Portal de Periódicos da CAPES

Acute Kidney Injury and CKD: Chicken or Egg?

2012; Elsevier BV; Volume: 59; Issue: 4 Linguagem: Inglês

10.1053/j.ajkd.2011.09.010

1523-6838

Michael Bedford, Chris Farmer, Adeera Levin, Tariq Ali, Paul E. Stevens,

Trauma, Hemostasis, Coagulopathy, Resuscitation

Recent longitudinal cohort studies have suggested that episodes of acute kidney injury (AKI) with only small transient decreases in kidney function are associated with the subsequent development of chronic kidney disease (CKD).1Ishani A. Xue J.L. Himmelfarb J. et al.Acute kidney injury increases risk of ESRD among elderly.J Am Soc Nephrol. 2009; 20: 223-228Crossref PubMed Scopus (877) Google Scholar, 2Triverio P.-A. Martin P.-Y. Romand J. Pugin J. Perneger T. Saudan P. Long-term prognosis after acute kidney injury requiring renal replacement therapy.Nephrol Dial Transplant. 2009; 24: 2186-2189Crossref PubMed Scopus (66) Google Scholar, 3Mehta R.L. Pascual M.T. Soroko S. et al.Spectrum of acute renal failure in the intensive care unit: the PICARD experience.Kidney Int. 2004; 66: 1613-1621Crossref PubMed Scopus (667) Google Scholar, 4Mehta R.L. Pascual M.T. Soroko S. Chertow G.M. Diuretics, mortality, and nonrecovery of renal function in acute renal failure.JAMA. 2002; 288: 2547-2553Crossref PubMed Scopus (511) Google Scholar, 5Chawla L.S. Amdur R.L. Amodeo S. Kimmel P.L. Palant C.E. The severity of acute kidney injury predicts progression to chronic kidney disease.Kidney Int. 2011; 79: 1361-1369Crossref PubMed Scopus (508) Google Scholar, 6Amdur R.L. Chawla L.S. Amodeo S. Kimmel P.L. Palant C.E. Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis.Kidney Int. 2009; 76: 1089-1097Crossref PubMed Scopus (237) Google Scholar Both CKD and, more recently, AKI are well recognized as global public health issues, associated with significant morbidity and mortality and resultant health care economic burden. There is considerable conceptual overlap and interplay between the underlying pathophysiology and pathology, definition, risk factors, and outcome of the 2 conditions. Do silent and unrecognized episodes of AKI precede the development of CKD and hasten its progression? Determining the pathophysiology and pathology underlying acute kidney disease and CKD helps us understand their conceptual overlap and how to accurately detect and define them. Changes in renal vasculature occur with age, as in other vascular beds, often due to comorbid conditions, but also in their absence.7Martin J.E. Sheaff M.T. Renal ageing.J Pathol. 2007; 211: 198-205Crossref PubMed Scopus (167) Google Scholar It is suggested that these changes eventually cause cortical glomerulosclerosis, interstitial fibrosis and tubular atrophy, and compensatory hypertrophy and hyperfiltration of glomeruli in the medulla, contributing to CKD development.8Chronopoulos A. Cruz D.N. Ronco C. Hospital-acquired acute kidney injury in the elderly.Nat Rev Nephrol. 2010; 6: 141-149Crossref PubMed Scopus (79) Google Scholar It also has been suggested that low birth weight is associated with subsequent CKD through low nephron number and compensatory hypertrophy and hyperfiltration of glomeruli.9White S. Perkovic V. Cass A. et al.Is low birth weight an antecedent of CKD in later life? A systematic review of observational studies.Am J Kidney Dis. 2009; 54: 248-261Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar With increasing age and CKD, function in both proximal and distal tubules is compromised, hampering the ability to control fluid and electrolyte balance and affecting tubuloglomerular feedback.7Martin J.E. Sheaff M.T. Renal ageing.J Pathol. 2007; 211: 198-205Crossref PubMed Scopus (167) Google Scholar, 10Fliser D. Ren sanus in corpore sano: the myth of the inexorable decline of renal function with senescence.Nephrol Dial Transplant. 2005; 20: 482-485Crossref PubMed Scopus (32) Google Scholar These changes may exacerbate clinical events such as dehydration and drug toxicity, which carry a high risk of AKI.8Chronopoulos A. Cruz D.N. Ronco C. Hospital-acquired acute kidney injury in the elderly.Nat Rev Nephrol. 