- Email: [email protected]
Uremic lung: new insights into a forgotten condition
co m m e nta r y
8.
introduction to stem cells. J Pathol 2002; 197: 419–423. da Silva Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 2006; 119: 2204–2213.
9.
Forbes SJ, Poulsom R, Wright NA. Hepatic and renal differentiation from blood-borne stem cells. Gene Ther 2002; 9: 625–630. 10. Takahashi K, Tanabe K, Ohnuki M et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131: 1–12.
see original article on page 901
Uremic lung: new insights into a forgotten condition Paul J. Scheel1, Manchang Liu1 and Hamid Rabb1 The high mortality rate of acute kidney injury (AKI) despite advances in dialysis led to a renewed appreciation of the impact of AKI on distant organ dysfunction. Mechanistic studies demonstrated that AKI induces increased lung vascular permeability, soluble and cellular inflammation, and dysregulated salt and water channels. AKI also affects the brain, heart, liver, bone marrow, and gastrointestinal tract. Klein et al. now demonstrate that interleukin-6 is a direct mediator of AKI-induced lung changes. Kidney International (2008) 74, 849–851. doi:10.1038/ki.2008.390
The modern era of the study of the pathophysiology of acute renal failure (currently referred to as acute kidney injury, AKI) began with the publication of the landmark observations of Bywaters and Beall1 in the early 1940s with their description of the physiologic changes observed in soldiers suffering from AKI attributed to crush injury. Unfortunately, only supportive therapy was available, and the mortality in this population was greater than 90%. In the 1950s it was identified that the lung can also be injured during AKI, with these patients manifesting abnormal chest X-rays postulated to be secondary to “increased permeability of congested pulmonary capillaries.”2 These lung changes were also identified in chronic kidney disease, and dubbed ‘uremic lung.’ With the introduction of dialysis in the 1950s, the mortality rates associated with AKI decreased to 50%–60%. With fluid removal by dialysis, many believed that ‘uremic lung’ was no 1Nephrology Division, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Correspondence: Hamid Rabb, Ross 965, Johns Hopkins University, 720 Rutland Avenue, Baltimore, Maryland 21205, USA. E-mail: [email protected]
Kidney International (2008) 74
longer a real entity, that the lung changes observed during kidney dysfunction were entirely due to increased effective blood volume, and that dialysis was the answer for patients with AKI. Unfortunately, over the past 50 years there has been minimal improvement in this high mortality rate despite improvements in dialysis technology and advances in supportive care. AKI still remains a common condition in hospitalized patients, especially those in an intensive care unit (ICU) setting. A multicenter, multinational study found that 6% of ICU patients had severe enough AKI to require renal replacement therapy.3 While newer studies have confirmed the high rates of renal injury in an ICU setting, these have also alerted the renal community to previously unforeseen effects of mild to moderate kidney injury — those of increased mortality with mild to moderate elevations in serum creatinine. Patients with a 25% increase in serum creatinine secondary to radiocontrast injection had a fivefold increase in hospital mortality.4 In an analysis of hospital records of 19,982 adult patients, a more than 0.5 mg/dl increase in serum creatinine was associated with a 6.5-fold increase in the
odds of death.5 Though most believed that the high mortality rate was from patients dying ‘with renal disease,’ increasing data now support that patients are dying ‘from renal disease.’ How does one explain the relationship between AKI and escalating mortality? Is AKI merely an indicator of severe organ injury, and dialysis only changing the cause of death rather than incidence and timing? Does AKI directly, either through direct kidney injury or inability to clear toxic substances, lead to distant organ dysfunction that in turn predisposes to death? To evaluate whether AKI directly effects distant organ function, and whether the entity called ‘uremic lung’ is indeed real, mechanistic studies with new tools have been performed in rodents during AKI. AKI increased pulmonary vascular albumin permeability, erythrocyte sludging in lung capillaries, and interstitial edema, even when animals did not acutely gain total body fluids.6 Furthermore, intervening by dampening systemic