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Acute Kidney Injury and Urinary Biomarkers in Human Immunodeficiency Virus–Associated Cryptococcal Meningitis

Acute Kidney Injury and Urinary Biomarkers in Human Immunodeficiency Virus–Associated... Open Forum Infectious Diseases MAJOR ARTICLE Acute Kidney Injury and Urinary Biomarkers in Human Immunodeficiency Virus–Associated Cryptococcal Meningitis 1,2 3 4 3 3,5 6 Charlotte Schutz, David R. Boulware, Katherine Huppler-Hullsiek, Maximilian von Hohenberg, Joshua Rhein, Kabanda Taseera, Friedrich 1,2 6 3,5,7 1,2 Thienemann, Conrad Muzoora, David B. Meya, and Graeme Meintjes 1 2 Department of Medicine, Faculty of Health Sciences, and Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, 3 4 South Africa; Division of Infectious Diseases & International Medicine, Department of Medicine, and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis; and 5 6 7 Infectious Disease Institute, Makerere University, Kampala, Mbarara University of Science and Technology, Mbarara, and Makerere University College of Health Sciences, School of Medicine, Kampala, Uganda Background. Cryptococcus is the most common etiology of adult meningitis in Africa. Amphotericin B deoxycholate remains paramount to treatment, despite toxicities, including acute kidney injury (AKI). We assessed the ability of the following urine mark- ers to predict AKI in patients who received amphotericin B: urine neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (CysC), tissue inhibitor of metalloproteinases-2 (TIMP-2), and protein. Methods. One hundred and thirty human immunodeficiency virus (HIV)–infected participants with cryptococcal meningitis were enrolled and received amphotericin and fluconazole for 2 weeks. We defined AKI as glomerular filtration rate (GFR) < 60 mL/ min/1.73 m ; measured urine NGAL, CysC, TIMP-2, and protein; and explored AKI incidence, risk factors, and associations with mortality using Cox proportional hazards models. Results. Participants were 48% female with a median age of 35 years, a median CD4 count of 21 cells/μL, and 44% died within 12 months. Incident AKI occurred in 42% and was associated with mortality (adjusted hazard ratio [aHR] = 2.8; P < .001). Development of AKI was associated with female sex (P = .04) and with higher CD4 count (49 vs 14 cells/μL; P < .01). Urine protein level in the highest quartile independently predicted AKI and mortality (aHR = 1.64, P = .04; aHR = 2.13, P = .02, respectively). Urine NGAL levels in the highest quartile independently predicted AKI (aHR = 1.65; P = .04). Conclusions. Acute kidney injury occurred in 42% of patients, and AKI was associated with mortality. Urine biomarkers, specif- ically urine protein, may be useful for antecedent prediction of amphotericin-associated AKI but need further evaluation. Keywords. acute kidney injury; amphotericin B; biological marker; cystatin C; neutrophil gelatinase-associated lipocalin; pro- tein; tissue inhibitor of metalloproteinase-2. Cryptococcal meningitis is a disseminated fungal infection treatment for cryptococcosis despite numerous toxicities. The caused by Cryptococcus species and remains a major cause most common and severe side effect of amphotericin is renal of mortality in human immunodeficiency virus (HIV)– toxicity, which has been reported in 49%–65% of patients [5]. infected persons, especially in resource-limited settings [1]. Renal toxicity is caused through a combination of mechanisms, Cryptococcosis causes approximately 2% of deaths of HIV- which are incompletely understood. First, systemic and renal infected persons in the United States [2] and approximately aer ff ent arteriolar vasoconstriction decrease kidney perfusion 15% of AIDS-related deaths in sub-Saharan Africa [1, 3, 4]. [6], and the resulting decrease in glomerular filtration rate Liposomal amphotericin formulations remain unavailable (GFR) may be mitigated by aggressive saline hydration [7, 8]. in resource-limited settings due to cost; thus amphotericin Second, regardless of hydration status, direct cumulative dam- B deoxycholate (hereaer a ft mphotericin) remains the key age to renal tubular cells occurs from induction of proinflamma- tory cytokines, channel formation across renal cell membranes, and apoptosis [9, 10]. Received 6 March 2017; editorial decision 14 June 2017; accepted 15 June 2017. Acute kidney injury (AKI) is a clinical syndrome, which has Correspondence: C. Schutz, MBChB, MPH (Clinical Research), Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, CIDRI Office, wide etiologies and was defined, staged, and classified in 2012 Rm N2.09.2, Wernher Beit North Building, Anzio Rd, Observatory, 7925, South Africa (charlotte. [11]. Acute kidney injury predicts mortality, independent of schutz@uct.ac.za). Open Forum Infectious Diseases underlying disease [12], and AKI is a common complication of © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases HIV infection [13, 14]. Definition and staging of AKI depends Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits on serum creatinine or urine output [11], which are both late unrestricted reuse, distribution, and reproduction in any medium, provided the original work indicators of kidney injury. This has led to a wide interest in is properly cited. DOI: 10.1093/ofid/ofx127 new urine and serum biomarkers that could detect AKI earlier Acute Kidney Injury and Urine Biomarkers • OFID • 1 in critically ill patients [15]. Neutrophil gelatinase-associated samples. We summarized incidence of AKI and explored risk lipocalin (NGAL; also known as Lipocalin-2) is a 25-kDa pro- factors for incident AKI using Cox univariate and multivariable tein produced in many tissues, including renal epithelial cells, proportional hazards models. Models were estimated with bio- and is an established sensitive early marker of acute ischemic markers on a continuous scale (aer log ft transformation, so that kidney injury [16, 17]. Elevated urine NGAL levels predict a the hazard ratio is per doubling of the biomarker). Other mod- composite outcome of dialysis initiation or death during hos- els compared the upper quartile versus the lower 3 quartiles (an pitalization when used as a risk stratification tool in unselected a priori comparison to assess clinical outliers). Each biomarker emergency department patients at the time of admission to the was first statistically tested individually and then in a multivari- hospital [18]. Cystatin C (CysC), a 13-kDa proteinase inhibi- able model adjusted for timing of ART initiation group, age, sex, tor, can be measured in serum and in urine and, unlike creati- altered mental status at diagnosis, CD4 cell count, and cerebrospi- nine, is not ae ff cted by muscle mass or age [19]. Urine CysC is nal fluid quantitative cryptococcal culture at diagnosis. We exam- a marker of tubular dysfunction or damage [20], and elevated ined the association of incident AKI with 12-month mortality levels may be associated with AKI [15]. Tissue inhibitor of using time-updated Cox proportional hazards models. With the metalloproteinases-2 (TIMP-2) is an inducer of G1 cell-cycle time-updated models, an indicator for incident AKI was recal- arrest, predicts severe AKI, and is associated with mortality culated at the time of each creatinine measurement to assess the in critically ill adult patients [21]. Neutrophil gelatinase-asso- impact of developing AKI on mortality. All analyses were com- ciated lipocalin and CysC are induced during inflammation. pleted using SAS 9.3. Relevant ethics and regulatory authority These biomarkers have not been evaluated in the context