2010; 6: 141-149Crossref PubMed Scopus (79) Google Scholar Given that people with CKD have an increased burden of vascular disease, they may be more susceptible to ischemic AKI. Supportive data from animal models suggest AKI as a “vasomotor nephropathy,”11Bonventre J.V. Weinberg J.M. Recent advances in the pathophysiology of ischemic acute renal failure.J Am Soc Nephrol. 2003; 14: 2199-2210Crossref PubMed Scopus (632) Google Scholar, 12Oken D.E. Hemodynamic basis for human acute renal failure (vasomotor nephropathy).Am J Med. 1984; 76: 702-710Abstract Full Text PDF PubMed Scopus (45) Google Scholar but what happens after AKI? Renal tissue has the ability to recover from sublethal or lethal cellular damage.13Bonventre J.V. Mechanisms of ischemic acute renal failure.Kidney Int. 1993; 43: 1160-1178Crossref PubMed Scopus (464) Google Scholar, 14Finn W.F. Recovery from acute renal failure.in: Lazarus J.M. Brenner B.M. Acute Renal Failure. Churchill Livingstone, New York, NY1993: 553-596Google Scholar, 15Humes H.D. Lake E.W. Liu S. Renal tubule cell repair following acute renal injury.Miner Electrolyte Metab. 1995; 21: 353-365PubMed Google Scholar, 16Humes H.D. Liu S. Cellular and molecular basis of renal repair in acute renal failure.J Lab Clin Med. 1994; 124: 749-754PubMed Google Scholar, 17Witzgall R. Brown D. Schwarz C. Bonventre J.V. Localization of proliferating cell nuclear antigen, vimentin, c-fos and clusterin in the post-ischemic kidney.J Clin Invest. 1994; 93: 2175-2188Crossref PubMed Scopus (527) Google Scholar However, function may not be fully restored, with the development of CKD.14Finn W.F. Recovery from acute renal failure.in: Lazarus J.M. Brenner B.M. Acute Renal Failure. Churchill Livingstone, New York, NY1993: 553-596Google Scholar Kidney function may be related directly to a cycle of cell injury and recovery after AKI (Fig 1A).18Sutton T.A. Fisher C.J. Molitoris B.A. Microvascular endothelial injury and dysfunction during ischemic acute renal failure.Kidney Int. 2002; 62: 1539-1549Crossref PubMed Scopus (446) Google Scholar Damage to renal tubular epithelial cells is thought to be extended by renal vascular endothelial injury and dysfunction. Endothelial repair is important to overall recovery and thus may have an impact on long-term function.19Basile D.P. Donohoe D. Roethe K. et al.Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function.Am J Physiol Renal Physiol. 2001; 281: F887-F899Crossref PubMed Scopus (569) Google Scholar This model describing cellular phases of AKI applies to acute tubular necrosis, but can be extrapolated to other causes of AKI. What happens most frequently is limited to the very early part of this process. In patients developing CKD (Fig 1B), the initiating insult leading to damage, inflammation, and repair (initiation) may result in fibrosis (extension) and then further damage in a self-perpetuating cycle of progression (maintenance) to end-stage renal disease (ESRD). Early intervention at the stages of initiation and extension may prevent CKD and ESRD, whereas later intervention during the maintenance stage may only delay progression, with the extent of delay determined by the success or otherwise of intervention. Patients with AKI may or may not have pre-existing CKD (Fig 1C). Okusa et al20Okusa M.D. Chertow G.M. Portilla D. The nexus of acute kidney injury, chronic kidney disease, and World Kidney Day 2009.Clin J Am Soc Nephrol. 