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Acute kidney injury and chronic kidney disease: an integrated clinical syndrome

2012; Elsevier BV; Volume: 82; Issue: 5 Linguagem: Inglês

10.1038/ki.2012.208

1523-1755

Lakhmir S. Chawla, Paul L. Kimmel,

Dialysis and Renal Disease Management

The previous conventional wisdom that survivors of acute kidney injury (AKI) tend to do well and fully recover renal function appears to be flawed. AKI can cause end-stage renal disease (ESRD) directly, and increase the risk of developing incident chronic kidney disease (CKD) and worsening of underlying CKD. In addition, severity, duration, and frequency of AKI appear to be important predictors of poor patient outcomes. CKD is an important risk factor for the development and ascertainment of AKI. Experimental data support the clinical observations and the bidirectional nature of the relationships between AKI and CKD. Reductions in renal mass and nephron number, vascular insufficiency, cell cycle disruption, and maladaptive repair mechanisms appear to be important modulators of progression in patients with and without coexistent CKD. Distinction between AKI and CKD may be artificial. Consideration should be given to the integrated clinical syndrome of diminished GFR, with acute and chronic stages, where spectrum of disease state and outcome is determined by host factors, including the balance of adaptive and maladaptive repair mechanisms over time. Physicians must provide long-term follow-up to patients with first episodes of AKI, even if they presented with normal renal function. The previous conventional wisdom that survivors of acute kidney injury (AKI) tend to do well and fully recover renal function appears to be flawed. AKI can cause end-stage renal disease (ESRD) directly, and increase the risk of developing incident chronic kidney disease (CKD) and worsening of underlying CKD. In addition, severity, duration, and frequency of AKI appear to be important predictors of poor patient outcomes. CKD is an important risk factor for the development and ascertainment of AKI. Experimental data support the clinical observations and the bidirectional nature of the relationships between AKI and CKD. Reductions in renal mass and nephron number, vascular insufficiency, cell cycle disruption, and maladaptive repair mechanisms appear to be important modulators of progression in patients with and without coexistent CKD. Distinction between AKI and CKD may be artificial. Consideration should be given to the integrated clinical syndrome of diminished GFR, with acute and chronic stages, where spectrum of disease state and outcome is determined by host factors, including the balance of adaptive and maladaptive repair mechanisms over time. Physicians must provide long-term follow-up to patients with first episodes of AKI, even if they presented with normal renal function. Acute kidney injury (AKI) is responsible for approximately 2 million deaths annually worldwide.1.Ali 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 (664) Google Scholar, 2.Murugan R. Kellum J.A. Acute kidney injury: what's the prognosis?.Nat Rev Nephrol. 2011; 7: 209-217Crossref PubMed Scopus (309) Google Scholar, 3.Uchino 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 (3154) Google Scholar AKI is increasingly common in critically ill patients, and those patients with the most severe form of AKI, requiring renal replacement therapy, have a mortality rate of 50–80%.3.Uchino 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 (3154) Google Scholar Over the past 10 years, there has been substantial progress in the field of AKI. In particular, work on consensus definitions, epidemiologic and database studies, AKI biomarkers, and the appropriate dosing of renal replacement therapy has continued at a brisk pace. The classic teaching regarding patients who survive an episode of AKI, in particular acute tubular necrosis (ATN), was that those patients achieved full or nearly full recovery.4.Kjellstrand C.M. Ebben J. Davin T. Time of death, recovery of renal function, development of chronic renal failure and need for chronic hemodialysis in patients with acute tubular necrosis.Trans Am Soc Artif Intern Organs. 1981; 27: 45-50PubMed Google Scholar This notion was based on studies that followed survivors of AKI after hospital discharge.4.Kjellstrand C.M. Ebben J. Davin T. Time of death, recovery of renal function, development of chronic renal failure and need for chronic hemodialysis in patients with acute tubular necrosis.Trans Am Soc Artif Intern Organs. 