macrophage function partially attenuated lung changes after AKI. The increased lung interstitial edema was associated with dysregulated lung salt and water transporters, notably ENaC, Na, K-ATPase, and aquaporin-5.7 The lung changes after AKI were found to start early and could be attenuated with α-melanocyte-stimulating hormone, a broad anti-inflammatory agent.8 Comorbid conditions such as sickle-cell disease accentuated AKI effects on the lung.9 Detailed genomic analysis followed by polymerase chain reaction and protein studies led to the prediction that multiple pathways, including interleukin-6 (IL-6), IL-10, endothelin, and serum amyloid 3, could mediate AKIinduced lung dysfunction.10,11 AKI leads to abnormalities in many other organs besides the lung (Figure 1). AKI has been reported to increase cardiac apoptosis and production of IL-1 and tumor necrosis factor.12 Given that severe AKI is well known to cause uremic encephalopathy, a classic indication to initiate dialysis, the effects of AKI on the brain have been studied experimentally. In mice, AKI led to increased expression of glial fibrillary acidic protein (a marker of inflammation) in astrocytes in the cortex and corpus callosum, activation of microglia (brain macrophages), increased vascular permeability to blood albumin, 849
co m m e nta r y
Brain KC & G-CSF GFAP & microglia Vascular permeability
Lung Vascular permeability Dysregulated channels Cytokines/chemokines Transcriptomic changes Leukocyte trafficking Altered response to ventilator-associated injury
Heart TNF-α, IL-1 Neutrophil trafficking Apoptosis Fractional shortening
AKI
Liver
Bone marrow Anemia Coagulation disorders Immune dysfunction
Leukocyte influx Oxidation products Antioxidants (GSH) Altered liver enzymes Gastrointestinal tract Channel-inducing factor Potassium excretion
Figure 1 | AKI-induced distant organ effects. AKI leads to changes in distant organs, including brain, lungs, heart, liver, gastrointestinal tract, and bone marrow. Changes have been described in organ function, microvascular inflammation and coagulation, cell apoptosis, transporter activity, oxidative stress, and transcriptional responses. Abbreviations: AKI, acute kidney injury; G-CSF, granular colony-stimulating factor; GFAP, glial fibrillary acidic protein; GSH, glutathione; IL-1, interleukin-1; KC, keratinocyte-derived chemokine; TNF-α, tumor necrosis factor-α.
increased levels of the proinflammatory chemokines keratinocyte-derived chemo attractant and granular colony-stimulating factor in the cerebral cortex and hippocampus, and decreased locomotor activity.13 Klein et al.14 (this issue) have now further explored pathways and mechanisms by which AKI leads to lung changes in a mouse model. They confirm previous results showing that AKI leads to increased lung vascular permeability and both cellular and soluble inflammation in the lung, and that lung dysfunction begins within hours. Additionally, they demonstrate that IL-6 is a direct mediator of AKI-induced increase in vascular permeability, leukocyte trafficking, and increased edema. This is elegantly proven with complementary in vivo approaches — use of IL6-deficient mice, IL-6-blocking antibody, and administration of IL-6 protein directly 850
into wild-type mice. They use an important control, bilateral nephrectomy, and demonstrate that IL-6 still mediates lung changes in the absence of kidneys; thus the kidney is not an essential source of the deleterious IL-6. Another important new finding is the linkage of IL-6 effects on the lung with keratinocyte-derived chemokine (KC). KC is a CXC chemokine that is structurally homologous to rat cytokineinduced neutrophil chemoattractant and human growth-related oncogene-α, which regulates neutrophil trafficking and is an early biomarker of AKI.15 KC rapidly increases in mouse lung after AKI, and this rise is blunted with manipulations in IL-6. As another chemokine, macrophage inflammatory protein 2, was unaffected by IL-6 interventions, a degree of specificity to the IL-6–KC pathway was postulated. A number of other interesting questions arise
