Consequences of AKI

AKI is associated with an increase in hospital length of stay (LOS), ICU-LOS, and higher morbidity and short and long-mortality [2, 14]. The 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines provided a classification of AKI in three different stages of severity based on serum creatinine levels and hourly urine output (Table 1) [15]. A correlation with AKI stages can be observed, where KDIGO stage 1 shows a twofold increase in mortality whereas severe AKI (stage 2–3) shows an almost 7-fold increase in mortality [5]. Clinical presentation of AKI is highly heterogeneous and depends on the severity of the injury. Many symptoms can be explained by an acute loss of glomerular filtration capability, which leads to azotemia and accumulation of protons, electrolytes, toxins, and drugs. The accumulation of uremic toxins has a direct impact on other organ systems and can start a vicious cycle of nephrotoxicity leading to reduced glomerular filtration rate (GFR) with further accumulation of toxins and subsequent increased toxicity [16, 17]. The development of metabolic acidosis is associated with a particularly poor prognosis [18]. Uremic toxicity can lead to arrhythmias (e.g. due to hyperkalemia), tiredness (e.g. due to azotemia), and in some cases it can cause confusion or even coma (e.g. accumulation of toxins, drugs). Furthermore, reduced urine output can lead to fluid overload and congestion which can cause or worsen ventilatory problems and lead to venous congestion with direct impact on other organs such as the liver and the kidney itself. After the initial resuscitation phase reduced kidney function can also complicate fluid deresuscitation [19].

Additionally, an episode of AKI may have longer-lasting effects on kidney function and increase the risk for the development or progression of CKD [20–23]. Even with apparent full recovery of kidney function the risk for ESKD stays elevated after single episodes of AKI [24–26]. The mechanisms underlying this progression are not solely explained by the loss of functioning nephrons but also by maladaptive repair mechanisms, disordered regeneration, and a vicious cycle of endothelial injury leading to hypoxia/ischemia and further endothelial injury [27–29]. As a result, AKI is regarded as a syndrome with multiple different consequences and not all clinical presentations of AKI can solely be explained by functional reductions of GFR [30]. Kidney cell injury and intrarenal inflammation play an important role in the pathophysiology of organ cross-talk in AKI and consequences thereof [31, 32]. AKI leads to (sterile) activation of kidney cells and local immune cells, including resident macrophages and dendritic cells, which causes the release of proinflammatory cytokines and subsequent systemic inflammation [32]. Over the past decades, the role of different immune cells (e.g. dendritic cells, macrophages), cytokines (e.g. interleukin-17 - IL-17, and tumor necrosis factor-alpha - TNF-α), and pattern recognition receptors (e.g. toll-like receptors - TLR) in development and progression of AKI was discovered. Moreover, epigenetic changes of fibroblasts, myofibroblasts, pericytes, and epithelial cells also play important roles in the progression of AKI and its consequences [33–37]. For example, after apparent recovery of kidney function profibrotic signaling might still persist locally [35, 38] and distantly through humoral pathways leading to long-term consequences in other organs [39]. This highlights AKI as a systemic syndrome with consequences going far beyond the acute complications resulting from acutely reduced GFR (Fig. 1).

The following section will address the impact of AKI on the lung, the brain, the heart, the liver and the immune system. For each organ system, the pathophysiological mechanisms and preclinical findings, focusing on inflammation triggered by AKI, will be discussed alongside clinical evidence, patient outcomes, and therapeutic strategies. Organ-specific damage biomarkers relevant to each of these systems, both experimental and clinically implemented, are summarized in Table 2 to complement the discussion.

Stage | Serum creatinine | Urine output
1 | 1.5–1.9 times baselineOR≥ 0.3 mg/dl (≥ 26.5mmol/l) increase | < 0.5 ml/kg/h for 6–12 h
2 | 2.0–2.9 times baseline | < 0.5 ml/kg/h for ≥ 12 h
3 | 3.0 times baselineORIncrease in serum creatinine to ≥ 4.0 mg/dl (≥ 353.6mmol/l)ORInitiation of renal replacement therapy OR, In patients < 18 years, decrease in eGFR to < 35 ml/min per 1.73 m2 | < 0.3 ml/kg/h for ≥ 24 h OR Anuria for ≥ 12 h

Fig. 1: Mechanisms of AKI-induced distant organ injuries. AKI=kidney injury; DAMPs= damage associated molecular patterns; IL-1 = interleukin-1; IL-6 = interleukin-6; IL-10 = interleukin-10; RAAS = renin-angiotensin-aldosterone system; ROS = reactive oxygen species; SNS= sympathetic nervous system; TLR2/4 = toll-like receptor 2/4; TNF-α = tumor necrosis factor-alpha

Organ/system | Biomarkers | Status | Purpose
Lung [40] | RAGE, SP-D, Ang-2 | Experimental | Epithelial/endothelial injury; ALI
Brain [41, 42] | NfL, GFAP, UCH-L1, TauS100B, NSE | ExperimentalImplemented | Brain dysfunction; prognosisPrognostication in TBI and cardiac arrest; still under evaluation for neuroprognostication in the critically ill
Heart [43] | BNP, cTnsST2, Galectin-3 | ImplementedExperimental | Diagnosis of HF/ACSPrognosis
Liver [44, 45] | Bilirubin, GGT, ALPAST, ALTmiR-122, GLDH, K18/ccK18, HMGB-1 | ImplementedImplementedExperimental | CongestionHepatocellular injuryHepatocellular injury
Infections [46] | PCT, CRP | Implemented | Infection and sepsis
Immune system [46] | IL-6, IL-8, IL-10 | Experimental | Inflammation/immunoparalysis
Kidney [47] | SCr, UO, Cystatin CNGAL, TIMP-2·IGFBP7CCL14, DKK3, proenkephalin A, KIM-1, L-FABP | ImplementedImplementedExperimental | AKI diagnosis and staging, GFR estimationNot routinely. Early tubular injury/stress; risk stratificationPersistent AKI, risk prediction, sub-phenotyping