of approvals were obtained. Written informed consent was obtained HIV infection and opportunistic infections. In resource-lim- to participate in the COAT trial, as previously described [22]. ited settings where liposomal amphotericin is not available, a urine biomarker that could predict development of AKI early RESULTS and accurately could be a valuable clinical tool to tailor dura- Incidence and Risk of Acute Kidney Injury tion of amphotericin therapy. The COAT trial enrolled 177 patients [22], of whom 130 We assessed these urine biomarkers together with urine patients had urine samples stored and were included in this protein and creatinine levels in patients with HIV-associated study. The median age was 35  years (IQR  =  30–40), and 52% cryptococcal meningitis treated with amphotericin therapy and (n = 68/130) were men. The median CD4 T-cell count was 21 investigated association with AKI and mortality. cells/μL (IQR  =  9–74). Forty-four percent (n  =  57/130) died METHODS within 12  months; 1 withdrew consent and 1 was lost to fol- low-up. Four persons (3%) had GFR  <60  mL/min/1.73 m Human immunodeficiency virus–infected, antiretroviral ther- at baseline. Incident AKI occurred in 42% (n  =  53/126) at a apy (ART)–naive adults with a new diagnosis of cryptococcal median of 8 days (IQR = 6–11) after diagnosis of cryptococcal meningitis were prospectively enrolled into the Cryptococcal meningitis. Persons developing AKI had higher baseline CD4 Optimal ART Timing (COAT) trial during 2010–2012 and T-cell counts (49 vs 14 cells/μL; P < .01), and a higher propor- treated with amphotericin B, fluconazole, and ART according tion were women (59% vs 40%; P = .04). Table 1 displays base- to the COAT trial protocol [22, 23]. Baseline and follow-up line characteristics, urine biomarker values, and mortality. serum creatinine concentrations were measured at regular intervals as per the COAT trial protocol (5–6 time points during Urine Biomarker Associations With Acute Kidney Injury amphotericin treatment and at 1 and 2 weeks after completion On a continuous scale, there was increased risk of AKI per of amphotericin therapy). Estimated GFR was calculated using doubling of urine TIMP-2 and protein levels (hazard ratio the Modification of Diet in Renal Disease (MDRD) study equa- [HR] = 1.47, 95% confidence interval [CI] = 1.08–2.00, P = .02; tion [24], and AKI was defined as a decrease in GFR to <60 mL/ HR = 2.28, 95% CI = 1.05–4.94, P = .04, respectively), but the min/1.73 m at any point within 3 weeks of cryptococcal diag- association became nonsignificant after adjustment (adjusted nosis. Urine output was not routinely monitored and could not HR [aHR]  =  1.34, 95% CI  =  0.95–1.88, P  =  .09; aHR =  2.23, be used to define AKI. Ten-week and 12-month mortality was 95% CI = 0.92–5.41, P = .07). In univariate models, those with ascertained. NGAL, TIMP-2, and protein levels in the upper quartile had an We included 130 participants with stored urine samples, which increased risk of AKI compared with those in the lower quar- were collected a median of  4 (interquartile range [IQR]  =  4–5) tiles. The risk remained significant for NGAL and protein in days from diagnosis of cryptococcal meningitis (which is multivariable models. Sixty percent of those with values in the similar to time from amphotericin initiation: median =  4; highest quartile of protein (>0.30  g/L protein) developed AKI IQR  =  4–5  days), and measured NGAL, CysC, and TIMP-2 by as compared with an average of 35% of those in the lower 3 enzyme-linked immunosorbent assay (R&D Systems) and pro- quartiles (aHR = 1.64; 95% CI = 1.02–2.62; P = .04) (Figure  1 tein and creatinine (Beckman Coulter DXC 800) on stored urine and Table 2). Similarly, of those in the upper quartile of NGAL 2 • OFID • Schutz et al Table  1. Urinary Biomarkers in Human Immunodeficiency Virus–Associated Cryptococcal Meningitis: Baseline Characteristics for the Overall Cohort, Participants Who Developed Acute Kidney Injury, and Those Who Did Not a b Baseline Variables Overall Cohort Incident Acute Kidney Injury No Acute Kidney Injury P Value No. 130 53 73 … Early ART initiation arm, no. (%) 63 (49) 26 (49) 37 (51) .92 Age, median (IQR), y 35 (30–40) 34 (30–40) 37 (29–40) .55 Female sex, no. (%) 62 (48) 31 (59) 29 (40) .04 Glasgow Coma Scale < 15, no. (%) 38 (29) 17 (32) 20 (28) .60 CSF quantitative culture, median (IQR), log CFU/mL 5.0 (3.8–5.4) 5.1 (3.8–5.5) 5.0 (4.0–5.6) .91 21 (9–74) 49 (16–87) 14 (7–54) <.01 CD4 count, median (IQR), cells/μL Weight , median (IQR), kg 54 (46–60) 54 (47–57) 54 (45–60) .81 Serum creatinine, median (IQR), μmol/L 70 (50–88) 69 (50–91) 70 (50–80) .36 Serum creatinine, median (IQR), mg/dL 0.79 (0.57–1.00) 0.78 (0.57–1.03) 0.79 (0.57–0.90) .36 Serum potassium, median (IQR), mEq/L 3.9 (3.4–4.2) 3.8 (3.3–4.1) 3.9 (3.5–4.2) .37 Amphotericin dose , mg/kg/d Overall 0.93 (0.85–1.00) 0.95 (0.89–1.0) 0.93 (0.83–1.0) .62 Men 0.93 (0.81–1.0) 0.96 (0.91–1.0) 0.92 (0.81–1.0) … Women 0.95 (0.89–1.00) 0.94 (0.89–1.0) 0.95 (0.91–1.0) … Urine biomarkers Cystatin C, ng/mL 2.2 (1.3–3.5) 2.6 (1.5–3.5) 2.0 (1.2–3.3) .32 Neutrophil gelatinase-associated lipocalin, ng/mL 4.1 (3.0–5.7) 4.2 (3.1–6.1) 4.0 (3.0–5.0) .41 Tissue inhibitor of metalloproteinases-2, ng/mL 1.8 (1.4–2.5) 1.9 (1.5–2.7) 1.6 (1.3–2.1) <.01 Urinary creatinine, mg/dL 4.6 (3.6–5.4) 4.8 (3.3–5.7) 4.4 (3.7–5.1) .39 Urinary protein, g/L 0.21 (0.11–0.39) 0.29 (0.16–0.46) 0.16 (0.08–0.30) <.01 Protein/creatinine ratio 0.56 (0.36–0.83) 0.57 (0.30–0.79) 0.56 (0.38–0.96) .49 Ten-week mortality, no. (%) 48 (37) 27 (51) 21 (29) .01 Twelve-month mortality, no. (%) 57 (44) 29 (55) 28 (38) .07 Bolded P values indicate statistically significant difference between patients who developed AKI and those who did not. Abbreviations: ART, antiretroviral therapy; CFU, colony-forming unit; CSF, cerebrospinal fluid; IQR, interquartile range. a 2 Includes 4 people with prevalent estimated glomerular filtration rate <60 mL/min/1.73m at cryptococcal meningitis diagnosis. b 2 Kruskall-Wallis or χ tests as appropriate, comparing those who develop incident acute kidney injury to those who do not. Glasgow Coma Scale <15 denotes altered mental status. Weight was measured for n = 111 participants (44 of 53 who later developed incident acute kidney injury; 63 of 73 who did not develop incident acute kidney injury). Amphotericin dose (mg/kg/d) is calculated only for those with a weight measurement. Samples collected at median of 4 days on amphotericin B therapy and stored at −80°C (>47.7 ng/mL), 61% developed AKI as compared with an aver- died a median of 8  days (IQR  =  4–23  days) aer AKI de ft vel- age of 36% of those in the lower 3 quartiles (aHR = 1.65; 95% oped. All 9 patients who developed severe AKI (estimated GFR CI = 1.01–2.69) (Figure 2 and Table 2). of <30 mL/min/1.73 m ) died. Associations with 12-Month Mortality Ten-Week Outcomes in Acute Kidney Injury Patients Elevated urine NGAL and protein-to-creatinine ratio, The outcome of abnormal renal function was assessed in survivors respectively, were associated with mortality in univar- at 10 weeks after diagnosis of cryptococcal meningitis. Among 53 iate analysis (HR =  1.16, 95% CI  =  1.01–1.34, P  =  .04; HR patients who developed AKI, 51% (n = 27) died before 10 weeks, =  1.86, 95% CI  =  1.01–3.41, P  =  .05) but not in multivari- and renal function recovered to eGFR  >60  mL/min/1.73 m in able analysis (aHR  =  1.14, 95% CI  =  0.98–1.34, P  =  .09; the remaining 49% (n  =  26/53) by 8 weeks. All 4 patients with aHR =  1.53, 95% CI  =  0.73–3.20, P  =  .26) when evaluated abnormal renal