Univariate and multivariate analyses was done to compare demographic and biochemical characteristics between ‘No AKI’ and ‘AKI progression’ groups. P value <0.05 was considered significant.

Of 79 children enrolled, 56 (71%) were new onset diabetes presenting as DKA. In children with documented healthcare contacts prior to referral (n=51), DKA was diagnosed only in 18 (35.3%), of which just 8 (44.4%) received appropriate fluids and insulin prior to referral. Majority of the children (n=59, 75%) had presented as severe DKA.

Twenty eight (35%) children were diagnosed with AKI; 13 (46.4%) at admission and rest within 24 hours of hospital stay. The number (proportion) of children categorized into pRIFLE-0,1,2,3 at admission and end of 24 hours were 35 (44.3%), 31 (39.2%), 11 (13.9%), 2 (2.5%) and 54 (68.4%), 10 (12.6%), 9 (11.4%) and 6 (7.6%), respectively. Twenty (71.4%) children recovered with hydration alone while 8 (28.6%) required renal replacement therapy (RRT).

None of the admission variables could predict AKI. However on multivariable analysis, elevated chloride levels at 24 hours had an independent association with AKI progression [Adjusted OR 1.14 (95% CI 1.04-1.27), P=0.007] (Table I and II). Serum chloride >112 mmol/L at 24 hours had a sensitivity, specificity and area under ROC curve of 73.3%, 82.4% and 0.835, respectively for development of AKI (P<0.001).

TABLE I Comparison of ‘No AKI’ and ‘AKI Progression’ –  Univariate Analysis

TABLE II	Comparison of ‘No AKI’ and ‘AKI Progression’ – Multivariate analysis

Time to resolution of acidosis was significantly longer in those with AKI than those without [Median (IQR) 31 (24, 77) vs 26 (20, 35) hours, P=0.006]. Children with AKI had higher odds for needing vasoactive drugs and ventilation, and developing cerebral edema. Those with AKI had prolonged PICU stay [Median (IQR) 3 (2, 5) vs 2 (1, 2) days, P<0.001] and lesser likelihood to survive to hospital discharge
(Table III).

TABLE III  PICU Needs, Complications and Outcome of children with DKA and AKI

One-third of our patients with DKA had AKI at some point during their PICU stay, with nearly half of them having AKI at presentation. Majority of the children were new-onset DKA, who remained undiagnosed prior to referral and tended to present as severe DKA . This trend was similar to our previous observations [1,2] and in sharp contrast to the data from the developed world [8]. Those with missed diagnosis had more likelihood of complications like cerebral edema (CE) and AKI, possibly related to uncorrected hypovolemia [2]. The small proportion in whom AKI did not revert with fluids, needed RRT, indicating that factors other than hypovolemia could have contributed to AKI.

Although children with ‘AKI progression’ had higher PRISM III and admission chloride levels, only the 24 hours serum chloride was independently associated with ‘AKI progression’. Independent association of 24 hour serum chloride rather than admission value leads one to believe that hyperchloremia could have been an iatrogenic element caused by the type of intravenous fluids received. Though the current guidelines favour isotonic saline as the initial fluid in DKA, the recommended duration of infusion is not clear. Since half normal saline without dextrose was not easily available in our setup, children continued to receive isotonic saline till blood glucose fell to 250 mg/dL.

Hyperchloremia, in many clinical settings has been hypothesised to cause renal hypoperfusion and AKI by virtue of its renal vascular smooth muscle constrictor effect [9,10]. Hursh, et al. [1] reported AKI in a high proportion of children with DKA (64.2%) using Kidney Disease/Improving Global Outcomes criteria, but none in association with hyperchloremia. Although studies from developing world have reported about 4-11% incidence of renal injury in children with DKA [12,13] neither standard definitions were used nor association with hyperchloremia was reported. The disparity in incidence of AKI between studies is largely related to use of different definitions. Though we demonstrated a significant association between hyperchloremia at 24 hrs and AKI in our study, a causal link cannot be ascertained due to the retrospective nature of our data. Use of balanced crystalloids with lower chloride content have been studied in adults with DKA [14,15], but mostly in relation to hyperchloremia induced normal anion gap acidosis.

There is, thus, a need for for future prospective studies on risk factors of AKI, cause-effect relationship between AKI and type of fluid, and role of balanced salt solutions in preventing AKI in children with DKA.

Contributors: MB: study conceptualization, data collection, statistical analysis, drafting the manuscript; MJ: study conceptualization, supervised data collection and statistical analysis, critical review of the manuscript; KN, SS, AB: data analysis, critical review of the manuscript, drafted the manuscript. All authors approved the final version of the manuscript.

Funding: None; Competing Interest: None stated.

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