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NEPHROLOGY macrophages (most with an alternatively activated phenotype and aligned along cyst walls). Macrophage depletion by intraperitoneal liposomal clodronate administration inhibits epi thelial cell proliferation and cyst growth and improves renal function. 7 How the loss of polycystin expression leads to increased cytokine production remains to be determined. Approaches that inhibit the expression or action of homing and proliferation signals provide novel strategies for treating PKD. Three studies have shown marked upregula tion of the signal transducer and transcription activator (STAT)3 in patients with ADPKD and in rodent PKD models. 8–10 In the STAT3 signaling pathway, activation of various cell surface growth factor receptors and cytokine receptors induces specific tyrosine phosphorylation of the receptors, which creates docking sites for latent cytoplasmic STAT3. STAT3 is then phosphorylated at tyrosine 705 by intrinsic tyrosine kinase activity of the activated growth factor receptors or by cytokine receptor-associated Janus kinase. The trigger for phosphorylation and activation of STAT3 in PKD is uncertain. Talbot et al. showed that phosphorylated STAT3 is highly expressed in cyst-lining cells and normal- appearing tubules and inter stitial cells in proximity to cysts. 8 This finding suggests that diffusible factors such as cytokines and growth factors are involved in the activation of STAT3. Phosphorylated STAT3 homodimers translocate to the nucleus and bind to promoter elements of genes that regulate cell differentiation, proliferation, apoptosis and angiogenesis. Because STAT3 is critical during development (deletion of STAT3 leads to embryonic lethality), but is dispensable postnatally in conditional knockouts, targeting STAT3 might be well tolerated in patients with PKD. Takakura et al. screened a small-molecule library using a cell-based functional assay and found that pyrimethamine, a drug used to treat malaria and toxoplasmosis, inhibits STAT3 signaling. 9 Pyrimethamine and S3I-201, an inhibitor of STAT3 homodimer complex formation, suppressed epithelial cell proliferation and cystogenesis in an inducible Pkd1-knockout mouse model without toxic effects. In another study, Leonhard et al. found that curcumin, a compound with anti-inflammatory and antiproliferative properties, reduced STAT3 activation, attenuated cell proliferation and cysto genesis and delayed renal failure from 105 to 119 days in an inducible Pkd1knockout model. 10 As curcumin has poor bioavailability, however, novel analogues with improved pharmacological profiles might be more effective than curcumin itself. In summary, insights into the complex network of signaling pathways disrupted in PKD have increasingly led to the identification of potential therapies, some of which are currently used for other indications. Those compounds best supported by preclinical studies and with the desired pharmacological profile should be prioritized for clinical trials. Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA (V. E. Torres, P. C. Harris). Correspondence to: V. E. Torres torres.vicente@mayo.edu Acknowledgments V. E. Torres and P. C. Harris are supported by the NIH grant DK090728. Competing interests V. E. Torres declares an association with the following company: Otsuka Pharmaceuticals. See the article online for full details of the relationship. P. C. Harris declares no competing interests. 1. Fedeles, S. V. et al. A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat. Genet. 43, 639–647 (2011). 2. Reif, G. A. et al. Tolvaptan inhibits ERKdependent cell proliferation, Cl – secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. Am. J. Physiol. Renal Physiol. 301, F1005–F1013 (2011). 3. Higashihara, E. et al. for the TEMPOFormula and 156-05-002 Study Investigators. Tolvaptan in autosomal dominant polycystic kidney disease: three years’ experience. Clin. J. Am. Soc. Nephrol. 6, 2499–2507 (2011). 4. Takiar, V. et al. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc. Natl Acad. Sci. USA 108, 2462–2467 (2011). 5. Yoshihara, D. et al. PPAR-γ agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease. Am. J. Physiol. Renal Physiol. 300, F465–F474 (2011). 6. Blazer-Yost, B. L. et al. Pioglitazone attenuates cystic burden in the PCK rodent model of polycystic kidney disease. PPAR Res. 2010, 274376 (2010). 7. Karihaloo, A. et al. Macrophages promote cyst growth in polycystic kidney disease. J. Am. Soc. Nephrol. 22, 1809–1814 (2011). 8. Talbot, J. J. et al. Polycystin-1 regulates STAT activity by a dual mechanism. Proc. Natl Acad. Sci. USA 108, 7985–7990 (2011). 9. Takakura, A. et al. Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways. Hum. Mol. Genet. 20, 4143–4154 (2011). 10. Leonhard, W. N. et al. Curcumin inhibits cystogenesis by simultaneous interference of multiple signaling pathways: in vivo evidence from a Pkd1-deletion model. Am. J. Physiol. Renal Physiol. 300, F1193–F1202 (2011). ACUTE KIDNEY INJURY IN 2011 Biomarkers are transforming our understanding of AKI Lakhmir S. Chawla and John A. Kellum Acute kidney injury (AKI) is a syndrome of decreased renal function that is associated with an increased risk of death. Studies from 2011, particularly in the field of AKI biomarkers, have provided important insights into the diagnosis, prognosis, and treatment of AKI. These advances are now being brought to the bedside to improve diagnosis and treatment of AKI. Chawla, L. S. & Kellum, J. A. Nat. Rev. Nephrol. 8, 68–70 (2012); published online 17 January 2012; doi:10.1038/nrneph.2011.216 Over 2 million people are afflicted by acute kidney injury (AKI) worldwide. 