function at baseline survived and recovered renal on a continuous log scale. Urine protein levels in the upper function to eGFR >60 mL/min/1.73 m by 10 weeks. quartile independently predicted 12-month mortality, DISCUSSION and 68% of patients with urine protein levels in the high- est quartile died within 12  months as compared with 23%, To our knowledge, this is the first study to evaluate urine bio- 44%, and 36% of those in the lower quartiles, respectively markers in patients with HIV-associated cryptococcal men- (aHR = 2.13; 95% CI = 1.15–3.96) (Figure 3 and Table 3). ingitis treated with amphotericin. Acute kidney injury was a Incident AKI was independently associated with 12-month common complication and associated with high mortality. mortality (time-updated aHR  =  2.82; 95% CI  =  1.55–5.17; Urine protein level in the highest quartile independently pre- P  <  .001). Patients developed AKI at a median of 8  days aer ft dicted AKI and 12-month mortality, whereas the other bio- diagnosis of cryptococcal meningitis (IQR  =  6–11  days) and markers tested showed no strong associations. Urine biomarkers Acute Kidney Injury and Urine Biomarkers • OFID • 3 60 a cheap and readily available test in resource-limited settings. 60% This could be a useful marker to investigate in similar settings as an adjunctive tool to aid clinical decision making. Elevated urine protein levels at initiation of therapy could prompt more intensive fluid replacement, closer monitoring of renal func- 44% tion, and possible decreased duration of amphotericin, but this needs to be evaluated in further studies. 36% Acute kidney injury, as defined in this study, developed in 42% of patients in this cohort. The Kidney Disease: Improving Global Outcomes (KDIGO) published case definition of AKI 23% consists of (1) increase in serum creatinine within 48 hours of ≥26.5 μmol/L (0.3 mg/dL) or (2) increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred in the prior 7 days, or urine volume of <0.5 mL/kg/h for 6 hours [11]. We did not measure urine output in this cohort, and using serial serum creatinine values, 80% of our patients Q1 (Low) Q2 Q3 Q4 (High) met creatinine-based KDIGO AKI case definition criteria. We Figure  1. Urinary biomarkers in human immunodeficiency virus–associated used an amended case definition, which is equal to a grade 3 cryptococcal meningitis: acute kidney injury by quartiles of urine protein values. χ (severe) adverse event [25] and has clinical relevance in this P value comparing the 4 groups = .03. Abbreviation: Q, quartile. critically ill cohort who required treatment with a nephrotoxic drug. Amphotericin therapy is generally interrupted or stopped are being increasingly applied in clinical practice, particularly when a patient’s GFR declines to <60 mL/min/1.73 m . in settings where AKI is common and can potentially be mit- People with higher CD4 T-cell counts developed AKI more igated by amending management strategies, such as intensive commonly in our study. The reason for this is unclear. It is pos- care units. Urine biomarkers have not been studied in the con- sible that patients with very low CD4 T-cell counts did not sur- text of HIV-associated cryptococcosis where AKI is a common vive to develop AKI, and there is thus a competing risk of death; complication of amphotericin therapy and mortality is high. however, CD4 count was not associated with survival in this Urine protein can also be measured by urine dipstick, which is cryptococcal cohort [22]. More women developed AKI in our Table  2. Urinary Biomarkers in Human Immunodeficiency Virus–Associated Cryptococcal Meningitis: Urinary Biomarkers Associated With Incident Acute Kidney Injury Association Between Urinary Biomarkers (per doubling of value) and Acute Kidney Injury a a,c Urine Biomarker Univariate Hazard Ratio (95% CI) P Value Multivariable Hazard Ratio (95% CI) P Value CysC 1.04 (0.88–1.23) .62 1.05 (0.88–1.25) .61 NGAL 1.06 (0.91–1.24) .46 1.01 (0.85–1.19) .91 TIMP-2 1.47 (1.08–2.00) .02 1.34 (0.95–1.88) .09 Protein 2.28 (1.05–4.94) .04 2.23 (0.92–5.41) .07 Creatinine 1.04 (0.82–1.32) .74 1.07 (0.83–1.38) .59 Protein/creatinine ratio 0.83 (0.38–1.80) .63 0.63 (0.28–1.45) .28 Association of Upper Quartile of Urinary Biomarkers With Acute Kidney Injury: Fourth Quartile of Biomarkers Compared With Quartiles 1–3 b c Hazard Ratio (95% CI) P Value Hazard Ratio (95% CI) P Value CysC 1.05 (0.70–1.59) .81 1.05 (0.68–1.63) .82 NGAL 1.92 (1.25–2.94) <.01 1.65 (1.01–2.69) .04 TIMP-2 1.70 (1.10–2.61) .02 1.46 (0.91–2.33) .12 Protein 1.73 (1.12–2.68) .01 1.64 (1.02–2.62) .04 Creatinine 1.41 (0.92–2.16) .12 1.48 (0.94–2.32) .09 Protein/creatinine ratio 0.92 (0.60–1.42) .71 0.84 (0.53–1.34) .47 Bolded P values indicate statistically significant difference between patients who developed AKI and those who did not. Abbreviations: CI, confidence interval; CysC, cystatin C; NGAL, neutrophil gelatinase-associated lipocalin; TIMP-2, tissue inhibitor of metalloproteinases-2. Proportional hazards regression analyses using log transformed biomarker data. The hazard ratio presents the risk per doubling of the biomarker for developing incident acute kidney injury (GFR < 60 mL/min/1.73 m ) within 3 weeks of diagnosis of cryptococcal meningitis. Fourth quartile versus quartile 1–3. The hazard ratio presents the risk of developing acute kidney injury if the urine biomarker level falls within the highest quartile compared with the lower 3 quartiles. Adjusted for antiretroviral treatment (ART) group (early ART or deferred ART group), age, sex, decreased level of consciousness at diagnosis, CD4 cell count, and cerebrospinal fluid quan- titative cryptococcal culture at diagnosis (but not for other biomarkers). 4 • OFID • Schutz et al Cumulative Incidence (Percent) 60 70 61% 68% 41% 48% 39% 28% 33% 29% Q1 (Low) Q2 Q3 Q4 (High) Q1 (Low) Q2 Q3 Q4 (High) Figure  2. Urinary biomarkers in human immunodeficiency virus–associated Figure  3. Urinary biomarkers in human immunodeficiency virus–associated cryptococcal meningitis: acute kidney injury by quartiles of urine neutrophil gelati- cryptococcal meningitis: 12-month mortality by quartiles of urine protein values. χ nase-associated lipocalin (NGAL) values. χ P value comparing the 4 groups = .06. P value comparing the 4 groups = .01. Abbreviation: Q, quartile. Abbreviation: Q, quartile. study, which is consistent with the literature, which lists women analysis but not aer ad ft justing for potential confounders on as more susceptible to AKI [26]. a continuous scale. Urine TIMP-2 combined with insulin-like Tissue inhibitor of metalloproteinases-2 and urine protein growth factor-binding protein 7 (IGFBP7) has been shown levels were associated with development of AKI in univariate to predict development of severe AKI in acutely ill patients Table 3. Urinary Biomarkers in Human Immunodeficiency Virus–Associated Cryptococcal Meningitis: Analyses of Urinary Biomarkers and Acute Kidney Injury With 12-Month Mortality Association Between Urinary Biomarkers (per doubling of value) and 12-Month Mortality a a,c Urine Biomarker Univariate Hazard Ratio (95% CI) P Value Multivariable Hazard Ratio (95% CI) P Value CysC 1.15 (0.99–1.34) .06 1.14 (0.98–1.33) .10 NGAL 1.16 (1.01–1.34) .04 1.14 (0.98–1.34) .09 TIMP-2 1.25 (0.91–1.73) .17 1.23 (0.87–1.75) .24 Protein 1.92 (0.90–4.11) .09 1.94 (0.83–4.57) .12 Creatinine 1.08 (0.88–1.33) .45 1.16 (0.92–1.47) .21 Protein/creatinine ratio 1.86 (1.01–3.41) .05 1.53 (0.73–3.20) .26 Acute kidney injury (GFR < 60) 3.27 (1.87–5.73) <.001 2.82 (1.55–5.17) <.001 Severe acute kidney injury (GFR < 30) 12.17 (4.98–29.73) <.001 