Clinical trial NCT03128229: Diabetic Kidney Alarm (DKA) Study
Official title: Diabetic Kidney Alarm (DKA) Study - Tubulopathy in Diabetic Ketoacidosis
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Type 1 Diabetes Mellitus
Diabetic Ketoacidosis
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: Thrasher Research Fund
First posted: 2017-04-25
Enrollment: 41
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Participants (3-18 years) with T1D presenting with DKA will be recruited from the Emergency Department (ED) at Children's Hospital Colorado.

Brief summary: The overarching goals of this study are to determine whether tubular dysfunction (elevated urine sodium, bicarbonate and amino acids) and injury (elevated kidney injury molecule 1 \[KIM-1\], neutrophil gelatinase-associated lipocalin \[NGAL\] and matrix metallopeptidase 9 \[MMP9\]) exist in diabetic ketoacidosis (age 3-18), whether it is reversible and whether it is related to uricosuria and copeptin. The investigators propose to study a cohort of youth (ages 3-18, n=40) with T1D who have serum and urine collection at DKA diagnosis and 3-month follow-up.

Detailed description: Every year over 86,000 children (0-14 years) worldwide are diagnosed with type 1 diabetes (T1D) translating to a lifetime of exposure and risk for early death from cardiovascular disease (CVD) and diabetic kidney disease (DKD). DKD, which manifests in children and adolescents, remains the leading cause of renal failure and dialysis in the Western world (4). While diabetic glomerulopathy has received significant attention from researchers, determinants of tubular injury in diabetes are less well examined. Compared to glomerular injury, tubular injury is known to associate better with renal function. The majority of youth diagnosed with T1D in the US present with diabetic ketoacidosis (DKA), a condition associated with risks factors for tubular injury including dehydration, metabolic acidosis and acute glycemia. It is unknown whether DKA is associated with tubular injury. The investigators published the first report showing that youth with established T1D have more acidic urine and higher fractional excretion of uric acid (FeUA) than their non-diabetic peers, which may predispose to UUA-mediated tubulopathy. Furthermore, T1D is associated with vasopressin overactivity, and the investigators reported strong relationships between serum copeptin, a reliable surrogate marker for vasopressin, and DKD in T1D. The overarching goals of this study are to determine whether tubular dysfunction (elevated urine sodium, bicarbonate and amino acids) and injury (elevated KIM-1, NGAL and MMP9) exist in DKA, whether it is reversible and whether it is related to uricosuria and copeptin. The investigators propose to study a cohort of youth (ages 3-18, n=40) with T1D who have serum and urine collection at DKA diagnosis and 3-month follow-up.

Eligibility criteria: Inclusion Criteria:

* New onset T1D and known T1D
* DKA (mild, moderate and severe DKA eligible)
* 3-17 years of age
* Toilet trained
* Boys and girls
* All ethnicities
* Initial presentation to Children's Hospital Colorado (CHCO) Main ED

Exclusion Criteria:

* Non-T1D etiology
* History of chronic kidney disease (eGFR \<60ml/min/1.73m2) or dialysis dependent
* History of tubulopathy (e.g. Fanconi syndrome)
* Currently menstruating
* Patient visiting Colorado with plan to establish diabetes care outside of Colorado
* On ACE-inhibitors or angiotensin II-receptor blockers (ARB)
* On sodium-glucose co-transporter 2 inhibitors (SGLT2 inhibitors)

Primary outcomes:
measure: Proximal tubular dysfunction
timeFrame: At DKA (0-8 and 12-24 hours after starting IV insulin)
measure: Proximal tubular injury
timeFrame: At DKA (0-8 and 12-24 hours after starting IV insulin)
Secondary outcomes:
measure: Proposed mediators of tubular dysfunction and injury
timeFrame: At DKA (0-8 and 12-24 hours after starting IV insulin)
measure: Proposed mediators of tubular dysfunction and injury
timeFrame: At DKA (0-8 hours after starting IV insulin)
measure: Proposed mediators of tubular dysfunction and injury
timeFrame: At DKA (12-24 hours after starting IV insulin)
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
Study officials:
References:
citation: Bjornstad P, Johnson RJ, Snell-Bergeon JK, Pyle L, Davis A, Foster N, Cherney DZ, Maahs DM. Albuminuria is associated with greater copeptin concentrations in men with type 1 diabetes: A brief report from the T1D exchange Biobank. J Diabetes Complications. 2017 Feb;31(2):387-389. doi: 10.1016/j.jdiacomp.2016.11.015. Epub 2016 Dec 7.
citation: Bjornstad P, Maahs DM, Jensen T, Lanaspa MA, Johnson RJ, Rewers M, Snell-Bergeon JK. Elevated copeptin is associated with atherosclerosis and diabetic kidney disease in adults with type 1 diabetes. J Diabetes Complications. 2016 Aug;30(6):1093-6. doi: 10.1016/j.jdiacomp.2016.04.012. Epub 2016 Apr 19.
citation: Roncal-Jimenez CA, Milagres T, Andres-Hernando A, Kuwabara M, Jensen T, Song Z, Bjornstad P, Garcia GE, Sato Y, Sanchez-Lozada LG, Lanaspa MA, Johnson RJ. Effects of exogenous desmopressin on a model of heat stress nephropathy in mice. Am J Physiol Renal Physiol. 2017 Mar 1;312(3):F418-F426. doi: 10.1152/ajprenal.00495.2016. Epub 2016 Dec 21.
citation: Bakes K, Haukoos JS, Deakyne SJ, Hopkins E, Easter J, McFann K, Brent A, Rewers A. Effect of Volume of Fluid Resuscitation on Metabolic Normalization in Children Presenting in Diabetic Ketoacidosis: A Randomized Controlled Trial. J Emerg Med. 2016 Apr;50(4):551-9. doi: 10.1016/j.jemermed.2015.12.003. Epub 2016 Jan 25.
citation: Rewers A, Dong F, Slover RH, Klingensmith GJ, Rewers M. Incidence of diabetic ketoacidosis at diagnosis of type 1 diabetes in Colorado youth, 1998-2012. JAMA. 2015 Apr 21;313(15):1570-2. doi: 10.1001/jama.2015.1414. No abstract available.
citation: Dabelea D, Rewers A, Stafford JM, Standiford DA, Lawrence JM, Saydah S, Imperatore G, D'Agostino RB Jr, Mayer-Davis EJ, Pihoker C; SEARCH for Diabetes in Youth Study Group. Trends in the prevalence of ketoacidosis at diabetes diagnosis: the SEARCH for diabetes in youth study. Pediatrics. 2014 Apr;133(4):e938-45. doi: 10.1542/peds.2013-2795. Epub 2014 Mar 31.
citation: Rewers A, Chase HP, Mackenzie T, Walravens P, Roback M, Rewers M, Hamman RF, Klingensmith G. Predictors of acute complications in children with type 1 diabetes. JAMA. 2002 May 15;287(19):2511-8. doi: 10.1001/jama.287.19.2511.
citation: Bjornstad P, Roncal C, Milagres T, Pyle L, Lanaspa MA, Bishop FK, Snell-Bergeon JK, Johnson RJ, Wadwa RP, Maahs DM. Hyperfiltration and uricosuria in adolescents with type 1 diabetes. Pediatr Nephrol. 2016 May;31(5):787-93. doi: 10.1007/s00467-015-3299-8. Epub 2015 Dec 23.