Impact of Folate Administration on One-Year Mortality in Patients With Infection-Associated Acute Kidney Injury: An Open-Label Randomised Controlled Study

1. Background Information Acute Kidney Injury (AKI) affects over 13 million people each year and has a hospital mortality of 20-40%. It is characterized by an abrupt loss of kidney function and is associated with multiple long-term sequelae including chronic kidney disease (CKD) and reliance on renal replacement therapy (RRT). Patients with AKI place a substantial financial burden on healthcare resources . Approximately 19%-37% of patients with AKI do not recover kidney function within one year, and 33% of patients progress to acute kidney disease (AKD), and from this subset, nearly 27% develop CKD within 90 days post-AKI diagnosis. This highlights the critical importance of early detection and effective management of AKI to prevent progression.

1.1 Epidemiology of AKI AKI affects all countries, and its prevalence ranges from <1% to 66%. Apart from population variation, different classification systems used in epidemiological studies contributes to the varied estimation of AKI incidence. Little epidemiological data is available for AKI in Hong Kong (HK). Szeto and Pang reported AKI was present in 9.1% of all adult hospital admissions in HK. The crude mortality rate of AKI in patients attending an emergency department (ED) in HK is 25%.

1.2 Etiology of AKI AKI is a complex syndrome. The causes of AKI can be classified into prerenal, intrinsic renal and postrenal. Prerenal causes involve reduced renal perfusion due to medications, heart failure, infections, sepsis or volume depletion (e.g., diuretic overuse, severe dehydration and diarrhea). Intrinsic renal causes involve direct damage to the kidney structures including pre-existing renal impairment (e.g., glomerulonephritis, interstitial nephritis and vasculitis), and nephrotoxic drugs. Postrenal AKI is due to obstruction of urinary flow (e.g., kidney stone and tumors), and is especially common in elderly men. Sepsis, infections and use of nephrotoxic drugs are common causes of AKI overall, leading to reduced renal blood flow. In intensive care unit (ICU) settings, AKI occurs in more than half of patients, and half of all patients with AKI in ICU have sepsis. Drug induced AKI occurs in 20% of hospital cases. Associated drugs include non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers [ARBs], metformin, aminoglycosides, diuretics and iodine containing X-ray contrast.

The diverse etiologies of AKI along with other comorbidities make it difficult to determine and understand the pathophysiology of AKI. Recently, oxidative stress has been accepted as the primary mediator of adverse outcomes in AKI, playing a critical role in both initiating and further development of AKI. In the context of deficient renal blood flow in AKI, ischemia-reperfusion represents the most common mechanism in which oxygen and nutrient delivery as well as waste removal are impaired; this mismatch of oxygen supply and demand, and accumulation of waste lead to cellular injury and even death. Sepsis-induced AKI also triggers oxidative stress. Oxidative stress as a key component in the pathophysiology of AKI provides a target for potential therapeutics.

1.3 Treatment for AKI The KDIGO serum creatinine-based criteria is mostly used to stage AKI. The management of AKI is primarily supportive. The key to management is assuring hemodynamic stability and preventing hypovolemia so as to ensure sufficient renal perfusion. Depending on the cause and severity of AKI, treatments in hospital usually include: blood pressure and circulating electrolyte control; body fluid balance (e.g., with fluid replacement and/or diuretics); review and cessation of nephrotoxic medication; removing the obstruction if there is obstruction; and use of antibiotics. Malnutrition also affects patients with AKI, which requires a kidney-friendly diet, adequate nutrition and restricting potassium. There are no approved pharmacological agents for treating AKI.