Copeptin and urine concentrating capacity predict kidney function decline in lithium-treated patients

A common early side effect of lithium treatment in bipolar disorder is a reduced urine concentrating capacity possibly progressing to arginine vasopressin (AVP) resistance (AVP-R), also known as lithium-induced nephrogenic diabetes insipidus (Li-NDI). Long term lithium therapy can also lead to chronic kidney disease (CKD) with kidney function decline. Due to lack of markers to identify Li-NDI, it is often overseen even though prevalence and impact on quality of life are substantial. Moreover, the correlation between reduction of urine concentrating capacity and CKD remains unclear. This study aims to identify markers for Li-NDI and future kidney function decline.

98 patients treated with lithium underwent a desmopressin (DDAVP) test to determine maximal urine concentrating capacity (MUCC) after inclusion in 2012/2013. Plasma copeptin, urine biomarkers AQP-2, NAG, KIM-1, HFABP, NGAL and urine-to-plasma urea ratio (UPU) were measured. Long term follow-up data of kidney function decline during lithium therapy was collected of 93 out of 98 patients.

Fifty patients (51%) had an mildly impaired MUCC (urine osmolality 600-800 mOsmol/kg), 16 patients (16%) a moderately decreased MUCC (300-600 mOsm/kg) and 1 patient (1%) a severely impaired MUCC (<300 mOsm/kg). Baseline eGFR, UPU, copeptin, KIM-1, HFABP and NGAL were significantly associated with MUCC when corrected for age, sex and eGFR (when appropriate) (eGFR: St. β=0.44, P ≤ 0.001, UPU: St. β=0.34, P ≤ 0.001; copeptin: St. β=-0.23, P = 0.02; KIM-1: St. β=-0.23, P = 0.02, HFABP: St. β=-0.21, P = 0.03) NGAL: St. β=-0.25, P = 0.02). eGFR, MUCC and copeptin at baseline were associated with kidney function during follow-up using mixed linear model analysis (eGFR: β=0.97 95%CI [0.88;1.06], P < 0.001; MUCC: β=0.05 95%CI[0.03;0.06], P < 0.001 and copeptin:-β=7.10 95%CI[-10.9;-3.28], P < 0.001).

Multiple biomarkers were identified to test for MUCC. Copeptin is particularly interesting as it was, together with MUCC, associated with future kidney function decline.