from these data. Given that most patients are seen after the initial kidney injury, the lung effects of starting IL-6 antibody after different reperfusion times, rather than only before treatment, would have been useful to study. The lung, like the kidney, has regional heterogeneity; thus, did AKI have uniform or localized effects on the lung? What cells produce IL-6 after AKI, and what cells in the lung were targets of IL-6? What are the mechanisms by which IL-6 leads to alterations in microvascular inflammation and permeability? On a technical note, it is interesting that 22 minutes of kidney ischemia led to AKI and distant organ changes in this laboratory, whereas in most other laboratories, longer ischemic times are needed to induce a rise in serum creatinine in mice. Differences among laboratories, including those in temperature regulation, fluids, and perhaps even altitude in this case (these studies were performed in Denver, Colorado, one mile above sea level), could have effects. This underscores the importance of tight internal controls and careful descriptions of how the study was performed. Studies in rodents are crucial to identify mechanisms and to examine safety before human studies are conducted, and it is important to know whether the current findings are applicable to larger mammal models and, ultimately, humans. It is well established that injury to the gut or limb alters the lung, but given the important clearance function of the kidney, what distinguishes the effects of AKI on the lung from the effects of injury to other organs? What other soluble factors besides IL-6 mediate AKI-induced distant organ injury, and what is the role of other non-inflammatory pathways — such as neural arcs? Though we assume that AKI only leads to worsening of distant organ function, this is probably simplistic: AKI in mice reduced the decline in peripheral blood oxygenation normally caused by lung injury induced by acid aspiration and injurious mechanical ventilation.16 How can we use these studies to decrease the high mortality and morbidity rate in patients with AKI? Given that increased dosing of dialysis from three to five to six times per week is unlikely to improve mortality during AKI,17 what other strategies can be designed to better Kidney International (2008) 74
co m m e nta r y
clear AKI-induced distant organ toxins? Earlier initiation of dialysis? Continuous dialysis over intermittent? Improved membranes? Novel dialysis approaches, such as the renal assist device? Pharmacologic approaches to block deleterious pathways induced by AKI? A major opportunity clearly exists to improve our care of AKI patients, and studies on complex inter-organ cross talk will guide rational interventions in this common, often catastrophic, syndrome. DISCLOSURE The authors declared no competing interests. References
1.
2. 3. 4. 5.
6.
7. 8.
9.
10.
11.
12. 13.
14.
15.
Bywaters EG, Beall D. Crush injuries with impairment of renal function. Br Med J 1941; 1: 427–432. Bass HE, Singer E. Pulmonary changes in uremia. J Am Med Assoc 1950; 144: 819–823. Uchino S, Kellum JA, Bellomo R et al. Acute renal failure in critically ill patients. A multinational, multicenter study. JAMA 2005; 294: 813–818. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A cohort analysis. JAMA 1996; 275: 1489–1494. Chertow G, Burdick E, Honour M et al. Acute kidney injury, mortality, length of stay and costs in hospitalized patients. J Am Soc Nephrol 2005; 16: 3365–3370. Kramer AA, Postler G, Salhab KF et al. Renal ischemia/reperfusion leads to macrophagemediated increase in pulmonary vascular permeability. Kidney Int 1999; 55: 2362–2367. Rabb H, Wang Z, Nemoto T et al. Acute renal failure leads to dysregulation of lung salt and water channels. Kidney Int 2003; 63: 600–606. Deng J, Hu X, Yuen PS, Star RA. Alpha-melanocytestimulating hormone inhibits lung injury after renal ischemia/reperfusion. Am J Respir Crit Care Med 2004; 169: 749–756. Nath KA, Grande JP, Croatt AJ et al. Transgenic sickle mice are markedly sensitive to renal ischemia-reperfusion injury. Am J Pathol 2005; 166: 963–967. Hassoun HT, Grigoryev DN, Lie ML et al. Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy. Am J Physiol Renal Physiol 2007; 293: F30–F40. Grigoryev DN, Liu M, Hassoun HT et al. The local and systemic inflammatory transcriptome after acute kidney injury. J Am Soc Nephrol 2008; 19: 547–558. Kelly KJ. Distant effects of experimental renal ischemia/reperfusion injury. J Am Soc Nephrol 2003; 14: 1549–1558. Liu M, Liang Y, Chigurupati S et al. Acute kidney injury leads to inflammation and functional changes in the brain. J Am Soc Nephrol 2008; 19: 1360–1370. Klein CL, Hoke TS, Fang W-F et al. Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy. Kidney Int 2008; 74: 901–909. Molls RR, Savransky V, Liu M et al. Keratinocytederived chemokine is an early biomarker of ischemic acute kidney injury. Am J Physiol Renal Physiol 2006; 290: F1187–F1193.