1981; 27: 45-50PubMed Google Scholar,5.Liano F. Felipe C. Tenorio M.T. et al.Long-term outcome of acute tubular necrosis: a contribution to its natural history.Kidney Int. 2007; 71: 679-686Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar The most recent comprehensive study of AKI survivors followed 187 patients with ATN for 10 years.5.Liano F. Felipe C. Tenorio M.T. et al.Long-term outcome of acute tubular necrosis: a contribution to its natural history.Kidney Int. 2007; 71: 679-686Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar The authors concluded that for those who survived ‘renal function is adequate in most patients’.5.Liano F. Felipe C. Tenorio M.T. et al.Long-term outcome of acute tubular necrosis: a contribution to its natural history.Kidney Int. 2007; 71: 679-686Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar However, the notion that most patients with AKI return to pre-morbid renal function is contradicted by a series of small but careful clinical studies conducted over 50 years ago.6.Lowe K.G. The late prognosis in acute tubular necrosis; an interim follow-up report on 14 patients.Lancet. 1952: 1086-1088Google Scholar,7.Finkenstaedt J.T. Merrill J.P. Renal function after recovery from acute renal failure.N Engl J Med. 1956; 254: 1023-1026Crossref PubMed Google Scholar ‘Good clinical recovery, which is sustained, is the rule’ was reported by Lowe6.Lowe K.G. The late prognosis in acute tubular necrosis; an interim follow-up report on 14 patients.Lancet. 1952: 1086-1088Google Scholar in his study of 14 selected patients who survived an episode of oliguria or anuria associated with ATN. Three patients (of the eight who had the assessment) in this series, however, had creatinine clearance of <80ml/min. Lowe attributed any renal dysfunction to scarring or vascular damage. Finkenstaedt and Merrill7.Finkenstaedt J.T. Merrill J.P. Renal function after recovery from acute renal failure.N Engl J Med. 1956; 254: 1023-1026Crossref PubMed Google Scholar reported inulin clearances of <70ml/min in 6 of the 16 patients with no evidence of renal disease before occurrence of acute renal failure (ARF) 13–76 months after the episode. They concluded that the findings demonstrated that an episode of ARF ‘resulted in more chronic renal damage than would be expected’ and that ‘subnormal renal function late in the follow-up period occurred in the majority of cases studied.’ They attributed chronic dysfunction to rupture of basement membranes with abnormal epithelial regeneration, resulting in nephron loss. Up to 2007, however, when the epidemiology of AKI survivorship was assessed, there was a lack of large longitudinal studies to assess the effects of AKI on long-term renal function.8.Xue J.L. Daniels F. Star R.A. et al.Mortality and advancing to end-stage renal disease in patients with hospital and non-hospital acquired renal failure.J Am Soc Nephrol. 2007; 15: SA-PO965Google Scholar More recently, from 2008 through 2012, multiple observational studies assessing unique cohorts of patients, often using large administrative databases, demonstrated that patients who survive an episode of AKI have a significant risk for progression to advanced-stage chronic kidney disease (CKD).9.Chawla L.S. Amdur R.L. Amodeo S. et al.The severity of acute kidney injury predicts progression to chronic kidney disease.Kidney Int. 2011; 79: 1361-1369Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar, 10.Ishani 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 (885) Google Scholar, 11.Lo L.J. Go A.S. Chertow G.M. et al.Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease.Kidney Int. 2009; 76: 893-899Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar, 12.Amdur R.L. Chawla L.S. Amodeo S. et al.Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis.Kidney Int. 2009; 76: 1089-1097Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar, 13.Wald R. Quinn R.R. Luo J. et al.Chronic dialysis and death among survivors of acute kidney injury requiring dialysis.JAMA. 2009; 302: 1179-1185Crossref PubMed Scopus (555) Google Scholar, 14.Garg A.X. Suri R.S. Barrowman N. et al.Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression.JAMA. 2003; 290: 1360-1370Crossref PubMed Scopus (403) Google Scholar We review data suggesting that AKI is a cause of CKD and that prevalent CKD is a cause of incident AKI, and focus on the interrelationships between these two entities. We review the potential mechanistic factors underlying links between AKI and CKD, and offer clinical considerations based on these observations. Ishani et al.10.Ishani 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 (885) Google Scholar assessed a random sample of Medicare beneficiaries and found that patients diagnosed with an episode of AKI were more likely to develop end-stage renal disease (ESRD) compared with patients without a history of either AKI or CKD. In their analysis, the risk of developing ESRD was eightfold higher in those with AKI compared with patients without a history of AKI or CKD. As this study used ICD-9 diagnostic codes, it is difficult to determine the proportion of patients who suffered AKI and then progressed directly to ESRD compared with patients who suffered AKI, recovered renal function, and then progressed to ESRD.10.Ishani 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 (885) Google Scholar Lo et al.,11.Lo L.J. Go A.S. Chertow G.M. et al.Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease.Kidney Int. 2009; 76: 893-899Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar by using a Kaiser Permanente database in Northern California, retrospectively studied inpatient admissions. Patients with an episode of AKI treated with dialysis were compared with patients without an episode of AKI. Patients with a history of ESRD or a preadmission estimated glomerular filtration rate (eGFR) <45ml/min per 1.73m2 were excluded. In this study, the investigators found that an episode of dialysis-requiring AKI was associated with a 28-fold increased risk of developing advanced CKD, and a 2-fold increase in mortality. As patients who developed ESRD within 30 days of discharge were excluded from the long-term follow-up of advanced CKD, these data are consistent with a severe form of AKI followed by renal recovery and then progression to advanced-stage CKD.11.Lo L.J. Go A.S. Chertow G.M. et al.Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease.Kidney Int. 2009; 76: 893-899Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar It should be noted that some patients assessed had pre-existing CKD. Wald et al.13.Wald R. Quinn R.R. Luo J. et al.Chronic dialysis and death among survivors of acute kidney injury requiring dialysis.JAMA. 2009; 302: 1179-1185Crossref PubMed Scopus (555) Google Scholar conducted a population-based cohort study in Ontario, Canada of AKI patients who required in-hospital dialysis and survived free of dialysis for at least 30 days after discharge. These patients were matched with patients without AKI or dialysis therapy during their index hospitalization. Patients with AKI requiring dialysis were over three times more likely to develop ESRD compared with control-matched patients. We and colleagues at the Veterans Affairs Medical Center in Washington, DC assessed a United States Department of Veterans Affairs database to ascertain long-term renal function in over 79,000 hospitalized patients with and without AKI.12.Amdur R.L. Chawla L.S. Amodeo S. et al.Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis.Kidney Int. 2009; 76: 1089-1097Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar A particular focus was on the long-term outcome in patients with a diagnosis of ATN. Patients hospitalized for acute myocardial infarction or pneumonia without AKI were designated as controls. The remaining 5404 hospitalized patients who comprised the AKI group had diagnostic codes indicating ARF or ATN. Patients with pre-existing CKD were excluded. Over the 5-year follow-up period, renal function deteriorated over time in all groups, but with significantly greater severity in those who had ATN and ARF compared with controls. Patients with AKI, especially those with ATN, with pre-existing normal renal function were more likely than controls to enter stage 4 or 5 CKD. We found that patients who had an episode of AKI were at high risk for the development of stage 4 CKD and had reduced survival time compared with control patients.12.Amdur R.L. Chawla L.S. Amodeo S. et al.Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis.Kidney Int. 2009; 76: 1089-1097Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar Our studies in AKI survivors identified advanced age, the presence of diabetes mellitus, and decreased baseline eGFR as risk factors for the progression to advanced-stage CKD.12.Amdur R.L. Chawla L.S. Amodeo S. et al.Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis.Kidney Int. 2009; 76: 1089-1097Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar,15.Chawla L.S. Seneff M.G. Nelson D.R. et al.Elevated plasma concentrations of IL-6 and elevated APACHE II score predict acute kidney injury in patients with severe sepsis.Clin J Am Soc Nephrol. 