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The pivotal role of intracellular cAMP on cyst origin and expansion is well documented and is the unique therapeutic target to ameliorate the ADPKD progression through blockage of V2 receptor to ADH. Since renal intracellular cAMP is not a feasible measurement, urine cAMP has been become an affordable surrogate marker. Our group also unraveled an additional action of cAMP as cargo of urinary extracellular vesicles (EVs). However, no information about cAMP-EV on osmoregulation and natural evolution in ADPKD is available. This study aims to determine how total and/or EV cAMP content participates in disease progression and water balance.
Fourteen ADPKD patients, naïve for V2 receptor antagonism treatment, were studied. ADPKD progression was evaluated by both estimated GFR (eGFR) and height-adjusted total kidney volume (htTKV), and water balance by osmolar and free water clearances. Fresh morning urine was collected for EV isolation by an adapted centrifugation method and determined EV- and total (the sum of free available and EV content)- cAMP by competitive radioligand assay. Plasma and urine creatinine (Cr) were quantified by the alkaline picrate colorimetric method. Plasma and urine osmolalities were measured by the freezing point decrease method.
The mean clinical characteristics of 14 ADPKD patients with 44 ± 2 years old and predominance of female gender (10 out of 14) were moderate CKD (eGFR: 58 ± 8 mL/min/1.73 m2), enlarged kidneys (1.6 ± 0.3 L of TKV) and normal blood pressure (126 ± 3 and 75 ± 2 mmHg for systolic and diastolic blood pressure values, respectively), mostly (10/14 patients) due to renin-angiotensin-aldosterone system antagonist treatment. Plasma and urine (24 hs) osmolalities were 288 ± 2 and 396 ± 58 mOsm/kg, respectively; and osmolar and free-water clearances were 2.34 ± 0.29 and -0.48 ± 0.33 ml/min.
Urine total cAMP/Cr and cAMP/Osm levels were 1.71 ± 0.31 pmol/mg and 3.25 ± 0.61 pmol/mOsm.Total cAMP/Cr positively correlated with cAMP/Osm (R=0.90, p < 0.0001). Total cAMP/Cr, but not cAMP/Osm, significantly correlated with eGFR (R= 0.65, p = 0.012) and its annual change (R = 0.67, p = 0.008), and inversely correlated to htTKV (R = 0.57, p = 0.044). Both cAMP/Cr and cAMP/Osm inversely correlated with osmolar clearance (R= -0.68, p= 0.006, and R= -0.56, p= 0.023, respectively).
The cAMP-EVs, prorated by Cr as well as by Osm, showed a bimodal pattern with htTKV, increasing to ≈1 L/m and falling at larger sizes.
Our results demonstrate that urine total cAMP correlates with both renal osmolar handling and ADPKD progression markers, whereas its extracellular delivery by EVs reflects the architectural disturbances of the organ. These evidence propose the study of cAMP as a biomarker of disease progression and hydration status, and suggest their utility as potential test for the tolvaptan treatment response.