8.11 (3.19–20.60) <.001 Association of Upper Quartile of Urinary Biomarkers with 12-Month Mortality: Fourth Quartile of Biomarkers Compared With Quartiles 1–3 b c Hazard Ratio (95% CI) P Value Hazard Ratio (95% CI) P Value CysC 1.04 (0.57–1.87) .91 1.18 (0.63–2.19) .61 NGAL 1.12 (0.62–2.02) .71 0.99 (0.52–1.88) .97 TIMP-2 1.56 (0.85–2.85) .15 1.66 (0.87–3.17) .12 Protein 2.30 (1.30–4.08) <.01 2.13 (1.15–3.96) .02 Creatinine 1.11 (0.59–2.08) .75 1.20 (0.61–2.35) .59 Protein/creatinine ratio 2.03 (1.14–3.62) .02 1.53 (0.80–2.93) .20 Bolded P values indicate statistically significant difference between patients who died within 12 months after diagnosis of cryptococcal meningitis and those who did not. Abbreviations: CI, confidence interval; CysC, cystatin C; GFR, estimated glomerular filtration rate using the Modification of Diet in Renal Disease study equation; NGAL, neutrophil gelati- nase-associated lipocalin; TIMP-2, tissue inhibitor of metalloproteinases-2. Proportional hazards regression analyses using log -transformed biomarker data. The hazard ratio presents the 12-month mortality risk per doubling of the biomarker. Fourth quartile versus quartile 1–3. The hazard ratio presents the 12-month mortality risk if the urine biomarker level falls within the highest quartile compared to the lower three quartiles. Adjusted for antiretroviral treatment (ART) group (early ART or deferred ART group), age, sex, decreased level of consciousness at diagnosis, CD4 cell count, and cerebrospinal fluid quan- titative cryptococcal culture at diagnosis (but not for other biomarkers). d 2 From time-updated models with indicators for GFR <30 or <60 mL/min/1.73m at each visit. Acute Kidney Injury and Urine Biomarkers • OFID • 5 Cumulative Incidence (Percent) Cumulative Incidence (Percent) within 12 hours of collection of urine sample [27]. Higher urine of amphotericin-associated AKI. The utility of measuring urine TIMP-2 has also been associated with mortality in acutely ill protein levels for aiding decisions regarding duration of ampho- patients [21] but not in our study. Our urine samples were tericin therapy needs further evaluation. collected at a median of 4 days aer di ft agnosis of cryptococcal Acknowledgments meningitis, and AKI developed at a median of 8 days on ther- e C Th OAT Trial team worked on this trial in Uganda and South Africa apy, which is a different scenario to the previous studies investi- from 2010 to 2012. The enzyme-linked immunosorbent assays on Cape gating the predictive value of TIMP-2. Town samples were performed in the laboratory of Professor Robert J.  Wilkinson at the University of Cape Town. Dr Nicola Wearne at the Higher urine CysC was not associated with development of University of Cape Town, Department of Medicine, Renal Unit provided AKI or mortality in our study when evaluated on a continuous input on the study during the planning phase. log scale or comparing the upper quartile with lower quartiles. 2 Financial support. This work was supported by provided by the Cystatin C is an early marker of tubular dysfunction or damage, National Institute of Allergy and Infectious Diseases (U01AI089244 and T32AI055433), Wellcome Trust (081667 and 098316 to G.  M.), a Fogarty and it is possible that (1) the mechanism of development of AKI International Center South Africa TB/AIDS Training Award (NIH/ in our cohort was different or (2) that we measured CysC levels FIC 1U2RTW007373- 01A1 and U2RTW007373 ICORTA to G.  M.  and too long before AKI events to detect elevated levels. C. S.). e Th South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South We found AKI to be independently associated with mortal- Africa (64787 to G.  M.), NRF incentive funding (UID: 85858 to G.  M.) ity. Patients in this study were severely immune suppressed, and the South African Medical Research Council through its TB and HIV and although it is possible that AKI secondary to amphotericin Collaborating Centres Programme with funds received from the National Department of Health (RFA no. SAMRC-RFA-CC: TB/HIV/AIDS-01-2014 therapy could have played a role in mortality, there are other to G.  M.). The funders had no role in the study design, data collection, factors such as nosocomial sepsis, opportunistic infections, and data analysis, data interpretation, or writing of this report. The opinions, decreased level of consciousness with decreased oral intake that findings and conclusions expressed in this manuscript reflect those of the likely contributed to both AKI and mortality. authors alone. Potential coni fl ct of interest. All authors: No reported conflicts of interest. A limitation of our study is that we used a nonstandard case All authors have submitted the ICMJE Form for Disclosure of Potential definition of AKI. This limits comparability across studies, and Conflicts of Interest. Conflicts that the editors consider relevant to the con- importantly, patients who had normal renal function at base- tent of the manuscript have been disclosed. line would have had to experience a much larger proportional References decline in renal function before being classified as an AKI case 1. Park BJ, Wannemuehler KA, Marston BJ, et al. Estimation of the current global compared with patients who entered the study with a GFR close burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009;23:525–30. to the threshold of 60 mL/min/1.73 m . Furthermore, urine was 2. Pyrgos V, Seitz AE, Steiner CA, et al. Epidemiology of cryptococcal meningitis in collected aer ini ft tiation of amphotericin therapy, and urine bio- the US: 1997–2009. PLoS One. 2013;8:e56269. 3. Liechty CA, Solberg P, Were W, et al. Asymptomatic serum cryptococcal antigen- marker findings may reflect early subclinical amphotericin-re- emia and early mortality during antiretroviral therapy in rural Uganda. Trop Med lated AKI and not purely the theoretical potential to develop Int Health. 2007;12:929–35. 4. French N, Gray K, Watera C, et al. Cryptococcal infection in a cohort of HIV-1- AKI. e Th timing of best measurement of urine biomarkers is infected Ugandan adults. AIDS. 2002;16:1031–8. unknown, and further elucidation of the change in biomarkers 5. Bagnis CI, Deray G. Amphotericin B nephrotoxicity. Saudi J Kidney Dis Transpl. over time would be of interest. Ultimately, the clinical utility of 2002;13:481–91. 6. Burgess JL, Birchall R. Nephrotoxicity of amphotericin B, with emphasis on urine biomarkers would be optimal if future AKI could be pre- changes in tubular function. Am J Med. 1972;53:77–84. dicted accurately early aer di ft agnosis to guide dosing and dura- 7. Girmenia C, Cimino G, Di Cristofano F, et al. Effects of hydration with salt reple- tion on renal toxicity of conventional amphotericin B empirical therapy: a pro- tion of amphotericin therapy. There is considerable interest in spective study in patients with hematological malignancies. Support Care Cancer. shortening amphotericin regimens for treatment of cryptococ- 2005;13:987–92. 8. Anderson CM. 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Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney ment arm, and cerebrospinal fluid quantitative culture (data not International Suppl. 2012;2:1–138. shown) compared with this cohort. 12. Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int. 2012;81:442–8. In conclusion, AKI occurred in 42% of HIV-infected patients 13. Li Y, Shlipak MG, Grunfeld C, Choi AI. Incidence and risk factors for acute kid- treated with amphotericin B deoxycholate for cryptococcal ney injury in HIV Infection. Am J Nephrol. 2012;35:327–34. 