A Salivary Urea Nitrogen Dipstick to Detect Obstetric-Related Acute Kidney Disease in Malawi

Introduction: Obstetric-related acute kidney injury (AKI) is associated with adverse outcomes for mother and fetus, particularly in low-income countries. However, laboratory-independent tools to facilitate diagnosis are lacking. We assessed the diagnostic performance of a salivary urea nitrogen (SUN) dipstick to detect obstetric-related acute kidney disease in Malawi. Methods: Women at high risk for AKI admitted to an obstetric unit in Blantyre, Malawi, were recruited between 21 September and 11 December 2015. Patients underwent serum creatinine (SCr) testing alongside measurement of SUN using a dipstick on admission, and every 48 hours thereafter if evidence of kidney disease was found. Results: A total of 301 patients were included (mean age 25.9 years, 11% HIV positive). Of the patients, 23 (7.6%) had AKI, stage 1 in 47.8%, most commonly due to preeclampsia/eclampsia. Mean presenting SCr values were 108.8 ± 21.8 μmol/l (1.23 ± 0.25 mg/dl), 118 ± 34.45 μmol/l (1.33 ± 0.39 mg/dl), and 136.1 ± 30.4 μmol/l (1.54 ± 0.34 mg/dl) in AKI stages 1 to 3 respectively. SUN > 14 mg/dl had a sensitivity of 12.82% and a specificity of 97.33% to detect acute kidney disease; the area under the receiver operating characteristic curve was 0.551. In patients with normal SUN on admission, perinatal mortality was 11.8%, and was 25.0% if SUN was?> 14 mg/dl (P = 0.18). Conclusion: The SUN dipstick was specific but insensitive when used to diagnose obstetric-related AKI. Limited biochemical derangement and low salivary urea concentrations due to physiological changes in pregnancy, as opposed to a technical limitation of the dipstick itself, are the likely reason for the lack of sensitivity in this study. We conducted a prospective observational study at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi. This hospital acts as a district hospital for Blantyre and also provides tertiary obstetric and nephrology care to the southern region of Malawi. The majority of obstetric admissions are from Blantyre district, encompassing both urban and rural populations, and the obstetric unit delivers approximately 12,000 babies per year. Despite its being ranked as one of the poorest countries worldwide, health care in Malawi is government funded and provided to all free at the point of delivery. At QECH, this includes access to a high-dependency obstetric unit and hemodialysis for AKI. We included women admitted to QECH obstetric department who were > 20 weeks’ gestation or < 6 weeks postpartum presenting with conditions predetermined as being at risk of leading to AKI. These were admissions with a working diagnosis of the following: gestational hypertension, preeclampsia, eclampsia, antepartum hemorrhage, postpartum hemorrhage, sepsis, renal failure (diagnosed by admitting team prior to study recruitment), and heart failure (Supplementary Table S1). All participants provided written informed consent. The University of Malawi, College of Medicine Research Ethics Committee, approved the study (ref. P.11/14/1660). Patients were enrolled between 21 September and 11 December 2015. Those fulfilling the inclusion criteria were assessed within 48 hours of admission. Baseline clinical data were recorded, and screening for kidney disease (community-acquired) was undertaken with a SCr alongside simultaneous measurement of SUN using a dipstick (Integrated Biomedical Technology, Elkhart, IN).10, 12, 13, 14 Patients were excluded if they were unable to undergo concomitant measurement of both SCr and SUN. A SCr of > 82μmol/l was considered to be elevated, predefined as 2 SDs above the mean in the third trimester of pregnancy.15 Patients with elevated SCr were managed jointly by the obstetric and nephrology teams, and the nature (as per definitions below) and cause of kidney injury were determined. The women underwent daily measurement of SCr and urine output, and further measurement of SUN dipstick and serum urea at 48 hours. The obstetric team alone managed patients without raised SCr on admission. Patients and neonates were followed up until hospital discharge. Maternal and fetal outcomes (gestational age at delivery, birth weight, first Apgar score,16 in-hospital maternal and perinatal mortality) were recorded in the entire study population. After a period of 15 minutes without eating or drinking, patients provided unstimulated saliva into a plastic cup, and a 50-μl quantity was used to moisten the test pad of a colorimetric SUN dipstick. The change in color of the test pad was assessed at 1 minute and compared to 6 reference pads corresponding to increasing SUN concentrations: 5 to 14 mg/dl (pad 1), 15 to 24 mg/dl (pad 2), 25 to 34 mg/dl (pad 3), 35 to 54 mg/dl (pad 4), 55 to 74 mg/dl (pad 5), and ≥ 75 mg/dl (pad 6) (Supplementary Figure S1). During analysis, SUN was transformed to a continuous variable by converting the test pad result to the midpoint for each range (e.g., a SUN result of 5−14 mg/dl was transformed to 9.5 mg/dl). SCr and urea were measured by the Jaffe and urease methods, respectively, using either a Flexor Junior Clinical Chemistry Analyzer (Vital Scientific, Dieren, Netherlands) or a Mindray Chemistry Analyzer BS-120 (Shenzen Mindray Bio-Medical Electronics Company, Shenzen, China) in a local laboratory. Analyzers were calibrated in accordance with the manufacturer’s instructions. AKI and CKD were defined and staged by Kidney Disease Improving Global Outcomes (KDIGO) criteria.17, 18 Patients with elevated SCr (>82 μmol/l) on admission that did not fulfill KDIGO criteria for AKI or CKD were defined, by our own definition, as having acute kidney disease (AKD) without AKI. Any acute kidney disease encompassed both AKI and AKD without AKI. Patients with normal SCr on admission were deemed as having no kidney disease (NKD) (Supplementary Table S2). The nephrology study team determined the primary cause of AKI. Perinatal mortality was defined as fetal death after 20 weeks’ gestation (stillbirth or termination of pregnancy) or in-hospital neonatal death. The primary outcome was the diagnostic performance of the SUN dipstick to detect obstetric-related acute kidney disease (AKI and AKD without AKI). Secondary outcomes were comparison of SUN concentrations in those with and without AKI, and assessment of maternal and perinatal in-hospital outcomes (gestational age, birth weight, first Apgar score, maternal and perinatal mortality) according to the presence of AKI and SUN results. Descriptive data are presented as mean ± SD and as median ± interquartile range (IQR), depending on the distribution of data and the standard parametric and nonparametric tests used. Diagnostic performance of SUN was determined by sensitivity and specificity, and by the area under the receiver operating characteristic (ROC) curve. The optimal threshold of SUN to diagnose kidney disease was calculated according to the Youden Index. Statistical analysis was performed using Graphpad Prism version 7 (www.graphpad.com). A P value of < 0.05 was considered statistically significant.