Biomarkers for Early Diagnosis of Acute Kidney Injury: Current Progress and Clinical Prospects.

Acute kidney injury (AKI) is one of the most common complications in critically ill patients, resulting in high morbidity and mortality. AKI usually occurs after major surgery, severe infection or drug-induced nephrotoxicity and is associated with prolonged hospital stays, increased costs and adverse clinical outcomes. The diagnosis of AKI is currently based on decreased glomerular filtration rate (GFR) and urine output, and increased serum creatinine. Novel biomarkers are required for early identification of patients with AKI to allow timely therapy and improve patient outcomes. With the advent of proteomics and genomics techniques, a vast array of biomarkers are now available in clinical practice.

Urinary markers of acute kidney injury in newborns with perinatal asphyxia (.).

BACKGROUND: Acute kidney injury (AKI) affects up to 60% of severely asphyxiated neonates. The diagnosis of AKI can be and is further challenged by a lack of good biomarkers. We studied the role of novel markers for AKI, neutrophil gelatinase-associated lipocalin (NGAL), interleukin-8 (IL-18), Netrin-1 (NTN-1), and sodium hydrogen exchanger isoform 3 (NHE3) on development and early diagnosis of AKI in newborns with perinatal asphyxia (PA). METHODS: Forty-one newborns with a diagnosis of PA (15 with AKI and 26 without AKI) and 20 healthy matched controls were involved to the study. Urinary samples were obtained on postnatal days 1 and 4 for patients with PA and on postnatal day 1 for the control subjects. AKI was defined using a serum creatinine-based modification of the acute kidney injury network criteria. RESULTS: The levels of NGAL, NTN-1, NHE3, and IL-18 on the first postnatal day urine samples were higher in patients compared to controls (p < 0.001, p <0.001, p  <0.02, p  <0.001, respectively). In patients with AKI, the levels of NGAL and IL-18 were higher when compared to patients without AKI (p = 0.002, p  <0.001, respectively). The levels of NTN-1 and NHE3 were similar in both groups. For the samples obtained on postnatal day 4, only NGAL levels were significantly higher in patients with AKI (p = 0.004) compared to those without AKI. CONCLUSION: To our knowledge, this is the largest study, which evaluated the utility of urinary biomarkers in the diagnosis of AKI in newborns with PA. First day, urine NGAL and IL-18 levels have an important diagnostic power in such patients.

Acute Kidney Injury (AKI) biomarker.

The kidney has a remarkable capacity to withstand insults for an extended period of time. The sensitivities of individual renal cells to injury vary depending on their type, position in the nephron, local vascularization, and the nature of injury. The resulting kidney injury is a product of the interplay between cell dysfunction, cell death, proliferation, inflammation, and recovery. The Acute Kidney Injury Network (AKIN) defined Acute Kidney Injury (AKI) as "functional and structural disorder or signs of renal damage including any defect from blood and urine test, or tissue imaging that is less than 3 months". RIFLE (Risk, Injury, Failure, Loss, End-Stage Kidney Disease) criteria is the most frequently used system. Ideal biomarker for AKI should be affordable, quick and measurable, precise and accurate, with prognostic ability to define severity of renal dysfunction, specific for renal, increase in the early stage dysfunction, with high sensitivity and specificity. Efforts to detect AKI in the earlier stage has resulted in some promising biomarkers such as KIM-1, NGAL, IL-18, Clusterin, etc. Cystatin C is a biomarker for glomerular filtration function, while 2-microglobulin, 1-microglobulin, NAG, RBP, IL-18, NGAL, Netrin-1, KIM-1, Clusterin, Sodium Hydrogen Exchanger Isoform and Fetuin A are biomarkers for tubular reabsorption function.

Acute kidney injury in the elderly population.

Acute kidney injury (AKI) is associated with significant morbidity, mortality, and health care costs. In spite of significant advances in health-care technology over the past few years, the incidence of AKI appears to be increasing over time. Elderly subjects represent the segment of the general population in which the incidence of AKI has been increasing the most. AKI is usually diagnosed by an abrupt change in serum creatinine concentration. The rate and magnitude of the rise in serum creatinine may be blunted in the elderly because of the reduced muscle mass and, thus, serum creatinine is not an ideal biomarker for AKI in this population. In the last few years, several studies have suggested new biomarkers that may help the physician to better define AKI overall and in elderly patients in particular. The prevention of AKI is a crucial consideration in the management of elderly patients, since they are at high risk of developing AKI and in this particular population AKI is associated with significantly increased morbidity and mortality. Improved awareness, aiming for early detection, and implementation of preventive strategies, might lead to a decreased incidence of AKI and better outcomes in elderly patients.

Renal tubular dysfunction in patients with American cutaneous leishmaniasis.