14. Franceschini N, Napravnik S, Eron JJ Jr, et al. Incidence and etiology of acute renal meningitis, and AKI was associated with mortality. However, failure among ambulatory HIV-infected patients. Kidney Int. 2005;67:1526–31. AKI was transient among survivors. Urine protein levels are 15. Tsigou E, Psallida V, Demponeras C, et al. Role of new biomarkers: functional and easy to measure and may be useful for antecedent prediction structural damage. Crit Care Res Pract. 2013;2013:361078. 6 • OFID • Schutz et al 16. Bennett M, Dent CL, Ma Q, et al. Urine NGAL predicts severity of acute kidney injury cryptococcal meningitis in resource-limited settings. Open Forum Infect Dis. after cardiac surgery: a prospective study. Clin J Am Soc Nephrol. 2008;3:665–73. 2014;1:ofu070. 17. Singer E, Markó L, Paragas N, et  al. Neutrophil gelatinase-associated lipoca- 24. Levey AS, Bosch JP, Lewis JB, et  al. A more accurate method to estimate lin: pathophysiology and clinical applications. Acta Physiol (Oxf ). 2013;207: glomerular filtration rate from serum creatinine: a new prediction equa- 663–72. tion. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 18. Nickolas TL, Schmidt-Ott KM, Canetta P, et al. 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Kashani K, Al-Khafaji A, Ardiles T, et  al. Discovery and validation of cell cycle metalloproteinase-2 in acute kidney injury: a prospective observational study. arrest biomarkers in human acute kidney injury. Crit Care. 2013;17:R25. Crit Care. 2014;18:716. 28. Jackson AT, Nussbaum JC, Phulusa J, et al. A phase II randomized controlled trial 22. Boulware DR, Meya DB, Muzoora C, et  al.; COAT Trial Team. Timing of adding oral flucytosine to high-dose fluconazole, with short-course amphotericin antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. B, for cryptococcal meningitis. AIDS. 2012;26:1363–70. 2014;370:2487–98. 29. Muzoora CK, Kabanda T, Ortu G, et  al. Short course amphotericin B with 23. Bahr NC, Rolfes MA, Musubire A, et  al. Standardized electrolyte supplementa- high dose fluconazole for HIV-associated cryptococcal meningitis. J Infect. tion and fluid management improves survival during amphotericin therapy for 2012;64:76–81. Acute Kidney Injury and Urine Biomarkers • OFID • 7 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Acute Kidney Injury and Urinary Biomarkers in Human Immunodeficiency Virus–Associated Cryptococcal Meningitis

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Open Forum Infectious Diseases MAJOR ARTICLE Acute Kidney Injury and Urinary Biomarkers in Human Immunodeficiency Virus–Associated Cryptococcal Meningitis 1,2 3 4 3 3,5 6 Charlotte Schutz, David R. Boulware, Katherine Huppler-Hullsiek, Maximilian von Hohenberg, Joshua Rhein, Kabanda Taseera, Friedrich 1,2 6 3,5,7 1,2 Thienemann, Conrad Muzoora, David B. Meya, and Graeme Meintjes 1 2 Department of Medicine, Faculty of Health Sciences, and Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, 3 4 South Africa; Division of Infectious Diseases & International Medicine, Department of Medicine, and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis; and 5 6 7 Infectious Disease Institute, Makerere University, Kampala, Mbarara University of Science and Technology, Mbarara, and Makerere University College of Health Sciences, School of Medicine, Kampala, Uganda Background. Cryptococcus is the most common etiology of adult meningitis in Africa. Amphotericin B deoxycholate remains paramount to treatment, despite toxicities, including acute kidney injury (AKI). We assessed the ability of the following urine mark- ers to predict AKI in patients who received amphotericin B: urine neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (CysC), tissue inhibitor of metalloproteinases-2 (TIMP-2), and protein. Methods. One hundred and thirty human immunodeficiency virus (HIV)–infected participants with cryptococcal meningitis were enrolled and received amphotericin and fluconazole for 2 weeks. We defined AKI as glomerular filtration rate (GFR) < 60 mL/ min/1.73 m ; measured urine NGAL, CysC, TIMP-2, and protein; and explored AKI incidence, risk factors, and associations with mortality using Cox proportional hazards models. Results. Participants were 48% female with a median age of 35 years, a median CD4 count of 21 cells/μL, and 44% died within 12 months. Incident AKI occurred in 42% and was associated with mortality (adjusted hazard ratio [aHR] = 2.8; P < .001). Development of AKI was associated with female sex (P = .04) and with higher CD4 count (49 vs 14 cells/μL; P < .01). Urine protein level in the highest quartile independently predicted AKI and mortality (aHR = 1.64, P = .04; aHR = 2.13, P = .02, respectively). Urine NGAL levels in the highest quartile independently predicted AKI (aHR = 1.65; P = .04). Conclusions. Acute kidney injury occurred in 42% of patients, and AKI was associated with mortality. Urine biomarkers, specif- ically urine protein, may be useful for antecedent prediction of amphotericin-associated AKI but need further evaluation. Keywords. acute kidney injury; amphotericin B; biological marker; cystatin C; neutrophil gelatinase-associated lipocalin; pro- tein; tissue inhibitor of metalloproteinase-2. Cryptococcal meningitis is a disseminated fungal infection treatment for cryptococcosis despite numerous toxicities. The caused by Cryptococcus species and remains a major cause most common and severe side effect of amphotericin is renal of mortality in human immunodeficiency virus (HIV)– toxicity, which has been reported in 49%–65% of patients [5]. infected persons, especially in resource-limited settings [1]. Renal toxicity is caused through a combination of mechanisms, Cryptococcosis causes approximately 2% of deaths of HIV- which are incompletely understood. First, systemic and renal infected persons in the United States [2] and approximately aer ff ent arteriolar vasoconstriction decrease kidney perfusion 15% of AIDS-related deaths in sub-Saharan Africa [1, 3, 4]. [6], and the resulting decrease in glomerular filtration rate Liposomal amphotericin formulations remain unavailable (GFR) may be mitigated by aggressive saline hydration [7, 8]. in resource-limited settings due to cost; thus amphotericin Second, regardless of hydration status, direct cumulative dam- B deoxycholate (hereaer a ft mphotericin) remains the key age to renal tubular cells occurs from induction of proinflamma- tory cytokines, channel formation across renal cell membranes, and apoptosis [9, 10]. Received 6 March 2017; editorial decision 14 June 2017; accepted 15 June 2017. Acute kidney injury (AKI) is a clinical syndrome, which has Correspondence: C. Schutz, MBChB, MPH (Clinical Research), Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, CIDRI Office, wide etiologies and was defined, staged, and classified in 2012 Rm N2.09.2, Wernher Beit North Building, Anzio Rd, Observatory, 7925, South Africa (charlotte. [11]. Acute kidney injury predicts mortality, independent of schutz@uct.ac.za). Open Forum Infectious Diseases underlying disease [12], and AKI is a common complication of © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases HIV infection [13, 14]. Definition and staging of AKI depends Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits on serum creatinine or urine output [11], which are both late unrestricted reuse, distribution, and reproduction in any medium, provided the original work indicators of kidney injury. This has led to a wide interest in is properly cited. DOI: 10.1093/ofid/ofx127 new urine and serum biomarkers that could detect AKI earlier Acute Kidney Injury and Urine Biomarkers • OFID • 1 in critically