2007; 2: 22-30Crossref PubMed Scopus (147) Google Scholar In addition to these risk factors, along with our colleagues, we recently showed that low serum albumin concentration (SAlb) is a strong predictor of poor long-term renal outcome.9.Chawla L.S. Amdur R.L. Amodeo S. et al.The severity of acute kidney injury predicts progression to chronic kidney disease.Kidney Int. 2011; 79: 1361-1369Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar The value of the SAlb as a predictor of CKD progression is not surprising, because this parameter has been associated with poor outcomes in both the general population and in a variety of diseases including ESRD, surgical illness, and acute stroke.16.Engelman D.T. Adams D.H. Byrne J.G. et al.Impact of body mass index and albumin on morbidity and mortality after cardiac surgery.J Thorac Cardiovasc Surg. 1999; 118: 866-873Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar, 17.Gariballa S.E. Parker S.G. Taub N. et al.Influence of nutritional status on clinical outcome after acute stroke.Am J Clin Nutr. 1998; 68: 275-281PubMed Google Scholar, 18.Owen Jr., W.F. Lew N.L. Liu Y. et al.The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis.N Engl J Med. 1993; 329: 1001-1006Crossref PubMed Scopus (1254) Google Scholar Low SAlb levels can be a result of nutrition-related factors and/or high levels of inflammation.19.Friedman A.N. Fadem S.Z. Reassessment of albumin as a nutritional marker in kidney disease.J Am Soc Nephrol. 2010; 21: 223-230Crossref PubMed Scopus (255) Google Scholar,20.Don B.R. Kaysen G. Serum albumin: relationship to inflammation and nutrition.Semin Dial. 2004; 17: 432-437Crossref PubMed Scopus (722) Google Scholar As several recent studies have shown that markers of inflammation predict AKI, it is likely that the relationship between SAlb level and CKD progression is based on a complex set of factors, including those related to diet, nutrition, and catabolism, as well as increased inflammation.15.Chawla L.S. Seneff M.G. Nelson D.R. et al.Elevated plasma concentrations of IL-6 and elevated APACHE II score predict acute kidney injury in patients with severe sepsis.Clin J Am Soc Nephrol. 2007; 2: 22-30Crossref PubMed Scopus (147) Google Scholar,21.Liu K.D. Glidden D.V. Eisner M.D. et al.Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury.Crit Care Med. 2007; 35: 2755-2761Crossref PubMed Scopus (18) Google Scholar Collectively, these studies underscore the strong association between AKI and the future development of CKD. More recently, severity of AKI has been linked to CKD progression in survivors of AKI. Ishani et al.22.Ishani A. Nelson D. Clothier B. et al.The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death.Arch Intern Med. 2011; 171: 226-233Crossref PubMed Scopus (287) Google Scholar assessed patients who underwent cardiac surgery, and found that the magnitude of serum creatinine concentration during the postoperative hospital course was directly linked to progression. This effect was seen in patients with AKI with previously normal renal function (de novo AKI), as well as in patients with an episode of AKI superimposed on CKD (acute on chronic renal failure).22.Ishani A. Nelson D. Clothier B. et al.The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death.Arch Intern Med. 2011; 171: 226-233Crossref PubMed Scopus (287) Google Scholar The magnitude of increase in serum creatinine after cardiac surgery was associated in a graded manner with increased risk of CKD progression and mortality. This same trend has been demonstrated in patients who had percutaneous coronary revascularization. James et al.23.James M.T. Ghali W.A. Knudtson M.L. et al.Associations between acute kidney injury and cardiovascular and renal outcomes after coronary angiography.Circulation. 2011; 123: 409-416Crossref PubMed Scopus (274) Google Scholar showed that patients undergoing percutaneous coronary revascularization who had AKI were at risk for future development of ESRD. Patients with AKIN stage I AKI were over 4 times more likely to develop ESRD, whereas patients with AKIN stage II/III were over 11 times more likely to develop ESRD.23.James M.T. Ghali W.A. Knudtson M.L. et al.Associations between acute kidney injury and cardiovascular and renal outcomes after coronary angiography.Circulation. 