Kidney International (2008) 74
16. Zarbock A, Schmolke M, Spieker T et al. Acute uremia but not renal inflammation attenuates aseptic acute lung injury: a critical role for uremic neutrophils. J Am Soc Nephrol 2006; 17:
3124–3131. 17. VA/NIH Acute Renal Failure Trial Network. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med 2008; 359: 7–20.
see original article on page 890
Renin–angiotensin system blockade and diabetes: moving the adipose organ from the periphery to the center Oliver Lenz1 and Alessia Fornoni1,2 Lee et al. report that an angiotensin II type 1 receptor blocker (ARB) improved glucose intolerance in OLETF rats, an experimental model of type 2 diabetes. ARB treatment resulted in modulation of the adipose tissue, leading to an increased number of small, differentiated adipocytes able to produce more adiponectin and less monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1. This supports the relevance of the functional interplay between adipose tissue and the renin–angiotensin system in states of insulin resistance. Kidney International (2008) 74, 851–853. doi:10.1038/ki.2008.391
A large body of literature suggests that renin–angiotensin system (RAS) blockade with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker (ARB) will prevent new-onset type 2 diabetes.1 Two receptors for angio tensin II have been described in humans, the angiotensin II type 1 (AT1) and type 2 (AT2) receptors. Among them, the AT1 receptor seems to be primarily responsible for the metabolic effect of RAS blockade.2 In fact, the AT1 and AT2 receptors may have antagonistic activities on glucose 1Division of Nephrology and Hypertension,
Department of Medicine, University of Miami Leonard Miller School of Medicine, Miami, Florida, USA; and 2Diabetes Research Institute, University of Miami Leonard Miller School of Medicine, Miami, Florida, USA Correspondence: Alessia Fornoni, Division of Nephrology and Hypertension and Diabetes Research Institute, University of Miami Leonard Miller School of Medicine, 1450 NW 10th Ave., Room 500, Miami, Florida, 33136, USA. E-mail: [email protected]
uptake and cell differentiation in adipose tissue, as suggested by studies performed in AT2-null mice.3 How RAS blockade leads to a diminished incidence of type 2 diabetes remains to be fully elucidated. The following mechanisms are being investigated (Figure 1): upregulation of muscle glucose uptake via modulation of glucose transporter-4 (GLUT4) and blood flow;4 improvement of pancreatic β-cell function;5 modulation of hormonal responses from adipose tissue;2 decreased hepatic gluconeogenesis and increased free fatty acid oxidation;6 improvement of endothelial function through downregulation of NADPH oxidase;2 direct stimulation of insulin signaling at multiple levels;7 and direct regulation of peroxisome proliferator-activated receptor-γ (PPARγ) by selected ARBs, such as telmisartan and irbesartan.8 Experimental data suggest that RAS-blocking agents that act on more than one pathway might be more effective for the prevention of 851
8.
introduction to stem cells. J Pathol 2002; 197: 419–423. da Silva Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 2006; 119: 2204–2213.
9.
Forbes SJ, Poulsom R, Wright NA. Hepatic and renal differentiation from blood-borne stem cells. Gene Ther 2002; 9: 625–630. 10. Takahashi K, Tanabe K, Ohnuki M et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131: 1–12.
see original article on page 901
Uremic lung: new insights into a forgotten condition Paul J. Scheel1, Manchang Liu1 and Hamid Rabb1 The high mortality rate of acute kidney injury (AKI) despite advances in dialysis led to a renewed appreciation of the impact of AKI on distant organ dysfunction. Mechanistic studies demonstrated that AKI induces increased lung vascular permeability, soluble and cellular inflammation, and dysregulated salt and water channels. AKI also affects the brain, heart, liver, bone marrow, and gastrointestinal tract. Klein et al. now demonstrate that interleukin-6 is a direct mediator of AKI-induced lung changes. Kidney International (2008) 74, 849–851. doi:10.1038/ki.2008.390
The modern era of the study of the pathophysiology of acute renal failure (currently referred to as acute kidney injury, AKI) began with the publication of the landmark observations of Bywaters and Beall1 in the early 1940s with their description of the physiologic changes observed in soldiers suffering from AKI attributed to crush injury. Unfortunately, only supportive therapy was available, and the mortality in this population was greater than 90%. In the 1950s it was identified that the lung can also be injured during AKI, with these patients manifesting abnormal chest X-rays postulated to be secondary to “increased permeability of congested pulmonary capillaries.”2 These lung changes were also identified in chronic kidney disease, and dubbed ‘uremic lung.’ With the introduction of dialysis in the 1950s, the mortality rates associated with AKI decreased to 50%–60%. With fluid removal by dialysis, many believed that ‘uremic lung’ was no 1Nephrology Division, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Correspondence: Hamid Rabb, Ross 965, Johns Hopkins University, 720 Rutland Avenue, Baltimore, Maryland 21205, USA. E-mail: [email protected]