ill patients [15]. Neutrophil gelatinase-associated samples. We summarized incidence of AKI and explored risk lipocalin (NGAL; also known as Lipocalin-2) is a 25-kDa pro- factors for incident AKI using Cox univariate and multivariable tein produced in many tissues, including renal epithelial cells, proportional hazards models. Models were estimated with bio- and is an established sensitive early marker of acute ischemic markers on a continuous scale (aer log ft transformation, so that kidney injury [16, 17]. Elevated urine NGAL levels predict a the hazard ratio is per doubling of the biomarker). Other mod- composite outcome of dialysis initiation or death during hos- els compared the upper quartile versus the lower 3 quartiles (an pitalization when used as a risk stratification tool in unselected a priori comparison to assess clinical outliers). Each biomarker emergency department patients at the time of admission to the was first statistically tested individually and then in a multivari- hospital [18]. Cystatin C (CysC), a 13-kDa proteinase inhibi- able model adjusted for timing of ART initiation group, age, sex, tor, can be measured in serum and in urine and, unlike creati- altered mental status at diagnosis, CD4 cell count, and cerebrospi- nine, is not ae ff cted by muscle mass or age [19]. Urine CysC is nal fluid quantitative cryptococcal culture at diagnosis. We exam- a marker of tubular dysfunction or damage [20], and elevated ined the association of incident AKI with 12-month mortality levels may be associated with AKI [15]. Tissue inhibitor of using time-updated Cox proportional hazards models. With the metalloproteinases-2 (TIMP-2) is an inducer of G1 cell-cycle time-updated models, an indicator for incident AKI was recal- arrest, predicts severe AKI, and is associated with mortality culated at the time of each creatinine measurement to assess the in critically ill adult patients [21]. Neutrophil gelatinase-asso- impact of developing AKI on mortality. All analyses were com- ciated lipocalin and CysC are induced during inflammation. pleted using SAS 9.3. Relevant ethics and regulatory authority These biomarkers have not been evaluated in the context of approvals were obtained. Written informed consent was obtained HIV infection and opportunistic infections. In resource-lim- to participate in the COAT trial, as previously described [22]. ited settings where liposomal amphotericin is not available, a urine biomarker that could predict development of AKI early RESULTS and accurately could be a valuable clinical tool to tailor dura- Incidence and Risk of Acute Kidney Injury tion of amphotericin therapy. The COAT trial enrolled 177 patients [22], of whom 130 We assessed these urine biomarkers together with urine patients had urine samples stored and were included in this protein and creatinine levels in patients with HIV-associated study. The median age was 35  years (IQR  =  30–40), and 52% cryptococcal meningitis treated with amphotericin therapy and (n = 68/130) were men. The median CD4 T-cell count was 21 investigated association with AKI and mortality. cells/μL (IQR  =  9–74). Forty-four percent (n  =  57/130) died METHODS within 12  months; 1 withdrew consent and 1 was lost to fol- low-up. Four persons (3%) had GFR  <60  mL/min/1.73 m Human immunodeficiency virus–infected, antiretroviral ther- at baseline. Incident AKI occurred in 42% (n  =  53/126) at a apy (ART)–naive adults with a new diagnosis of cryptococcal median of 8 days (IQR = 6–11) after diagnosis of cryptococcal meningitis were prospectively enrolled into the Cryptococcal meningitis. Persons developing AKI had higher baseline CD4 Optimal ART Timing (COAT) trial during 2010–2012 and T-cell counts (49 vs 14 cells/μL; P < .01), and a higher propor- treated with amphotericin B, fluconazole, and ART according tion were women (59% vs 40%; P = .04). Table 1 displays base- to the COAT trial protocol [22, 23]. Baseline and follow-up line characteristics, urine biomarker values, and mortality. serum creatinine concentrations were measured at regular intervals as per the COAT trial protocol (5–6 time points during Urine Biomarker Associations With Acute Kidney Injury amphotericin treatment and at 1 and 2 weeks after completion On a continuous scale, there was increased risk of AKI per of amphotericin therapy). Estimated GFR was calculated using doubling of urine TIMP-2 and protein levels (hazard ratio the Modification of Diet in Renal Disease (MDRD) study equa- [HR] = 1.47, 95% confidence interval [CI] = 1.08–2.00, P = .02; tion [24], and AKI was defined as a decrease in GFR to <60 mL/ HR = 2.28, 95% CI = 1.05–4.94, P = .04, respectively), but the min/1.73 m at any point within 3 weeks of cryptococcal diag- association became nonsignificant after adjustment (adjusted nosis. Urine output was not routinely monitored and could not HR [aHR]  =  1.34, 95% CI  =  0.95–1.88, P  =  .09; aHR =  2.23, be used to define AKI. Ten-week and 12-month mortality was 95% CI = 0.92–5.41, P = .07). In univariate models, those with ascertained. NGAL, TIMP-2, and protein levels in the upper quartile had an We included 130 participants with stored urine samples, which increased risk of AKI compared with those in the lower quar- were collected a median of  4 (interquartile range [IQR]  =  4–5) tiles. The risk remained significant for NGAL and protein in days from diagnosis of cryptococcal meningitis (which is multivariable models. Sixty percent of those with values in the similar to time from amphotericin initiation: median =  4; highest quartile of protein (>0.30  g/L protein) developed AKI IQR  =  4–5  days), and measured NGAL, CysC, and TIMP-2 by as compared with an average of 35% of those in the lower 3 enzyme-linked immunosorbent assay (R&D Systems) and pro- quartiles (aHR = 1.64; 95% CI = 1.02–2.62; P = .04) (Figure  1 tein and creatinine (Beckman Coulter DXC 800) on stored urine and Table 2). Similarly, of those in the upper quartile of NGAL 2 • OFID • Schutz et al Table  1. Urinary Biomarkers in Human Immunodeficiency Virus–Associated Cryptococcal Meningitis: Baseline Characteristics for the Overall Cohort, Participants Who Developed Acute Kidney Injury, and Those Who Did Not a b Baseline Variables Overall Cohort Incident Acute Kidney Injury No Acute Kidney Injury P Value No. 130 53 73 … Early ART initiation arm, no. (%) 63 (49) 26 (49) 37 (51) .92 Age, median (IQR), y 35 (30–40) 34 (30–40) 37 (29–40) .55 Female sex, no. (%) 62 (48) 31 (59) 29 (40) .04 Glasgow Coma Scale < 15, no. (%) 38 (29) 17 (32) 20 (28) .60 CSF quantitative culture, median (IQR), log CFU/mL 5.0 (3.8–5.4) 5.1 (3.8–5.5) 5.0 (4.0–5.6) .91 21 (9–74) 49 (16–87) 14 (7–54) <.01 CD4 count, median (IQR), cells/μL Weight , median (IQR), kg 54 (46–60) 54 (47–57) 54 (45–60) .81 Serum creatinine, median (IQR), μmol/L 70 (50–88) 69 (50–91) 70 (50–80) .36 Serum creatinine, median (IQR), mg/dL 0.79 (0.57–1.00) 0.78 (0.57–1.03) 0.79 (0.57–0.90) .36 Serum potassium, median (IQR), mEq/L 3.9 (3.4–4.2) 3.8 (3.3–4.1) 3.9 (3.5–4.2) .37 Amphotericin dose , mg/kg/d Overall 0.93 (0.85–1.00) 0.95 (0.89–1.0) 0.93 (0.83–1.0) .62 Men 0.93 (0.81–1.0) 0.96 (0.91–1.0) 0.92 (0.81–1.0) … Women 0.95 (0.89–1.00) 0.94 (0.89–1.0) 0.95 (0.91–1.0) … Urine biomarkers Cystatin C, ng/mL 2.2 (1.3–3.5) 2.6 (1.5–3.5) 2.0 (1.2–3.3) .32 Neutrophil gelatinase-associated lipocalin, ng/mL 4.1 (3.0–5.7) 4.2 (3.1–6.1) 4.0 (3.0–5.0) .41 Tissue inhibitor of metalloproteinases-2, ng/mL 1.8 (1.4–2.5) 1.9 (1.5–2.7) 1.6 (1.3–2.1) <.01 Urinary creatinine, mg/dL 4.6 (3.6–5.4) 4.8 (3.3–5.7) 4.4 (3.7–5.1) .39 Urinary protein, g/L 0.21 (0.11–0.39) 0.29 (0.16–0.46) 