1 AKI is a serious complication of acute illness, typically occurring as a result of underlying conditions such as sepsis, and is independently associated with death. It has become increasingly clear that AKI is associated with the development of endstage renal disease (ESRD) and chronic kidney disease (CKD). 2,3 Individuals fortunate enough to survive a severe episode of AKI are therefore at risk of develop ing CKD-related disease. Our understanding of AKI has advanced over the past decade, with a unified definition and standard criteria for staging, a quantification of renal replacement therapy (RRT) dosing, and the emergence of biomarkers related to AKI. In 2011, multiple studies were published that improve our understanding of AKI through the use of various biomarkers. Perhaps the most illuminating study published in 2011 was one by Paragas et al. that examined the expression of neutrophil-related gelatinase lipocalin (NGAL) using a luciferase reporter assay. 4 S46 | JANUARY 2012 www.nature.com/reviews
Although NGAL has been shown in multiple large cohort studies to be a biomarker for early AKI diagnosis and for AKI prognosis, 5 NGAL is expressed in multi ple organs and is thus not kidney specific. Understanding how non-kidney sources of NGAL impact the urinary NGAL signal and indeed establishing the sources of NGAL in AKI is essential. Paragas and colleagues 4 conducted their novel experiment by creating a reporter mouse for NGAL. They inserted a double-fusion reporter gene that encoded luciferase-2 and mCherry (Luc2-mC) in the locus for NGAL (lcn-2). In so doing, the investigators could assess the endogenous NGAL message in real time and assess in which organs the message was being transcribed. In separate experiments, mice were subjected to unilateral renal ischemia, bilateral renal ischemia or nephrotoxic injury with cisplatin. In addition, the investigators tested whether NGAL-Luc2-mC was activated in pre-renal azotemia and ascertained the segments of the nephron responsible for urinary NGAL (uNGAL) production in AKI. The investi gators determined that the principal or exclusive source of uNGAL was the thick ascending limb and the collecting ducts of the nephron. In addition, in the prerenal azotemia model, serum creatinine level rose, but NGAL-Luc2-mC was not activated and no increase in uNGAL level occurred. These data show that uNGAL is an appropriate kidney-injury-specific biomarker despite not being exclusively expressed in the kidney. Another study involving NGAL displayed the range of methods by which AKI biomarkers can assist clinicians caring for patients with AKI. NGAL has been primarily thought of as a biomarker for the early diagnosis of AKI, 5 but utility of this biomarker and others may be much broader. Using a large multicenter cohort of patients with community-acquired pneumonia, Srisawat and colleagues 6 examined plasma of patients on the first day they experienced severe AKI (defined as RIFLE-F by the Risk, Injury, Failure, Loss and ESRD (RIFLE) criteria). In this study, recovery was defined as being alive and neither requiring RRT during hospitalization nor having a persistent RIFLE-F classification at hospital discharge. The investigators found that elevated plasma NGAL (pNGAL) levels were associated with renal non-recovery. Although the absolute predictive value of pNGAL alone was only fair (area under the receiver operating characteristic curve 0.74), the reclassification of risk of not Key advances ■ The source of urinary neutrophil-related gelatinase lipocalin (NGAL) seems to be nearly exclusively from the renal tubule and does not seem to be released during pre-renal azotemia in healthy animals 4 ■ Plasma NGAL level helps predict which patients with severe acute kidney injury (AKI) will recover renal function 6 ■ Urine output remains an important ‘biomarker’ of AKI, and predicts death even in the absence of a rise in serum creatinine level 7 ■ Micro RNAs are a new class of AKI biomarkers that may prove to be important new tools in the diagnosis and treatment of AKI 8 recovering renal function was increased by 17%. These data are most notable for two reasons. First, because AKI can cause CKD and ESRD, decisions regarding longterm care (for example, use of dialysis, vascular access, and follow-up) are often made in a piecemeal approach. If objective metrics coupled with clinical assessment can improve prognostic accuracy, a better informed decision can be made for survivors of AKI. Second, the association between pNGAL and renal non-recovery suggests that renal injury is ongoing, and even if a patient is under going dialysis, thera pies directed at mitiga ting ongoing injury may have a role in AKI treatment. ‘‘ ...some existing biomarkers such as NGAL will begin to shape clinical practice... Within the advancing field of AKI, the oldest known biomarker is urine output. The precise utility of oliguria has been controversial, and within the Acute Kidney Injury Network (AKIN) staging system, there has been discussion on the precise definition of oliguria over time (for example, consecutive hours of oliguria versus average urine output over a period of time). To further the understanding, Macedo and colleagues7 ’’ utilized high-fidelity urimeters to compare various definitions of oliguria in critically ill patients. In their study, 317 patients had speciali zed high-accuracy urimeters placed on their urinary catheters in order to measure their urine output hourly. Serum creatinine was measured every 12 h, and definitions of AKI based on urine output were compared with those based on serum creatinine. Urine output was classified in NEPHROLOGY three ways: consecutive hours of oliguria (oligo6-cons), an average amount of oliguria over a fixed block of time (
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