2009; 4: 520-522Crossref PubMed Scopus (94) Google Scholar (pathophysiologic concepts from Sutton et al18Sutton T.A. Fisher C.J. Molitoris B.A. Microvascular endothelial injury and dysfunction during ischemic acute renal failure.Kidney Int. 2002; 62: 1539-1549Crossref PubMed Scopus (446) Google Scholar) suggest that after AKI, there are 4 possible outcomes: (1) full recovery, (2) incomplete recovery resulting in CKD, (3) exacerbation of pre-existing CKD accelerating progression to ESRD, and (4) nonrecovery of function leading to ESRD. AKI also may recover incompletely, leading to a step down in glomerular filtration rate (GFR) falling short of CKD. Patients with AKI are also likely to have risk factors for CKD; thus, patients without known background CKD who develop AKI may already have unrecognized kidney disease and decreased functional reserve, not yet manifest as CKD. These patients are programmed to develop future CKD, and the AKI episode simply speeds up the development of overt CKD. In this respect, renal outcomes of AKI and CKD are the same, suggesting they are part of the same pathophysiologic pathway.Figure 1Conceptual model of glomerular filtration rate (GFR) and cellular pathology over time in acute kidney injury (AKI), chronic kidney disease (CKD), and AKI and CKD. (A) The cellular phases of AKI leading to repair, highlighting the possibility of initiating a self-perpetuating cycle of inflammation producing fibrosis leading to CKD. (B) The phases of cellular injury in CKD. After an initial insult, there is initiation of the inflammatory response with repair. This then may lead to the extension phase with added fibrosis. Past a point of no return, the disease process embarks on a self-perpetuating cycle of cellular damage and fibrosis (maintenance phase) leading to deterioration in GFR and progression to end-stage renal disease. The figure also shows the effect of intervention on the disease process. (C) The effect of episodes of AKI on the progression of CKD with 3 possible outcomes; complete recovery, stepwise progression, and inexorable decline.View Large Image Figure ViewerDownload Hi-res image Download (PPT) A key question is whether the “I” in AKI truly stands for injury or for impairment and/or injury. Is it underpinned by histopathologic damage and, if so, when does this become relevant in terms of future CKD and/or progression? Do undetected episodes of AKI in the community lead to CKD? When patients present with CKD without an obvious cause, is the pathophysiology related to multiple undetected AKI events in the community? From an ischemia-reperfusion injury model of AKI in rats, Basile et al19Basile D.P. Donohoe D. Roethe K. et al.Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function.Am J Physiol Renal Physiol. 2001; 281: F887-F899Crossref PubMed Scopus (569) Google Scholar hypothesized that as long as there is adequate functional reserve, the single-nephron GFR of surviving nephrons increases to maintain a constant total GFR. This suggests that even in patients in whom creatinine and GFR values return to baseline, there may be underlying permanent damage masked by compensatory mechanisms. These patients subsequently may have an increased risk of CKD and AKI due to underlying “subclinical” damage. Are AKI and CKD biologically part of the same pathologic pathway with eventual glomerulosclerosis and interstitial fibrosis, with AKI leading to fibrosis by setting up the cycle of inflammation and cell repair? The difficulty comes with the necessary time constraints. For AKI, there must be an increase in serum creatinine level over 2 (Acute Kidney Injury Network [AKIN] criteria21Mehta R.L. Kellum J.A. Shah S.V. et al.Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury.Crit Care. 2007; 11: R31Crossref PubMed Scopus (5164) Google Scholar) to 7 (RIFLE classification22American Society of NephrologyAmerican Society of Nephrology Renal Research Report.J Am Soc Nephrol. 2005; 16: 1886-1903Crossref PubMed Scopus (169) Google Scholar) days. For CKD to exist, GFR must be decreased or there must be evidence of kidney damage for at least 3 months.23National Kidney FoundationK/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: evaluation, classification and stratification.Am J Kidney Dis. 2002; 39 (suppl 1): S1-S266Abstract Full Text PDF PubMed Google Scholar, 24Levey A.S. Eckardt K.U. Tsukamoto Y. et al.Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).Kidney Int. 2005; 67: 2089-2100Crossref PubMed Scopus (2485) Google Scholar, 25Levey A.S. de Jong P.E. Coresh J. et al.Chronic Kidney Disease—definition, classification and prognosis: a KDIGO Controversies Conference reaches a consensus.Kidney Int. 2011; 80: 17-28Crossref PubMed Scopus (1495) Google Scholar These definitions may not capture all cases of acute kidney disease. Certain causes may lead to changes in serum creatinine and GFR values during a time outside those currently specified, precluding definition. These cases should not be neglected because intervention may be required. For this reason, the new KDIGO (Kidney Disease: Improving Global Outcomes) AKI guideline proposes an operational definition for acute kidney diseases and disorders (AKDs), of which AKI is a part, and provides a diagnostic algorithm for defining AKD, AKI, and CKD (Fig 2) .26Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work GroupKDIGO Clinical Practice Guideline for Acute Kidney Injury.Kidney Int Suppl. 2012; 2: 1-138Crossref Scopus (1936) Google Scholar Accurate definition has important research implications. Previously, variation in definitions used and populations studied made determination of epidemiology and the interplay between AKI and CKD more difficult. This has been improved by adoption of the RIFLE and AKIN classifications of AKI. However, problems arise when baseline creatinine level is not known. A retrospective cohort study by LaFrance and Miller27LaFrance J.P. Miller D.R. Defining acute kidney injury in database studies: the effects of varying the baseline kidney function assessment period and considering CKD status.Am J Kidney Dis. 2010; 56: 651-660Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar assessed 1,126,636 veterans (US Department of Veterans Affairs health care system) hospitalized at least once between 2000 and 2005. The highest serum creatinine level during hospitalization was compared with the lowest using 4 different baseline periods (in-hospital only and 3, 6, or 12 months preadmission). AKI was defined as a greater than 1.5-fold increase in serum creatinine level or an increase of 0.3-0.5 mg/dL over baseline.27LaFrance J.P. Miller D.R. Defining acute kidney injury in database studies: the effects of varying the baseline kidney function assessment period and considering CKD status.Am J Kidney Dis. 2010; 56: 651-660Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar The cumulative incidence of AKI ranged from 12.5% (in-hospital baseline) to 18.3% (baseline up to 12 months preadmission). By extending the baseline period to at least 3 months, they found that discriminative power increased slightly (C statistic increased from 0.846 to 0.855; P = 0.001). They suggested a need for consensus on defining baseline in database studies. The KDIGO AKI guideline suggests that an estimated creatinine level can be used provided there is no evidence of CKD.26Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work GroupKDIGO Clinical Practice Guideline for Acute Kidney Injury.Kidney Int Suppl. 2012; 2: 1-138Crossref Scopus (1936) Google Scholar However, there are cases of CKD in the community not previously appreciated. Estimating baseline creatinine level in these cases may lead to the diagnosis of AKI in patients with previously unrecognized CKD. Definitions of both AKI and CKD in the literature may not be accurate or comparable. For example, the definition of CKD based on diagnostic coding or preoperative GFR taken as baseline function can introduce bias in detection. Singh et al28Singh P. Rifkin D.E. Blantz R.C. Chronic kidney disease: an inherent risk factor for acute kidney injury.Clin J Am Soc Nephrol. 2010; 5: 1690-1695Crossref PubMed Scopus (70) Google Scholar suggested that differences also could reflect greater specificity of administrative codes for AKI in patients without CKD. This emphasizes the need for consensus about the definition of baseline function. By defining AKI and CKD, we are describing decreased function, which can lead to complications including ESRD and mortality. In disease prevention/detection, we therefore aim for risk modification. There clearly is a significant overlap in risk factors for AKI and CKD. Elderly patients have a higher prevalence of AKI and CKD related to an increased prevalence of comorbid conditions (hypertension, diabetes, atherosclerotic disease, and cardiac insufficiency).29Pascual J. Liaño F. Ortuño J. The elderly patient with acute renal failure.J Am Soc Nephrol. 