0.16 (0.08–0.30) <.01 Protein/creatinine ratio 0.56 (0.36–0.83) 0.57 (0.30–0.79) 0.56 (0.38–0.96) .49 Ten-week mortality, no. (%) 48 (37) 27 (51) 21 (29) .01 Twelve-month mortality, no. (%) 57 (44) 29 (55) 28 (38) .07 Bolded P values indicate statistically significant difference between patients who developed AKI and those who did not. Abbreviations: ART, antiretroviral therapy; CFU, colony-forming unit; CSF, cerebrospinal fluid; IQR, interquartile range. a 2 Includes 4 people with prevalent estimated glomerular filtration rate <60 mL/min/1.73m at cryptococcal meningitis diagnosis. b 2 Kruskall-Wallis or χ tests as appropriate, comparing those who develop incident acute kidney injury to those who do not. Glasgow Coma Scale <15 denotes altered mental status. Weight was measured for n = 111 participants (44 of 53 who later developed incident acute kidney injury; 63 of 73 who did not develop incident acute kidney injury). Amphotericin dose (mg/kg/d) is calculated only for those with a weight measurement. Samples collected at median of 4 days on amphotericin B therapy and stored at −80°C (>47.7 ng/mL), 61% developed AKI as compared with an aver- died a median of 8  days (IQR  =  4–23  days) aer AKI de ft vel- age of 36% of those in the lower 3 quartiles (aHR = 1.65; 95% oped. All 9 patients who developed severe AKI (estimated GFR CI = 1.01–2.69) (Figure 2 and Table 2). of <30 mL/min/1.73 m ) died. Associations with 12-Month Mortality Ten-Week Outcomes in Acute Kidney Injury Patients Elevated urine NGAL and protein-to-creatinine ratio, The outcome of abnormal renal function was assessed in survivors respectively, were associated with mortality in univar- at 10 weeks after diagnosis of cryptococcal meningitis. Among 53 iate analysis (HR =  1.16, 95% CI  =  1.01–1.34, P  =  .04; HR patients who developed AKI, 51% (n = 27) died before 10 weeks, =  1.86, 95% CI  =  1.01–3.41, P  =  .05) but not in multivari- and renal function recovered to eGFR  >60  mL/min/1.73 m in able analysis (aHR  =  1.14, 95% CI  =  0.98–1.34, P  =  .09; the remaining 49% (n  =  26/53) by 8 weeks. All 4 patients with aHR =  1.53, 95% CI  =  0.73–3.20, P  =  .26) when evaluated abnormal renal function at baseline survived and recovered renal on a continuous log scale. Urine protein levels in the upper function to eGFR >60 mL/min/1.73 m by 10 weeks. quartile independently predicted 12-month mortality, DISCUSSION and 68% of patients with urine protein levels in the high- est quartile died within 12  months as compared with 23%, To our knowledge, this is the first study to evaluate urine bio- 44%, and 36% of those in the lower quartiles, respectively markers in patients with HIV-associated cryptococcal men- (aHR = 2.13; 95% CI = 1.15–3.96) (Figure 3 and Table 3). ingitis treated with amphotericin. Acute kidney injury was a Incident AKI was independently associated with 12-month common complication and associated with high mortality. mortality (time-updated aHR  =  2.82; 95% CI  =  1.55–5.17; Urine protein level in the highest quartile independently pre- P  <  .001). Patients developed AKI at a median of 8  days aer ft dicted AKI and 12-month mortality, whereas the other bio- diagnosis of cryptococcal meningitis (IQR  =  6–11  days) and markers tested showed no strong associations. Urine biomarkers Acute Kidney Injury and Urine Biomarkers • OFID • 3 60 a cheap and readily available test in resource-limited settings. 60% This could be a useful marker to investigate in similar settings as an adjunctive tool to aid clinical decision making. Elevated urine protein levels at initiation of therapy could prompt more intensive fluid replacement, closer monitoring of renal func- 44% tion, and possible decreased duration of amphotericin, but this needs to be evaluated in further studies. 36% Acute kidney injury, as defined in this study, developed in 42% of patients in this cohort. The Kidney Disease: Improving Global Outcomes (KDIGO) published case definition of AKI 23% consists of (1) increase in serum creatinine within 48 hours of ≥26.5 μmol/L (0.3 mg/dL) or (2) increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred in the prior 7 days, or urine volume of <0.5 mL/kg/h for 6 hours [11]. We did not measure urine output in this cohort, and using serial serum creatinine values, 80% of our patients Q1 (Low) Q2 Q3 Q4 (High) met creatinine-based KDIGO AKI case definition criteria. We Figure  1. Urinary biomarkers in human immunodeficiency virus–associated used an amended case definition, which is equal to a grade 3 cryptococcal meningitis: acute kidney injury by quartiles of urine protein values. χ (severe) adverse event [25] and has clinical relevance in this P value comparing the 4 groups = .03. Abbreviation: Q, quartile. critically ill cohort who required treatment with a nephrotoxic drug. Amphotericin therapy is generally interrupted or stopped are being increasingly applied in clinical practice, particularly when a patient’s GFR declines to <60 mL/min/1.73 m . in settings where AKI is common and can potentially be mit- People with higher CD4 T-cell counts developed AKI more igated by amending management strategies, such as intensive commonly in our study. The reason for this is unclear. It is pos- care units. Urine biomarkers have not been studied in the con- sible that patients with very low CD4 T-cell counts did not sur- text of HIV-associated cryptococcosis where AKI is a common vive to develop AKI, and there is thus a competing risk of death; complication of amphotericin therapy and mortality is high. however, CD4 count was not associated with survival in this Urine protein can also be measured by urine dipstick, which is cryptococcal cohort [22]. More women developed AKI in our Table  2. Urinary Biomarkers in Human Immunodeficiency Virus–Associated Cryptococcal Meningitis: Urinary Biomarkers Associated With Incident Acute Kidney Injury Association Between Urinary Biomarkers (per doubling of value) and Acute Kidney Injury a a,c Urine Biomarker Univariate Hazard Ratio (95% CI) P Value Multivariable Hazard Ratio (95% CI) P Value CysC 1.04 (0.88–1.23) .62 1.05 (0.88–1.25) .61 NGAL 1.06 (0.91–1.24) .46 1.01 (0.85–1.19) .91 TIMP-2 1.47 (1.08–2.00) .02 1.34 (0.95–1.88) .09 Protein 2.28 (1.05–4.94) .04 2.23 (0.92–5.41) .07 Creatinine 1.04 (0.82–1.32) .74 1.07 (0.83–1.38) .59 Protein/creatinine ratio 0.83 (0.38–1.80) .63 0.63 (0.28–1.45) .28 Association of Upper Quartile of Urinary Biomarkers With Acute Kidney Injury: Fourth Quartile of Biomarkers Compared With Quartiles 1–3 b c Hazard Ratio (95% CI) P Value Hazard Ratio (95% CI) P Value CysC 1.05 (0.70–1.59) .81 1.05 (0.68–1.63) .82 NGAL 1.92 (1.25–2.94) <.01 1.65 (1.01–2.69) .04 TIMP-2 1.70 (1.10–2.61) .02 1.46 (0.91–2.33) .12 Protein 1.73 (1.12–2.68) .01 1.64 (1.02–2.62) .04 Creatinine 1.41 (0.92–2.16) .12 1.48 (0.94–2.32) .09 Protein/creatinine ratio 0.92 (0.60–1.42) .71 0.84 (0.53–1.34) .47 Bolded P values indicate statistically significant difference between patients who developed AKI and those who did not. Abbreviations: CI, confidence interval; CysC, cystatin C; NGAL, neutrophil gelatinase-associated lipocalin; TIMP-2, tissue inhibitor of metalloproteinases-2. Proportional hazards regression analyses using log transformed biomarker data. The hazard ratio presents the risk per doubling of the biomarker for developing incident acute kidney injury (GFR < 60 mL/min/1.73 m ) within 3 weeks of diagnosis of cryptococcal meningitis. Fourth quartile versus quartile 1–3. The hazard ratio presents the risk of developing acute kidney injury if the urine biomarker level falls within the highest quartile compared with the lower 3 quartiles. Adjusted for antiretroviral treatment (ART) group (early ART or deferred ART group), age, sex, decreased level of consciousness at diagnosis, CD4 cell count, and cerebrospinal fluid quan- titative cryptococcal culture at diagnosis (but not for other biomarkers). 