Kidney International (2008) 74
longer a real entity, that the lung changes observed during kidney dysfunction were entirely due to increased effective blood volume, and that dialysis was the answer for patients with AKI. Unfortunately, over the past 50 years there has been minimal improvement in this high mortality rate despite improvements in dialysis technology and advances in supportive care. AKI still remains a common condition in hospitalized patients, especially those in an intensive care unit (ICU) setting. A multicenter, multinational study found that 6% of ICU patients had severe enough AKI to require renal replacement therapy.3 While newer studies have confirmed the high rates of renal injury in an ICU setting, these have also alerted the renal community to previously unforeseen effects of mild to moderate kidney injury — those of increased mortality with mild to moderate elevations in serum creatinine. Patients with a 25% increase in serum creatinine secondary to radiocontrast injection had a fivefold increase in hospital mortality.4 In an analysis of hospital records of 19,982 adult patients, a more than 0.5 mg/dl increase in serum creatinine was associated with a 6.5-fold increase in the
odds of death.5 Though most believed that the high mortality rate was from patients dying ‘with renal disease,’ increasing data now support that patients are dying ‘from renal disease.’ How does one explain the relationship between AKI and escalating mortality? Is AKI merely an indicator of severe organ injury, and dialysis only changing the cause of death rather than incidence and timing? Does AKI directly, either through direct kidney injury or inability to clear toxic substances, lead to distant organ dysfunction that in turn predisposes to death? To evaluate whether AKI directly effects distant organ function, and whether the entity called ‘uremic lung’ is indeed real, mechanistic studies with new tools have been performed in rodents during AKI. AKI increased pulmonary vascular albumin permeability, erythrocyte sludging in lung capillaries, and interstitial edema, even when animals did not acutely gain total body fluids.6 Furthermore, intervening by dampening systemic macrophage function partially attenuated lung changes after AKI. The increased lung interstitial edema was associated with dysregulated lung salt and water transporters, notably ENaC, Na, K-ATPase, and aquaporin-5.7 The lung changes after AKI were found to start early and could be attenuated with α-melanocyte-stimulating hormone, a broad anti-inflammatory agent.8 Comorbid conditions such as sickle-cell disease accentuated AKI effects on the lung.9 Detailed genomic analysis followed by polymerase chain reaction and protein studies led to the prediction that multiple pathways, including interleukin-6 (IL-6), IL-10, endothelin, and serum amyloid 3, could mediate AKIinduced lung dysfunction.10,11 AKI leads to abnormalities in many other organs besides the lung (Figure 1). AKI has been reported to increase cardiac apoptosis and production of IL-1 and tumor necrosis factor.12 Given that severe AKI is well known to cause uremic encephalopathy, a classic indication to initiate dialysis, the effects of AKI on the brain have been studied experimentally. In mice, AKI led to increased expression of glial fibrillary acidic protein (a marker of inflammation) in astrocytes in the cortex and corpus callosum, activation of microglia (brain macrophages), increased vascular permeability to blood albumin, 849
co m m e nta r y
Brain KC & G-CSF GFAP & microglia Vascular permeability
Lung Vascular permeability Dysregulated channels Cytokines/chemokines Transcriptomic changes Leukocyte trafficking Altered response to ventilator-associated injury
Heart TNF-α, IL-1 Neutrophil trafficking Apoptosis Fractional shortening
AKI
Liver
Bone marrow Anemia Coagulation disorders Immune dysfunction
Leukocyte influx Oxidation products Antioxidants (GSH) Altered liver enzymes Gastrointestinal tract Channel-inducing factor Potassium excretion
Figure 1 | AKI-induced distant organ effects. AKI leads to changes in distant organs, including brain, lungs, heart, liver, gastrointestinal tract, and bone marrow. Changes have been described in organ function, microvascular inflammation and coagulation, cell apoptosis, transporter activity, oxidative stress, and transcriptional responses. Abbreviations: AKI, acute kidney injury; G-CSF, granular colony-stimulating factor; GFAP, glial fibrillary acidic protein; GSH, glutathione; IL-1, interleukin-1; KC, keratinocyte-derived chemokine; TNF-α, tumor necrosis factor-α.