1995; 6: 144-153PubMed Google Scholar This is at least partly due to an increased prevalence of comorbid conditions with age. With common risk factors that may be playing a pathophysiologic role, the entities of AKI and CKD may be a process of definition of the same pathophysiologic pathway. The significant overlap in risk factors also makes investigation of CKD as a risk factor for AKI, and the converse, difficult. Is it possible to accurately correct for all confounding variables? The literature suggests that CKD is a significant risk factor in the development of AKI.1Ishani A. Xue J.L. Himmelfarb J. et al.Acute kidney injury increases risk of ESRD among elderly.J Am Soc Nephrol. 2009; 20: 223-228Crossref PubMed Scopus (877) Google Scholar, 30Hoste E.A. Lameire N.H. 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Bellomo R. et al.Acute renal failure in critically ill patients: a multinational, multicenter study.JAMA. 2005; 294: 813-818Crossref PubMed Scopus (3123) Google Scholar In a number of studies, after multivariate adjustment for comorbid conditions, CKD consistently remains an independent risk factor for AKI after radiocontrast administration, cardiac surgery, and sepsis.35Waikar S.S. Liu K.D. Chertow G.M. Diagnosis, epidemiology and outcomes of acute kidney injury.Clin J Am Soc Nephrol. 2008; 3: 844-861Crossref PubMed Scopus (382) Google Scholar Table 1 lists evidence from the literature showing over-representation of CKD in the population that develops AKI, suggesting that CKD is a risk factor for AKI. There also is mounting evidence that AKI is a risk factor for or, more accurately, “contributes” significantly to CKD and CKD progression, leading to ESRD (Table 1). Hsu et al41Hsu C.Y. Vittinghoff E. Lin F. Shlipak M.G. The incidence of end-stage renal disease is increasing faster than the prevalence of chronic renal insufficiency.Ann Intern Med. 2004; 141: 95-101Crossref PubMed Google Scholar suggested that the growth of ESRD incidence in the United States could not be accounted for solely by an increase in CKD incidence and may be attributable in part to AKI. A population-based study by Ali et al42Ali T. Khan I. Simpson W. et al.Incidence and outcomes in acute kidney injury: a comprehensive population-based study.J Am Soc Nephrol. 2007; 18: 1292-1298Crossref PubMed Scopus (660) Google Scholar compared patients with acute on chronic kidney disease with those with AKI alone. Patients with acute-chronic kidney disease were older, with less chance of renal recovery.42Ali T. Khan I. Simpson W. et al.Incidence and outcomes in acute kidney injury: a comprehensive population-based study.J Am Soc Nephrol. 2007; 18: 1292-1298Crossref PubMed Scopus (660) Google ScholarTable 1The Association Between CKD and AKI From the LiteratureStudyPopulationConclusionsCKD as a Risk Factor for AKINash et al,36Nash K. Hafeez A. Hou S. Hospital-acquired renal insufficiency.Am J Kidney Dis. 2002; 39: 930-936Abstract Full Text Full Text PDF PubMed Scopus (1544) Google Scholar 2002Consecutive medical and surgical admissions of an urban tertiary-care hospital; N = 4,6227.2% developed AKI, of which 45.5% had baseline SCr >1.2 mg/dLChertow et al,37Chertow G.M. Soroko S.H. Paganini E.P. et al.Mortality after acute renal failure: models for prognostic stratification and risk adjustment.Kidney Int. 2006; 70: 1120-1126Crossref PubMed Scopus (235) Google Scholar 2006618 ITU patients with ARF; data from PICARD32% of patient with ARF had baseline GFR 60, 1.00 (reference) GFR 45-59, 1.95 GFR 30-44, 3.54 GFR 15-29, 28.5 GFR 50%. Intensive care unit and in-hospital mortality increase as the severity of AKI increases.3Mehta R.L. Pascual M.T. Soroko S. et al.Spectrum of acute renal failure in the intensive care unit: the PICARD experience.Kidney Int. 2004; 66: 1613-1621Crossref PubMed Scopus (667) Google Scholar, 34Uchino S. Kellum J.A. Bellomo R. et al.Acute renal failure in critically ill patients: a multinational, multicenter study.JAMA. 2005; 294: 813-818Crossref PubMed Scopus (3123) Google Scholar, 36Nash K. Hafeez A. Hou S. Hospital-acquired renal insufficiency.Am J Kidney Dis. 2002; 39: 930-936Abstract Full Text Full Text PDF PubMed Scopus (1544) Google Scholar, 42Ali T. Khan I. Simpson W. et al.Incidence and outcomes in acute kidney injury: a comprehensive population-based study.J Am Soc Nephrol. 