Heatstroke can cause acute kidney injury (AKI), which reportedly progresses to chronic kidney disease. Kidney macrophages may be involved in such injury. Although heat acclimation (HA) provides thermal resilience, its renoprotective effect and mechanism remain unclear. To investigate heat stress-induced kidney injuries in mice and the mitigating effect of HA on them, male C57/BL6J mice were exposed to heat stress (40℃, 1 h), with or without 5-day HA (38℃, 3 h/day) prior to heat stress. Heat stress damaged kidney proximal tubules with elevation of urinary kidney injury molecule-1 (KIM-1). Kidney fibrosis was observed on day 7 and correlated with the urinary KIM-1 levels on day 3. Kidney resident macrophages decreased on day 1, whereas the number of infiltrating macrophages in the kidney did not change. Both subsets of macrophages polarized to the pro-inflammatory M1 phenotype on day 1; however, they polarized to the anti-inflammatory M2 phenotype on day 7. HA significantly ameliorated heat stress-induced proximal tubular damage and kidney fibrosis. HA substantially increased heat shock protein 70 (Hsp70) expression in the tubules before heat stress and reduced an elevation of cleaved caspase-3 expression after heat stress. HA also induced the Hsp70 expression of resident macrophages and prevented heat stress-induced changes in both subsets of kidney macrophages. These results provide pathophysiological data supporting the renoprotective effect of HA. Further studies are needed to confirm that HA can prevent kidney damage due to heat stress in humans.

Heatstroke can cause multiple organ failure and systemic inflammatory response syndrome as the body temperature rises beyond the body’s ability to regulate temperature in a hot environment. Previous studies have indicated that heatstroke-induced acute kidney injury (AKI) can lead to chronic kidney disease. Therefore, there is an urgent need to elucidate the mechanism of heatstroke-induced AKI and to establish methods for its prevention and treatment. Recent reports have revealed that innate immunity, including neutrophils, macrophages, lymphocytes, and mast cells, is deeply involved in heat-induced AKI. In this review, we will discuss the roles of each immune cell in heat-induced renal injury and their potential therapeutic use.

Acute kidney injury (AKI) remains a high mortality in sepsis and effective therapies based on its pathogenesis remain elusive. Macrophages are crucial for clearing bacteria from vital organs, including the kidney, under septic conditions. Excessive macrophage activation results in organ injury. C-reactive protein (CRP) peptide (174-185), a functional product of proteolyzed CRP in vivo, effectively activates macrophages. We investigated the therapeutic efficacy of synthetic CRP peptide on septic AKI, focusing on effects on kidney macrophages. Mice underwent cecal ligation and puncture (CLP) to induce septic AKI and were intraperitoneally administered 20 mg/kg of synthetic CRP peptide 1 hour post-CLP. Early CRP peptide treatment improved AKI while still clearing infection. Ly6C-negative kidney tissue-resident macrophages did not significantly increase at 3 hours after CLP, while Ly6C-positive monocyte-derived macrophages significantly accumulated in the kidney 3 hours post-CLP. CRP peptide augmented the phagocytic ROS production in both subtypes of kidney macrophage at 3 hours. Interestingly, both subtypes of macrophage increased ROS production 24 hours post-CLP compared to control, while CRP peptide treatment maintained ROS production at the same level seen 3 hours post-CLP. Although bacterium-phagocytic kidney macrophages produced TNF-α, CRP peptide reduced bacterial propagation and tissue TNF-α levels in the septic kidney at 24 hours. Although both subsets of kidney macrophages showed populations of M1 at 24 hours post-CLP, CRP peptide therapy skewed the macrophages population towards M2 at 24 hours. CRP peptide alleviated murine septic AKI via the controlled activation of kidney macrophages and is an excellent candidate for future human therapeutic studies.

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Background Since heatstroke-induced acute kidney injury (AKI) can progress to chronic kidney disease, it would be useful to detect heatstroke-induced AKI and severe heat-related illness in the early phase. We studied the epidemiology of heat-related illness among patients in the Japanese Ground Self-Defense Force and evaluated the relationship between heat-related illness severity and early urinary biomarkers for AKI. Methods We enrolled patients who were diagnosed with heat-related illness at Self-Defense Force Fuji Hospital from May 1 to September 30, 2020. We compared the urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), liver fatty acid binding protein (L-FABP), N-acetyl-β-D-glucosaminidase (NAG), and β2-microglobulin levels according to the severity of heat-related illness as defined by positive scores of the Japanese Association of Acute Medicine Heatstroke Working Group (JAAM-HS-WG) criteria (0, mild; 1, moderate; ≥2 (2+), severe). Results Of the 44 patients, kidney injury, defined as serum creatinine (sCr) ≥1.2 mg/dL, was seen in 9 (20.5%) patients. Urinary NAG, NGAL and L-FABP levels were significantly higher in the 2 + JAAM-HS-WG criteria group than in the 0 group. Furthermore, urinary L-FABP levels were positively correlated with sCr levels. In contrast, the urinary KIM-1 levels showed the best correlation with serum cystatin C (sCysC) among these biomarkers. Conclusions We conclude even mild to moderate heatstroke could lead to AKI. Urinary L-FABP is useful for detecting heatstroke-induced AKI and patients with severe heat-related illness requiring immediate treatment. Urinary KIM-1 may detect heatstroke-induced AKI in terms of sCysC, although it was not related to heat-related illness severity.