity and mortality. Renal injury is closely involved in the pathophysiology of PE and is associated with future risk of kidney disease. Identifying an early biomarker of renal dysfunction is essential for the diagnosis and treatment of PE. Given the clinical and ethical complexities associated with pregnancy studies in humans, animal models provide a more feasible alternative to pregnancy research. Aim: In view of this, this study aimed to determine the physiological and biochemical features of the arginine vasopressin (AVP) induced pregnancy model in the Sprague Dawley rat and to demonstrate nephrotoxicity associated with this model. Methodology: Urine, blood and kidney samples (n = 6 per study group) were collected from female Sprague Dawley rats, based on four study groups, viz., pregnant AVP, pregnant saline, non-pregnant AVP, and non-pregnant saline groups. The AVP rat model was physiologically characterized by evaluating the clinical, biochemical, haematological and fetal parameters across all study groups. Renal injury in AVP-treated rats was histologically determined by haematoxylin and eosin staining, as well as immunolocalizing kidney injury molecule-1 (KIM-1) and podocalyxin in both AVPtreated and untreated kidneys using immunohistochemistry. Ultrastructural changes in AVP-treated rats were determined by transmission electron microscopy. The Multiplex kidney toxicity immunoassay panels were used to determine the urinary concentration of albumin, vascular endothelial growth factor-A, clusterin, cystatin C, beta-2- microglobulin, KIM-1, neutrophil gelatinase-associated lipocalin-2, osteopontin and tissue inhibitor of metalloproteinases-1 in AVP-treated rats. Key findings: Chronic infusion of AVP throughout gestation reproduced the phenotypes viz., increased blood pressure, elevated urinary protein levels and fetal growth restriction, characteristic of human PE development. Immunohistochemical analysis confirm KIM1 immunolocalization in the proximal convoluted tubules of AVP-treated vs. untreated groups. Comparatively, a mild immunolocalization of podocalyxin was observed in the glomeruli of pregnant AVP-treated vs. pregnant untreated rats. Histological and ultrastructural evaluation of the AVP-treated pregnant rats demonstrated several abnormalities including, reduced Bowman’s space, necrosis of tubules and blood vessels, along with podocyte effacement, glomerular basement membrane abnormalities, podocyte nuclear crenations, mitochondrial dysfunction and cytoplasmic lysis consistent with renal injury in PE. Our findings indicate that AVP significantly reduces the urinary levels of vascular endothelial growth factor A and concomitantly up-regulates the urinary expression of clusterin, cystatin C, beta-2-microglobulin, KIM-1, neutrophil gelatinaseassociated lipocalin-2, osteopontin and tissue inhibitor of metalloproteinases-1. Conclusion: This is the first study to demonstrate that AVP induces glomerular and tubular injury, as well as endothelial dysfunction in the pregnant Sprague Dawley rat model. These features are characteristic of renal injury observed in PE. Furthermore, AVP successfully elevated the urinary levels of most glomerular and tubular injury biomarkers as well as produced histological and ultrastructural renal abnormalities associated with human PE. Our data demonstrates the importance of kidney injury as early detection biomarkers for PE development. The findings support the use of the AVP rat model in future studies investigating the pathogenic processes involved in PE development.
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    Chemotherapy induced renal and haematological toxicities in patients with invasive cervical cancer undergoing concurrent chemo-radiation
    (2021-05-27) Motala, Fathima; Pillay, Pavitra; Govender, Kamendran
    Cervical cancer is the most commonly diagnosed form of cancer in women of the developing world. Globally, the standardised treatment for women with invasive cervical cancer is concurrent chemo-radiation. Despite the survival benefit of concurrent chemo-radiation, there are concerns about associated toxicities and their harmful effects. Limited evidence shows the monitoring of the renal and haematological effects in invasive cervical cancer patients receiving concurrent chemo-radiation, compounded by women's biological vulnerability to human immunodeficiency virus (HIV), particularly in South Africa. In this prospective quantitative descriptive study, participants that presented for treatment were selected upon meeting the inclusion criteria. The study used a sample of 82 women, 32 (39%) of whom were HIV positive. Females between the ages of 21 and 75 years formed part of the study. All participants were undergoing concurrent chemo-radiation treatment at the Inkosi Albert Luthuli Central Hospital at the time of data collection. This study aimed to determine the renal and haematological toxicities associated with the chemotherapy component of concurrent chemo-radiation in patients with invasive cervical cancer, using renal and haematological biomarkers. The biomarkers, urea, creatinine and estimated glomerular filtration rate assessed renal toxicity. The full blood count biomarkers haemoglobin, white blood cells, platelets and absolute neutrophil count assessed haematological toxicity. The main finding was haematological toxicity in both HIV positive and HIV negative participants. No renal toxicity was found in this study among both the HIV positive and negative participants. Seventy (85%) of participants had stage II invasive cervical cancer. Ninety three percent of the cohort was diagnosed with invasive squamous cell carcinoma. The study found that the chemotherapy treatment completion rates for HIV negative and HIV positive participants were similar. Both groups were just as likely to complete the chemotherapy part of concurrent chemo-radiation. Based on the findings of this study, the same concurrent chemo-radiation protocol may be applied to both HIV negative and HIV positive women with invasive cervical cancer, however, further research using a larger population followed over a longer period is highly recommended.