2011; 123: 409-416Crossref PubMed Scopus (274) Google Scholar We have similarly shown that the severity of AKI is linked to CKD progression.9.Chawla L.S. Amdur R.L. Amodeo S. et al.The severity of acute kidney injury predicts progression to chronic kidney disease.Kidney Int. 2011; 79: 1361-1369Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar We assessed a cohort of 11,589 patients with a spectrum of AKI from RIFLE stage R through F.9.Chawla L.S. Amdur R.L. Amodeo S. et al.The severity of acute kidney injury predicts progression to chronic kidney disease.Kidney Int. 2011; 79: 1361-1369Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar Severity of AKI, assessed by peak serum creatinine, was associated with progression to advanced CKD (Figure 1). In particular, patients who required dialysis were at much higher risk for progression to CKD than patients with less severe AKI.9.Chawla L.S. Amdur R.L. Amodeo S. et al.The severity of acute kidney injury predicts progression to chronic kidney disease.Kidney Int. 2011; 79: 1361-1369Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar Although it is seemingly intuitive that the severity of AKI would be associated with progression to advanced CKD, these three studies are the first to show this link.9.Chawla L.S. Amdur R.L. Amodeo S. et al.The severity of acute kidney injury predicts progression to chronic kidney disease.Kidney Int. 2011; 79: 1361-1369Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar, 22.Ishani A. Nelson D. Clothier B. et al.The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death.Arch Intern Med. 2011; 171: 226-233Crossref PubMed Scopus (287) Google Scholar, 23.James M.T. Ghali W.A. Knudtson M.L. et al.Associations between acute kidney injury and cardiovascular and renal outcomes after coronary angiography.Circulation. 2011; 123: 409-416Crossref PubMed Scopus (274) Google Scholar These findings suggest that when the severity of AKI reaches a certain threshold the course of AKI is altered, initiating a chronic, progressive disease. In addition to severity, the duration of AKI has been linked to mortality but not to CKD progression. Coca et al.24.Coca S.G. King Jr., J.T. Rosenthal R.A. et al.The duration of postoperative acute kidney injury is an additional parameter predicting long-term survival in diabetic veterans.Kidney Int. 2010; 78: 926-933Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar assessed a large cohort of patients with diabetes mellitus undergoing cardiac surgery in the Veterans Administration system. Both severity and duration of AKI were linked to long-term mortality. However, the duration of AKI was not linked to CKD progression.24.Coca S.G. King Jr., J.T. Rosenthal R.A. et al.The duration of postoperative acute kidney injury is an additional parameter predicting long-term survival in diabetic veterans.Kidney Int. 2010; 78: 926-933Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar Consistent with these findings, Brown et al.25.Brown J.R. Kramer R.S. Coca S.G. et al.Duration of acute kidney injury impacts long-term survival after cardiac surgery.Ann Thorac Surg. 2010; 90: 1142-1148Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar assessed a separate cohort of US Veterans after cardiac surgery and confirmed that the duration of AKI was linked to worse long-term survival. Not surprisingly, patients who sustain multiple episodes of AKI as compared with a single episode of AKI have higher likelihoods of CKD progression. Thakar et al.26.Thakar C.V. Christianson A. Himmelfarb J. et al.Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus.Clin J Am Soc Nephrol. 2011; 6: 2567-2572Crossref PubMed Scopus (338) Google Scholar have shown, in a cohort of US Veterans with diabetes, that those who experienced two or more episodes of AKI were much more likely to progress to stage 4 CKD than patients who experienced only one episode of AKI (Figure 2).26.Thakar C.V. Christianson A. Himmelfarb J. et al.Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus.Clin J Am Soc Nephrol. 2011; 6: 2567-2572Crossref PubMed Scopus (338) Google Scholar These data are consistent with the hypothesis that for some patients a single episode of AKI has biologic ramifications beyond the acute event, engendering an ongoing state that predisposes to the development of further injury, manifested differentially in time as worsened AKI (short-term) or the development or worsening of CKD over longer periods (Figure 3). Some patients can fully recover from their initial AKI, but subsets of AKI survivors appear to go on to experience vicious cycles of intertwined AKI and CKD.26.Thakar C.V. Christianson A. Himmelfarb J. et al.Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus.Clin J Am Soc Nephrol. 