LAUSR

Development of treatment strategies for kidney diseases largely relies on experimental models of ureteral obstruction/tubularinterstitial fibrosis,1,2 acute kidney injury/ ischemia/reperfusion,3,4 cyclosporine toxicity5,6 or diabetic nephropathy.7 However, experimental models only partly replicate the respective human disease. Moreover, despite an impressive leap in mechanistic knowledge, the therapeutic yield for human has remained rather poor. One notable exception is novel, orally available, highly specific, small molecule activators of hypoxiainducible factor (HIF). Within two decades of basic and clinical research, these compounds made their way from bench to bedside, crossing European Medicines Agency's goal line for approval, under the cheers of the Nobel Prize Committee. Is such fanfare justified? It's up to you to decide: Gregg Semenza, Sir Peter Ratcliffe, and William Kaelin have identified the cellular oxygen sensor, an enzyme named HIF prolyl hydroxylase (PHD), and HIF as the ubiquitous cellular conductor to orchestrate adaptation to hypoxia. This brings us back to the kidney, a very sophisticated organ, often hardly accessible to clinical research. Imagine a Swiss watch's clockwork with hundreds of delicate cogwheels perfectly fitting together. You may admire its thrilling design and impeccable function, yet, you would probably not dare to look inside if it were at the risk of damaging it. Accordingly, kidney biopsies are often performed for diagnostic purposes nonetheless, they are rarely available for scientific research. Hence, we seldom get a look inside the kidney's sophisticated clockwork. Thus, noninvasive methods are under development to gain insight into the pathophysiology of various kidney disorders.8 For example, blood oxygenation leveldependent (BOLD) MRI to assess kidney hypoxia is of great interest.6,9 Is there a link between kidney disease and hypoxia? Certainly yes, both, acute and chronic kidney disease are often accompanied by kidney hypoxia. What if a small pill could help the kidney cope with hypoxia? This exactly is the promise of PHD inhibitors, beyond the treatment of renal anemia, the label obtained by regulatory authorities. Roxadustat is the first PHD inhibitor that was authorized for use in the EU in 2021. What is more, further HIF activators, with daprodustat being an example, are undergoing clinical investigations.10 To gain a better understanding of their medical indication, let us catch a glimpse of their specific mechanism of action. As mentioned above, PHD inhibitors activate the HIF pathway. Under normoxic conditions, HIFα is ubiquitinylated by the von Hippel– Lindau tumor supressor (VHL) and subsequently degraded through the proteasomal pathway.11 The binding ability of VHL is dependent on the hydroxylation of HIFα by PHDs which need oxygen as a substrate. When oxygen is missing or PHDs are blocked, HIFα accumulates, and translocates to the nucleus. There, it forms dimers with HIFβ and binds to hypoxia response elements of target genes, thus activating transcription.12 In a nutshell, PHD inhibitors prevent the degradation of HIFα, which results in stimulation of erythropoietin (Epo). Epo transcription and release is the consequence of low blood oxygen level, which is sensed by fibroblastlike cells in the kidney.13 This leads to an increased number of red blood cells and hemoglobin levels. Therefore, the therapeutic area of PHD inhibitors is the treatment of symptomatic anemia that may occur in patients with chronic kidney disease (CKD). A major risk factor for the development of CKD is acute kidney injury, depending on its frequency, severity, and duration.14 Further, CKD may progress to endstage renal disease (ESRD), a condition, where the only treatment options are dialysis or kidney transplantation. To prevent allograft rejection, immunosuppressive therapy is essential. A widely used class of immunosuppressant drugs are the socalled calcineurin inhibitors, such as CyclosporineA (CsA).15 Let us take another peek at the mechanism of action of these class of therapeutics. Under normal conditions, calmodulin binds— together with calcium ions— the phosphatase calcineurin, thus, increasing its activity. The calcineurin inhibitors CsA and tacrolimus form a complex with