2007; 18: 1292-1298Crossref PubMed Scopus (660) Google Scholar, 44Hoste E.A.J. Clermont G. Kersten A. et al.RIFLE criteria for acute kidney injury is associated with hospital mortality in critically ill patients: a cohort analysis.Crit Care. 2006; 10: R73-R82Crossref PubMed Scopus (1150) Google Scholar, 45Uchino S. Bellomo R. Goldsmith D. An assessment of the RIFLE criteria for acute renal failure in hospitalized patients.Crit Care Med. 2006; 34: 1913-1917Crossref PubMed Scopus (729) Google Scholar, 46Ostermann M. Chang R.W. Acute kidney injury in the intensive care unit according to RIFLE.Crit Care Med. 2007; 35: 1837-1843Crossref PubMed Scopus (533) Google Scholar, 47Morgera S. Kraft A.K. Siebert G. et al.Long-term outcomes in acute renal failure patients treated with continuous renal replacement therapies.Am J Kidney Dis. 2002; 40: 275-279Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 48Cosentino F. Chaff C. Piedmonte M. Risk factors influencing survival in ICU acute renal failure.Nephrol Dial Transplant. 1994; 9: 179-182PubMed Google Scholar, 49Chertow G.M. Christiansen C.L. Cleary P.D. et al.Prognostic stratification in critically ill patients with acute renal failure requiring dialysis.Arch Intern Med. 1995; 155: 1505-1511Crossref PubMed Scopus (357) Google Scholar, 50Bernieh B. Al Hakim M. Boobes Y. et al.Outcome and predictive factors of acute renal failure in the intensive care unit.Transplant Proc. 2004; 36: 1784-1787Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 51Levy E.M. Viscoli C.M. Horwitz R.I. The effect of acute renal failure on mortality A cohort analysis.JAMA. 1996; 275: 1489-1494Crossref PubMed Google Scholar, 52Abosaif N.Y. Tolba Y.A. Heap M. et al.The outcome of acute renal failure in the intensive care unit according to RIFLE: model application, sensitivity, and predictability.Am J Kidney Dis. 2005; 46: 1038-1048Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar Even small isolated increases in serum creatinine level have an associated increase in short-term morbidity and mortality and longer term outcomes, including 1-year mortality.3Mehta R.L. Pascual M.T. Soroko S. et al.Spectrum of acute renal failure in the intensive care unit: the PICARD experience.Kidney Int. 2004; 66: 1613-1621Crossref PubMed Scopus (667) Google Scholar, 34Uchino S. Kellum J.A. Bellomo R. et al.Acute renal failure in critically ill patients: a multinational, multicenter study.JAMA. 2005; 294: 813-818Crossref PubMed Scopus (3123) Google Scholar, 44Hoste E.A.J. Clermont G. Kersten A. et al.RIFLE criteria for acute kidney injury is associated with hospital mortality in critically ill patients: a cohort analysis.Crit Care. 2006; 10: R73-R82Crossref PubMed Scopus (1150) Google Scholar, 53Levy M.M. Macias W.L. Vincent J.L. et al.Early changes in organ function predict eventual survival in severe sepsis.Crit Care Med. 2005; 33: 2194-2201Crossref PubMed Scopus (284) Google Scholar, 54McCullough P.A. Soman S.S. Contrast-induced nephropathy.Crit Care Clin. 2005; 21: 261-280Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 55Praught M.L. Shlipak M.G. Are small changes in serum creatinine an important risk factor?.Curr Opin Nephrol Hypertens. 2005; 14: 265-270Crossref PubMed Scopus (99) Google Scholar, 56Bellomo R. Ronco C. Kellum J.A. Mehta R.L. Palevsky P. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.Crit Care. 2004; 8: R204-R212Crossref PubMed Google Scholar, 57Metnitz P.G. Krenn C.G. Steltzer H. et al.Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients.Crit Care Med. 2002; 30: 2051-2058Crossref PubMed Scopus (720) Google Scholar However, could it be that AKI is not a risk factor for these outcomes, but is a risk marker of systemic illness? We know that isolated AKI without other organ involvement has a better prognosis than AKI in the context of multiorgan failure. CKD also has been shown as an independent predictor of morbidity and mortality.58Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8916) Google Scholar, 59Anavekar N.S. McMurray J.J. Velazquez E.J. et al.Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction.N Engl J Med. 2004; 351: 1285-1295Crossref PubMed Scopus (1653) Google Scholar We therefore would assume that AKI in CKD has a summative effect on outcome. Studies show lower in-hospital mortality in patients with AKI on a background of CKD compared with patients without a background of CKD.35Waikar S.S. Liu K.D. Chertow G.M. Diagnosis, epidemiology and outcomes of acute kidney injury.Clin J Am Soc Nephrol. 2008; 3: 844-861Crossref PubMed Scopus (382) Google Scholar, 37Chertow G.M. Soroko S.H. Paganini E.P. et al.Mortality after acute renal failure: models for prognostic stratification and risk adjustment.Kidney Int. 2006; 70: 1120-1126Crossref PubMed Scopus (235) Google Scholar, 49Chertow G.M. Christiansen C.L. Cleary P.D. et al.Prognostic stratification in critically ill patients with acute renal failure requiring dialysis.Arch Intern Med. 1995; 155: 1505-1511Crossref PubMed Scopus (357) Google Scholar, 60Mehta R.L. Pascual M.T. Gruta C.G. Zhuang S. Chertow G.M. Refining predictive models in critically ill patients with acute renal failure.J Am Soc Nephrol. 2002; 13: 1350-1357Crossref PubMed Scopus (293) Google Scholar, 61Paganini E.P. Larive B. Kanagasundaram N.S. Severity scores and outcomes with acute renal failure in the ICU setting.Contrib Nephrol. 2001; : 181-195Crossref PubMed Scopus (19) Google Scholar, 62Uchino S. Bellomo R. Morimatsu H. et al.External validation of severity scoring systems for acute renal failure using a multinational database.Crit Care Med. 2005; 33: 1961-1967Crossref PubMed Scopus (104) Google Scholar, 63Waikar S.S. Curhan G.C. Wald R. McCarthy E.P. Chertow G.M. Declining mortality in patients with acute renal failure, 1988 to 2002.J Am Soc Nephrol. 2006; 17: 1143-1150Crossref PubMed Scopus (467) Google Scholar This would seem counterintuitive. One explanation might be that patients with CKD require less of an insult to manifest clinically apparent AKI or are more likely to have their kidney function tested and AKI discovered; thus, severity of the AKI episode is less in these patients with CKD and hence outcomes are better. Conversely, those with CKD may have more resilience to acute insults secondary to conditioning or priming and tolerate AKI better. It is also possible that those with CKD receive better/different care than non-CKD counterparts when AKI is identified, thus affecting outcomes. It also has been suggested that results may be confounded by malnutrition (lower serum creatinine values from low muscle mass).50Bernieh B. Al Hakim M. Boobes Y. et al.Outcome and predictive factors of acute renal failure in the intensive care unit.Transplant Proc. 2004; 36: 1784-1787Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar To conclude, both AKI and CKD confer significant morbidity and mortality. Regardless of which is the chicken or the egg, the risk factors and pathophysiology underlying AKI and CKD are similar. Should we consider AKI and CKD as part of the same pathologic pathway and a continuum over time and surmise, based on a 2-hit theory, that AKI before the diagnosis of CKD contributes to CKD and that AKI after the diagnosis of CKD exacerbates it? With an ageing population and increasing comorbidity burden, AKI and CKD will continue to have a significant impact on health care economies. It is important that further effort is focused on improving the definition, diagnosis, effective prevention, and treatment of both conditions. Better understanding of this complex interplay will allow us to achieve this.