2011; 6: 2567-2572Crossref PubMed Scopus (338) Google Scholar It is likely that the severity of renal injury along with other clinical, treatment, and host risk factors mediate such processes. Hsu et al.27.Hsu C.Y. Vittinghoff E. Lin F. et al.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 showed that the incident growth of the ESRD population exceeded the prevalent CKD population. The authors hypothesized that physician-related decisions to start chronic dialysis earlier might account for this discrepancy. We believe that the more likely explanation is the marked effect of AKI on the development and progression of CKD. CKD has consistently been shown to be a significant risk factor for the development of AKI.28.Thakar C.V. Arrigain S. Worley S. et al.A clinical score to predict acute renal failure after cardiac surgery.J Am Soc Nephrol. 2005; 16: 162-168Crossref PubMed Scopus (755) Google Scholar,29.James M.T. Hemmelgarn B.R. Wiebe N. et al.Glomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: a cohort study.Lancet. 2010; 376: 2096-2103Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar Probable explanations include the hemodynamic instability and failure of autoregulation30.Bidani A.K. Griffin K.A. Williamson G. et al.Protective importance of the myogenic response in the renal circulation.Hypertension. 2009; 54: 393-398Crossref PubMed Scopus (134) Google Scholar in CKD patients, the ease of detection of small changes in GFR when renal function is impaired, and a predisposition to further injury in patients with diminished renal function.31.Daugherty S.L. Ho P.M. Spertus J.A. et al.Association of early follow-up after acute myocardial infarction with higher rates of medication use.Arch Intern Med. 2008; 168 (discussion 492): 485-491Crossref PubMed Scopus (57) Google Scholar,32.Venkatachalam M.A. Griffin K.A. Lan R. et al.Acute kidney injury: a springboard for progression in chronic kidney disease.Am J Physiol Renal Physiol. 2010; 298: F1078-F1094Crossref PubMed Scopus (391) Google Scholar These consist of at least susceptibility to nephrotoxic agents, and the effects of ongoing humoral and renal pathologic mechanisms in the setting of CKD. Unfortunately, this risk appears to be bidirectional. Ishani et al.10.Ishani 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 (885) Google Scholar showed that patients with CKD who experienced an episode of AKI were 41 times more likely to develop ESRD than patients without kidney disease, whereas patients with CKD and no episodes of AKI had an 8.4-fold higher risk compared with patients without kidney disease. The risk of developing ESRD was enhanced almost fourfold by the superimposition of AKI in CKD patients. AKI enhanced the risk almost 10-fold compared with patients without either CKD or AKI, and astonishingly was associated with greater risk of developing ESRD than those identified with CKD in the Medicare population. Similarly, Hsu et al.33.Hsu C.Y. Chertow G.M. McCulloch C.E. et al.Nonrecovery of kidney function and death after acute on chronic renal failure.Clin J Am Soc Nephrol. 2009; 4: 891-898Crossref PubMed Scopus (314) Google Scholar showed that patients with an eGFR 60ml/min per 1.73m2. In addition to low baseline eGFR, patients with CKD as assessed by proteinuria are at increased risk for AKI. James et al.29.James M.T. Hemmelgarn B.R. Wiebe N. et al.Glomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: a cohort study.Lancet. 2010; 376: 2096-2103Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar showed in a cohort of over 920,000 patients that the level of proteinuria and diminished baseline eGFR were independent risk factors for developing AKI.29.James M.T. Hemmelgarn B.R. Wiebe N. et al.Glomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: a cohort study.Lancet. 2010; 376: 2096-2103Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar The risk of progression to CKD in patients who develop AKI is not limited to adults but affects children as well.34.Goldstein S.L. Devarajan P. Acute kidney injury in childhood: should we be worried about progression to CKD?.Pediatr Nephrol. 2011; 26: 509-522Crossref PubMed Scopus (67) Google Scholar,35.Goldstein S.L. Devarajan P. Progression from acute kidney injury to chronic kidney disease: a pediatric perspective.Adv Chronic Kidney Dis. 2008; 15: 278-283Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Large pediatric cohort studies suggest that certain subsets of children (such as bone marrow transplant patients) are at high risk for C