increased levels of the proinflammatory chemokines keratinocyte-derived chemo attractant and granular colony-stimulating factor in the cerebral cortex and hippocampus, and decreased locomotor activity.13 Klein et al.14 (this issue) have now further explored pathways and mechanisms by which AKI leads to lung changes in a mouse model. They confirm previous results showing that AKI leads to increased lung vascular permeability and both cellular and soluble inflammation in the lung, and that lung dysfunction begins within hours. Additionally, they demonstrate that IL-6 is a direct mediator of AKI-induced increase in vascular permeability, leukocyte trafficking, and increased edema. This is elegantly proven with complementary in vivo approaches — use of IL6-deficient mice, IL-6-blocking antibody, and administration of IL-6 protein directly 850
into wild-type mice. They use an important control, bilateral nephrectomy, and demonstrate that IL-6 still mediates lung changes in the absence of kidneys; thus the kidney is not an essential source of the deleterious IL-6. Another important new finding is the linkage of IL-6 effects on the lung with keratinocyte-derived chemokine (KC). KC is a CXC chemokine that is structurally homologous to rat cytokineinduced neutrophil chemoattractant and human growth-related oncogene-α, which regulates neutrophil trafficking and is an early biomarker of AKI.15 KC rapidly increases in mouse lung after AKI, and this rise is blunted with manipulations in IL-6. As another chemokine, macrophage inflammatory protein 2, was unaffected by IL-6 interventions, a degree of specificity to the IL-6–KC pathway was postulated. A number of other interesting questions arise
from these data. Given that most patients are seen after the initial kidney injury, the lung effects of starting IL-6 antibody after different reperfusion times, rather than only before treatment, would have been useful to study. The lung, like the kidney, has regional heterogeneity; thus, did AKI have uniform or localized effects on the lung? What cells produce IL-6 after AKI, and what cells in the lung were targets of IL-6? What are the mechanisms by which IL-6 leads to alterations in microvascular inflammation and permeability? On a technical note, it is interesting that 22 minutes of kidney ischemia led to AKI and distant organ changes in this laboratory, whereas in most other laboratories, longer ischemic times are needed to induce a rise in serum creatinine in mice. Differences among laboratories, including those in temperature regulation, fluids, and perhaps even altitude in this case (these studies were performed in Denver, Colorado, one mile above sea level), could have effects. This underscores the importance of tight internal controls and careful descriptions of how the study was performed. Studies in rodents are crucial to identify mechanisms and to examine safety before human studies are conducted, and it is important to know whether the current findings are applicable to larger mammal models and, ultimately, humans. It is well established that injury to the gut or limb alters the lung, but given the important clearance function of the kidney, what distinguishes the effects of AKI on the lung from the effects of injury to other organs? What other soluble factors besides IL-6 mediate AKI-induced distant organ injury, and what is the role of other non-inflammatory pathways — such as neural arcs? Though we assume that AKI only leads to worsening of distant organ function, this is probably simplistic: AKI in mice reduced the decline in peripheral blood oxygenation normally caused by lung injury induced by acid aspiration and injurious mechanical ventilation.16 How can we use these studies to decrease the high mortality and morbidity rate in patients with AKI? Given that increased dosing of dialysis from three to five to six times per week is unlikely to improve mortality during AKI,17 what other strategies can be designed to better Kidney International (2008) 74
co m m e nta r y
clear AKI-induced distant organ toxins? Earlier initiation of dialysis? Continuous dialysis over intermittent? Improved membranes? Novel dialysis approaches, such as the renal assist device? Pharmacologic approaches to block deleterious pathways induced by AKI? A major opportunity clearly exists to improve our care of AKI patients, and studies on complex inter-organ cross talk will guide rational interventions in this common, often catastrophic, syndrome. DISCLOSURE The authors declared no competing interests. References
1.
2. 3. 4. 5.
6.
7. 8.
9.
10.
11.
12. 13.
14.
15.
