When Increase in Serum Creatinine Doesn’t Imply Kidney Damage

Abstract

Short-term increases in serum creatinine predict adverse outcomes including mortality, but this does not mean that the association is causal or even that all changes in creatinine are problematic. AKI can increase the risk of CKD through a number of mechanisms that lead to tubulointerstitial damage and fibrosis. AKI is defined by as little as a 0.3 mg/dl creatinine change (1). Gottlieb et al. (2) evaluated rise in creatinine in 1004 individuals hospitalized for heart failure. The majority of patients had an increase in creatinine, ranging from 72% having an increase of 0.1 mg/dl to 20% having an increase of at least 0.5 mg/dl, with the increase occurring primarily in the first few days of admission. Smaller changes in serum creatinine were sensitive for prediction of mortality or prolonged length of stay but were not very specific. Receptor operator characteristics indicated that the best cut-off was 0.3 mg/dl. Although the association of rise in creatinine with worse outcomes is generally accepted, more recent studies have found that a rise in creatinine with treatment for heart failure may not portend a worse outcome if it results from resolution of congestion (3). Further complicating the AKI definition is the finding that short-term rise in creatinine may reflect a beneficial effect in CKD. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers slow the progression of proteinuric kidney disease, but initiation of these medications often lead to an acute rise in creatinine. In the RENAAL study, this initial rise in creatinine predicted a slower long-term loss of kidney function (4). Unfortunately, this concern about the rise in creatinine can lead to underdosing or discontinuation of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Sodium-glucose transport protein two (SGLT2) inhibitors have recently been shown to slow progression of diabetic kidney disease. Initiation of SGLT2 inhibitors causes an acute fall in eGFR and then stabilization of slope and decreased risk of ESKD (5). Whether the degree of acute GFR lowering with SGLT2 inhibitors is similarly associated with slower loss of slope has not been reported. How do we reconcile this with the AKI findings? Recent studies have raised concerns about using the 0.3-mg/dl change definition alone. Coca et al. (6) performed a systematic review of interventions that can increase or decrease AKI and evaluated the subsequent effect on long-term outcomes. Interventions that increased the risk of AKI did not lead to higher risk of mortality or worsened CKD. Furthermore, interventions that decreased the risk of AKI did not reduce the risk of subsequent CKD or mortality. If one looks closer at the data in these studies, although the interventions did not lead to differences in long-term outcomes, individuals who developed AKI were at higher risk. This discrepancy suggests that the rise in creatinine may be telling us something about the patient, rather than being causally related to adverse outcomes. If the AKI is owing to hemodynamic changes, there may be no underlying kidney damage. Patients with AKI may have less kidney reserve, worse cardiac output, or other comorbidity that both increases the risk of AKI and leads to adverse outcomes. Urinary biomarkers have been proposed to help differentiate AKI owing to intrinsic kidney damage from that owing to hemodynamic changes. As the urinary biomarkers reflect different pathologic processes in the kidney, they can also potentially be used for finer phenotyping of the cause of the kidney damage. The optimal biomarker or panel of biomarkers has not yet been developed, but is an area of active study. What about their use in CKD? eGFR is primarily a marker of glomerular function. Albuminuria reflects both glomerular damage and tubular damage (decreased uptake in the proximal tubule). It was recognized over 25 years ago that the presence of tubular proteinuria, such as retinol binding protein, in the urine of individuals with type 1 diabetes can precede the development of albuminuria and may be a marker of proximal tubular dysfunction (7). The newer biomarkers, which reflect kidney damage at different sites, could be better at identifying tubular damage in CKD, as well as helping understand the pathophysiology. In this issue of CJASN, Malhotra et al. (8) evaluate baseline urinary markers of tubular damage with kidney function decline in participants with CKD in the Systolic BP Intervention Trial (SPRINT). SPRINT evaluated two systolic BP targets of <120 mm Hg (intensive) versus <140 mm Hg (standard) in adults with systolic BP 130–180 mm Hg. Intensive BP lowering lowered the risk of cardiovascular events and all-cause mortality, but with a greater decline in kidney function. CKD, defined as an eGFR of 20–59 ml/min per 1.73 m2, was a targeted population for recruitment; individuals with diabetes or with proteinuria >1 g/d (urine albumin-to-creatinine ratio >600 mg/g) were excluded. For this ancillary study, Malhotra et al. analyzed baseline values of IL-18, kidney injury marker-1 (KIM-1), Chitinase 3-like 1, and monocyte chemoattractant protein 1 with change in kidney function. The end points analyzed were (1) composite of confirmed 50% decline in eGFR or ESKD, and (2) annualized relative percent change. At baseline the mean eGFR was 46 ml/min per 1.73 m2, and median albumin-to-creatinine ratio was 15 mg/g. After adjustment for covariates, including urine albumin excretion, there appeared to be threshold effect where there were significant associations of the highest quartile of KIM-1, neutrophil gelatinase–associated lipocalin, monocyte chemoattractant protein 1, and Chitinase 3-like 1 with 50% decline in eGFR or ESKD, but not for urinary IL-18. In contrast, the third and fourth quartile of urinary IL-18 was associated with greater annualized change but the other markers were not. The lack of consistency between the two kidney outcomes is not explained. If a marker predicts a larger (50%) decline, one would expect that it would be associated with linear percent decline. The lack of consistency raises a concern about whether the relationship with kidney function decline reflects a chance finding. An interesting finding in the analysis is that the association of IL-18 and KIM-1 was different in the intensive BP arm and the standard treatment arm. IL-18 was associated with greater annualized decline in the standard arm only, whereas KIM-1 was associated with no change in the standard arm and a trend toward better (positive change) in the intensive arm. The authors postulate that this finding means that urinary IL-18 may help distinguish subtler changes in eGFR related to intrinsic kidney tubule injury versus hemodynamic changes. Whether that is true or not, it is not what the study shows. The biomarkers were measured at baseline, before any study intervention-related hemodynamic change occurred. To assess whether any of the biomarkers can separate tubular damage from hemodynamic change would require measurement at the time of the hemodynamic change. Another possible interpretation of the findings is that intensive BP control attenuates kidney damage in individuals with elevated tubular injury markers. If that is the case, the markers might help identify individuals who would most benefit from intensive BP control. This deserves further study, especially as this differing relationship of biomarkers in treatment arms was not seen for the 50% decline or ESKD outcome. The study by Malhotra et al. shows that urinary biomarkers provide further information on kidney risk over that of albuminuria. Biomarkers have promise in CKD to identify biologic processes, risk stratify, identify true damage from hemodynamic changes, and identify individuals who may benefit from particular interventions. Studies have reported different results among patients with CKD (9,10). Further studies are needed to learn whether this reflects differences in biologic processes among different diseases or inter-individual variation or reflects poor predictive ability. The Kidney Precision Medicine Project, by linking biopsy data with clinical data and biomarkers, could help elucidate the role of biomarkers in identifying individual disease processes. This would be a stepping stone to individualized treatment, the goal of precision medicine. Disclosures Dr. Fried has nothing to disclose.

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