Renal dysfunction seen in patients with American cutaneous leishmaniasis (ACL) has been attributed to the use of antimonials for treatment. To determine whether ACL itself causes tubular dysfunction, we measured renal function in 37 patients with ACL prior to their treatment and compared results to that in 10 healthy volunteers of similar mean age. None of the patients presented with glomerular dysfunction; however, 27 had a urinary concentrating defect. There was no statistical difference between groups in the pre- and post-desmopressin test of urine osmolality, but the post-test urine osmolality of the controls was significantly higher. Urinary AQP2 levels, determined by western blot of isolated exosomes, were found to be significantly lower in patients than in controls, whereas that of the cotransporter (NKCC2) was significantly higher. A urinary acidification defect (post-test pH greater than 5.50 following calcium chloride) was found in 15 patients. Pretest plasma bicarbonate was below normal in 12 patients as was the pretest plasma pH in 14. Expression of the Na/H exchanger (NHE3), H(+)-ATPase, and pendrin were all significantly higher in patients with ACL than in controls. A combined urinary concentration and acidification defect was found in 12 patients. Thus, the urinary concentrating defect of ACL may be caused by decreased AQP2, with increased NKCC2 compensatory. Pendrin upregulation may be related to the urinary acidification defect with increased NHE3 and H(+)-ATPase also compensatory. Hence, ACL can cause asymptomatic renal tubular dysfunction.

Biologic markers for the early detection of acute kidney injury.

PURPOSE OF REVIEW: This review discusses the current status of several biomarkers as potential diagnostic tools in patients with acute kidney disease. RECENT FINDINGS: Although the term "acute renal failure" has generally been used to describe acute kidney dysfunction that runs the spectrum from mild prerenal azotemia with no renal pathologic changes and no functional failure to severe oliguric renal dysfunction associated with tubular necrosis with failure of function, this spectrum is better described by the term "acute kidney injury." The mortality rate of hospitalized patients with severe acute kidney disease has not decreased significantly over the past 50 years despite advances in supportive care. The absence of sensitive and specific biomarkers for detecting injury early, grading the severity of the injury, and monitoring the response to therapy has impaired progress in the field and has had a very detrimental effect on the design and outcome of clinical trials in acute kidney disease. As a result of reliance on serum creatinine as a marker for injury and diagnosis, the institution of therapy is markedly delayed. SUMMARY: The search for new biomarkers for acute kidney injury is evolving rapidly with advancement in modern technologies. With better biomarkers we will have the ability to detect injury earlier, identify subclinical injury, provide prognostic information on the course of renal impairment, identify the nephron segments most affected, provide a rationale for segmentation of patients for clinical studies, guide timing of therapy, assess response to therapy, and screen patients at risk for renal injury.

Urinary measurement of Na+/H+ exchanger isoform 3 (NHE3) protein as new marker of tubule injury in critically ill patients with ARF.

BACKGROUND: It has been shown that apical sodium transporters of the renal tubule can be detected by immunoblotting of urine membrane fraction from rats. We raised the hypothesis that protein levels of the Na+/H+ exchanger isoform 3 (NHE3), the most abundant apical sodium transporter in renal tubule, should be increased in urine of patients presenting with acute renal failure (ARF) with severe tubular cell damage and thus might be a noninvasive marker of acute tubular necrosis (ATN). METHODS: Sixty-eight patients admitted to the intensive care unit were studied prospectively (54 patients with ARF, 14 controls without renal dysfunction). Patients with ARF were divided into 3 subgroups as follows: prerenal azotemia, ATN, and intrinsic ARF other than ATN. Urinary NHE3 protein abundance was estimated from semiquantitative immunoblots of urine membrane fraction samples collected from patients. The amount of urinary NHE3 was compared with the fractional excretion of sodium (FeNa) and urinary retinol-binding protein (RBP). RESULTS: NHE3 was not detected in urine from controls. Levels of urinary NHE3 normalized to urinary creatinine level were increased in patients with prerenal azotemia and 6 times as much in patients with ATN, without overlap (ATN, 0.78 +/- 0.36; prerenal azotemia, 0.12 +/- 0.08; P < 0.001). Conversely, urinary NHE3 protein was not detected in patients with intrinsic ARF other than ATN. Normalized NHE3 level correlated positively with serum creatinine level in patients with tubular injury (R2 = 0.305; P = 0.0003). Values for FeNa and normalized urinary RBP did not discriminate ATN from intrinsic ARF other than ATN and prerenal azotemia, respectively. CONCLUSION: In patients with ARF, urinary NHE3 abundance might be a novel noninvasive marker of renal tubule damage, helping to differentiate prerenal azotemia, ATN, and intrinsic ARF other than ATN.

Detection of Na(+) transporter proteins in urine.

Previous studies have established that the vasopressin-regulated water channel of the collecting duct, aquaporin-2, is excreted in the urine, providing a means for assessment of regulation and dysregulation of aquaporin-2 in humans. This article addresses the hypothesis that membrane transporters from upstream nephron segments are normally detectable in urine. The experiments employed rabbit polyclonal antibodies against the major Na transporters of the proximal tubule (the type 3 Na-H exchanger [NHE3]), the thick ascending limb of Henle's loop (the bumetanide-sensitive Na-K-2Cl cotransporter [NKCC2]), and the distal convoluted tubule (the thiazide-sensitive Na-Cl cotransporter [NCC]) in immunoblotting experiments. All three of these transporters were readily detectable as high molecular weight complexes present in lowdensity membrane fractions from urine of normal rats. Cross linking studies of NHE3, NKCC2, and NCC revealed that high molecular weight complexes are normally present in renal tissue. The molecular weights of the complexes in urine matched those of the cross-linked complexes in native kidney tissue. The presence in urine of integral membrane proteins representative of each nephron segment raises the possibility that limited or comprehensive proteomic analysis of urine samples may be useful in clinical settings.