4 • OFID • Schutz et al Cumulative Incidence (Percent) 60 70 61% 68% 41% 48% 39% 28% 33% 29% Q1 (Low) Q2 Q3 Q4 (High) Q1 (Low) Q2 Q3 Q4 (High) Figure  2. Urinary biomarkers in human immunodeficiency virus–associated Figure  3. Urinary biomarkers in human immunodeficiency virus–associated cryptococcal meningitis: acute kidney injury by quartiles of urine neutrophil gelati- cryptococcal meningitis: 12-month mortality by quartiles of urine protein values. χ nase-associated lipocalin (NGAL) values. χ P value comparing the 4 groups = .06. P value comparing the 4 groups = .01. Abbreviation: Q, quartile. Abbreviation: Q, quartile. study, which is consistent with the literature, which lists women analysis but not aer ad ft justing for potential confounders on as more susceptible to AKI [26]. a continuous scale. Urine TIMP-2 combined with insulin-like Tissue inhibitor of metalloproteinases-2 and urine protein growth factor-binding protein 7 (IGFBP7) has been shown levels were associated with development of AKI in univariate to predict development of severe AKI in acutely ill patients Table 3. Urinary Biomarkers in Human Immunodeficiency Virus–Associated Cryptococcal Meningitis: Analyses of Urinary Biomarkers and Acute Kidney Injury With 12-Month Mortality Association Between Urinary Biomarkers (per doubling of value) and 12-Month Mortality a a,c Urine Biomarker Univariate Hazard Ratio (95% CI) P Value Multivariable Hazard Ratio (95% CI) P Value CysC 1.15 (0.99–1.34) .06 1.14 (0.98–1.33) .10 NGAL 1.16 (1.01–1.34) .04 1.14 (0.98–1.34) .09 TIMP-2 1.25 (0.91–1.73) .17 1.23 (0.87–1.75) .24 Protein 1.92 (0.90–4.11) .09 1.94 (0.83–4.57) .12 Creatinine 1.08 (0.88–1.33) .45 1.16 (0.92–1.47) .21 Protein/creatinine ratio 1.86 (1.01–3.41) .05 1.53 (0.73–3.20) .26 Acute kidney injury (GFR < 60) 3.27 (1.87–5.73) <.001 2.82 (1.55–5.17) <.001 Severe acute kidney injury (GFR < 30) 12.17 (4.98–29.73) <.001 8.11 (3.19–20.60) <.001 Association of Upper Quartile of Urinary Biomarkers with 12-Month Mortality: Fourth Quartile of Biomarkers Compared With Quartiles 1–3 b c Hazard Ratio (95% CI) P Value Hazard Ratio (95% CI) P Value CysC 1.04 (0.57–1.87) .91 1.18 (0.63–2.19) .61 NGAL 1.12 (0.62–2.02) .71 0.99 (0.52–1.88) .97 TIMP-2 1.56 (0.85–2.85) .15 1.66 (0.87–3.17) .12 Protein 2.30 (1.30–4.08) <.01 2.13 (1.15–3.96) .02 Creatinine 1.11 (0.59–2.08) .75 1.20 (0.61–2.35) .59 Protein/creatinine ratio 2.03 (1.14–3.62) .02 1.53 (0.80–2.93) .20 Bolded P values indicate statistically significant difference between patients who died within 12 months after diagnosis of cryptococcal meningitis and those who did not. Abbreviations: CI, confidence interval; CysC, cystatin C; GFR, estimated glomerular filtration rate using the Modification of Diet in Renal Disease study equation; NGAL, neutrophil gelati- nase-associated lipocalin; TIMP-2, tissue inhibitor of metalloproteinases-2. Proportional hazards regression analyses using log -transformed biomarker data. The hazard ratio presents the 12-month mortality risk per doubling of the biomarker. Fourth quartile versus quartile 1–3. The hazard ratio presents the 12-month mortality risk if the urine biomarker level falls within the highest quartile compared to the lower three quartiles. Adjusted for antiretroviral treatment (ART) group (early ART or deferred ART group), age, sex, decreased level of consciousness at diagnosis, CD4 cell count, and cerebrospinal fluid quan- titative cryptococcal culture at diagnosis (but not for other biomarkers). d 2 From time-updated models with indicators for GFR <30 or <60 mL/min/1.73m at each visit. Acute Kidney Injury and Urine Biomarkers • OFID • 5 Cumulative Incidence (Percent) Cumulative Incidence (Percent) within 12 hours of collection of urine sample [27]. Higher urine of amphotericin-associated AKI. The utility of measuring urine TIMP-2 has also been associated with mortality in acutely ill protein levels for aiding decisions regarding duration of ampho- patients [21] but not in our study. Our urine samples were tericin therapy needs further evaluation. collected at a median of 4 days aer di ft agnosis of cryptococcal Acknowledgments meningitis, and AKI developed at a median of 8 days on ther- e C Th OAT Trial team worked on this trial in Uganda and South Africa apy, which is a different scenario to the previous studies investi- from 2010 to 2012. The enzyme-linked immunosorbent assays on Cape gating the predictive value of TIMP-2. Town samples were performed in the laboratory of Professor Robert J.  Wilkinson at the University of Cape Town. Dr Nicola Wearne at the Higher urine CysC was not associated with development of University of Cape Town, Department of Medicine, Renal Unit provided AKI or mortality in our study when evaluated on a continuous input on the study during the planning phase. log scale or comparing the upper quartile with lower quartiles. 2 Financial support. This work was supported by provided by the Cystatin C is an early marker of tubular dysfunction or damage, National Institute of Allergy and Infectious Diseases (U01AI089244 and T32AI055433), Wellcome Trust (081667 and 098316 to G.  M.), a Fogarty and it is possible that (1) the mechanism of development of AKI International Center South Africa TB/AIDS Training Award (NIH/ in our cohort was different or (2) that we measured CysC levels FIC 1U2RTW007373- 01A1 and U2RTW007373 ICORTA to G.  M.  and too long before AKI events to detect elevated levels. C. S.). e Th South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South We found AKI to be independently associated with mortal- Africa (64787 to G.  M.), NRF incentive funding (UID: 85858 to G.  M.) ity. Patients in this study were severely immune suppressed, and the South African Medical Research Council through its TB and HIV and although it is possible that AKI secondary to amphotericin Collaborating Centres Programme with funds received from the National Department of Health (RFA no. SAMRC-RFA-CC: TB/HIV/AIDS-01-2014 therapy could have played a role in mortality, there are other to G.  M.). The funders had no role in the study design, data collection, factors such as nosocomial sepsis, opportunistic infections, and data analysis, data interpretation, or writing of this report. The opinions, decreased level of consciousness with decreased oral intake that findings and conclusions expressed in this manuscript reflect those of the likely contributed to both AKI and mortality. authors alone. Potential coni fl ct of interest. All authors: No reported conflicts of interest. A limitation of our study is that we used a nonstandard case All authors have submitted the ICMJE Form for Disclosure of Potential definition of AKI. This limits comparability across studies, and Conflicts of Interest. Conflicts that the editors consider relevant to the con- importantly, patients who had normal renal function at base- tent of the manuscript have been disclosed. line would have had to experience a much larger proportional References decline in renal function before being classified as an AKI case 1. Park BJ, Wannemuehler KA, Marston BJ, et al. 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Acute Kidney Injury and Urine Biomarkers • OFID • 7

Journal

Open Forum Infectious Diseases – Oxford University Press

Published: Jun 20, 2017

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