Bywaters EG, Beall D. Crush injuries with impairment of renal function. Br Med J 1941; 1: 427–432. Bass HE, Singer E. Pulmonary changes in uremia. J Am Med Assoc 1950; 144: 819–823. Uchino S, Kellum JA, Bellomo R et al. Acute renal failure in critically ill patients. A multinational, multicenter study. JAMA 2005; 294: 813–818. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A cohort analysis. JAMA 1996; 275: 1489–1494. Chertow G, Burdick E, Honour M et al. Acute kidney injury, mortality, length of stay and costs in hospitalized patients. J Am Soc Nephrol 2005; 16: 3365–3370. Kramer AA, Postler G, Salhab KF et al. Renal ischemia/reperfusion leads to macrophagemediated increase in pulmonary vascular permeability. Kidney Int 1999; 55: 2362–2367. Rabb H, Wang Z, Nemoto T et al. Acute renal failure leads to dysregulation of lung salt and water channels. Kidney Int 2003; 63: 600–606. Deng J, Hu X, Yuen PS, Star RA. Alpha-melanocytestimulating hormone inhibits lung injury after renal ischemia/reperfusion. Am J Respir Crit Care Med 2004; 169: 749–756. Nath KA, Grande JP, Croatt AJ et al. Transgenic sickle mice are markedly sensitive to renal ischemia-reperfusion injury. Am J Pathol 2005; 166: 963–967. Hassoun HT, Grigoryev DN, Lie ML et al. Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy. Am J Physiol Renal Physiol 2007; 293: F30–F40. Grigoryev DN, Liu M, Hassoun HT et al. The local and systemic inflammatory transcriptome after acute kidney injury. J Am Soc Nephrol 2008; 19: 547–558. Kelly KJ. Distant effects of experimental renal ischemia/reperfusion injury. J Am Soc Nephrol 2003; 14: 1549–1558. Liu M, Liang Y, Chigurupati S et al. Acute kidney injury leads to inflammation and functional changes in the brain. J Am Soc Nephrol 2008; 19: 1360–1370. Klein CL, Hoke TS, Fang W-F et al. Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy. Kidney Int 2008; 74: 901–909. Molls RR, Savransky V, Liu M et al. Keratinocytederived chemokine is an early biomarker of ischemic acute kidney injury. Am J Physiol Renal Physiol 2006; 290: F1187–F1193.
Kidney International (2008) 74
16. Zarbock A, Schmolke M, Spieker T et al. Acute uremia but not renal inflammation attenuates aseptic acute lung injury: a critical role for uremic neutrophils. J Am Soc Nephrol 2006; 17:
3124–3131. 17. VA/NIH Acute Renal Failure Trial Network. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med 2008; 359: 7–20.
see original article on page 890
Renin–angiotensin system blockade and diabetes: moving the adipose organ from the periphery to the center Oliver Lenz1 and Alessia Fornoni1,2 Lee et al. report that an angiotensin II type 1 receptor blocker (ARB) improved glucose intolerance in OLETF rats, an experimental model of type 2 diabetes. ARB treatment resulted in modulation of the adipose tissue, leading to an increased number of small, differentiated adipocytes able to produce more adiponectin and less monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1. This supports the relevance of the functional interplay between adipose tissue and the renin–angiotensin system in states of insulin resistance. Kidney International (2008) 74, 851–853. doi:10.1038/ki.2008.391
A large body of literature suggests that renin–angiotensin system (RAS) blockade with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker (ARB) will prevent new-onset type 2 diabetes.1 Two receptors for angio tensin II have been described in humans, the angiotensin II type 1 (AT1) and type 2 (AT2) receptors. Among them, the AT1 receptor seems to be primarily responsible for the metabolic effect of RAS blockade.2 In fact, the AT1 and AT2 receptors may have antagonistic activities on glucose 1Division of Nephrology and Hypertension,
Department of Medicine, University of Miami Leonard Miller School of Medicine, Miami, Florida, USA; and 2Diabetes Research Institute, University of Miami Leonard Miller School of Medicine, Miami, Florida, USA Correspondence: Alessia Fornoni, Division of Nephrology and Hypertension and Diabetes Research Institute, University of Miami Leonard Miller School of Medicine, 1450 NW 10th Ave., Room 500, Miami, Florida, 33136, USA. E-mail: [email protected]
uptake and cell differentiation in adipose tissue, as suggested by studies performed in AT2-null mice.3 How RAS blockade leads to a diminished incidence of type 2 diabetes remains to be fully elucidated. The following mechanisms are being investigated (Figure 1): upregulation of muscle glucose uptake via modulation of glucose transporter-4 (GLUT4) and blood flow;4 improvement of pancreatic β-cell function;5 modulation of hormonal responses from adipose tissue;2 decreased hepatic gluconeogenesis and increased free fatty acid oxidation;6 improvement of endothelial function through downregulation of NADPH oxidase;2 direct stimulation of insulin signaling at multiple levels;7 and direct regulation of peroxisome proliferator-activated receptor-γ (PPARγ) by selected ARBs, such as telmisartan and irbesartan.8 Experimental data suggest that RAS-blocking agents that act on more than one pathway might be more effective for the prevention of 851