Copeptin, a surrogate marker for arginine vasopressin, is associated with disease severity and progression in IgA nephropathy patients.

Background: Besides its essential role for water homeostasis, arginine vasopressin (AVP) may have deleterious effects on the kidney. Copeptin, a surrogate marker for AVP, has been shown to be related to renal outcome in patients with diabetic nephropathy and polycystic kidney disease. We investigated the association of copeptin with disease severity and progression in immunoglobulin A nephropathy (IgAN). Methods: We included a prospective cohort of 59 patients with biopsy proven IgAN. Urinary excretion of α1 microglobulin (α1m), ß 2 microglobulin (ß2m), kidney injury molecule-1, neutrophil gelatinase-associated lipocalin and total protein were measured at baseline. Plasma copeptin was determined from stored baseline serum samples. Cox regression was performed for the composite renal outcome defined as doubling of serum creatinine, end-stage renal disease (ESRD) or start of immunosuppressive therapy, and for the individual components during 5-year follow-up. Results: In IgAN patients [male: 72%, age: 42 ± 13 years, mean arterial pressure (MAP): 101 ± 12 mmHg, proteinuria: 1.4 (0.7-2.3) g/day, estimated glomerular filtration rate (eGFR): 48 ± 21 mL/min/1.73 m 2 ] median copeptin was 9.4 (5.3-18.4) pmol/L. At baseline, copeptin was associated with α1m [standardized beta (St. ß) = 0.34, P = 0.009], ß2m (St. ß = 0.33, P = 0.01) and proteinuria (St. ß = 0.36, P = 0.053), adjusted for sex and eGFR. During follow-up, the highest tertile of baseline copeptin was positively associated with the incidence of the composite renal outcome as well as with the individual components of doubling of creatinine, ESRD and start of immunosuppressive therapy. In Cox regression models, copeptin showed prognostic value over MAP, proteinuria and eGFR for the composite renal outcome. Conclusions: Copeptin is associated with disease severity and prognosis in IgAN patients and may have additional prognostic value besides established risk markers.

Comparison of ex vivo stability of copeptin and vasopressin.

BACKGROUND: Copeptin, part of the vasopressin precursor, is increasingly used as marker for vasopressin and is claimed to have better ex vivo stability. However, no study has directly compared the ex vivo stability of copeptin and vasopressin. METHODS: Blood of ten healthy volunteers was collected in EDTA tubes. Next, we studied the effect of various pre-analytical conditions on measured vasopressin and copeptin levels: centrifugation speed, short-term storage temperature and differences between whole blood and plasma, long-term storage temperature and repeated freezing and thawing. The acceptable change limit (ACL), indicating the maximal percentage change that can be explained by assay variability, was used as cut-off to determine changes in vasopressin and copeptin. RESULTS: The ACL was 25% for vasopressin and 19% for copeptin. Higher centrifugation speed resulted in lower vasopressin levels, whereas copeptin concentration was unaffected. In whole blood, vasopressin was stable up to 2 h at 25°C and 6 h at 4°C. In plasma, vasopressin was stable up to 6 h at 25°C and 24 h at 4°C. In contrast, copeptin was stable in whole blood and plasma for at least 24h at both temperatures. At -20°C, vasopressin was stable up to 1 month and copeptin for at least 4 months. Both vasopressin and copeptin were stable after 4 months when stored at -80°C and -150°C. Vasopressin concentration decreased after four freeze-thaw cycles, whereas copeptin concentration was unaffected. CONCLUSION: Vasopressin levels were considerably affected by pre-analytical conditions, while copeptin levels were stable. Therefore, a strict sample handling protocol for measurement of vasopressin is recommended.

Dose-Titrated Vasopressin V2 Receptor Antagonist Improves Renoprotection in a Mouse Model for Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: In autosomal dominant polycystic kidney disease, renoprotective treatment with a vasopressin V2 receptor antagonist (V2RA) is given in a fixed dose (FD). Disease progression and drug habituation could diminish treatment efficacy. We investigated whether the renoprotective effect of the V2RA can be improved by dose titration of the V2RA aiming to maintain aquaresis at a high level. METHODS: The V2RA OPC-31260 was administered to Pkd1-deletion mice in an FD (0.1%) or in a titrated dose (TD, up to 0.8% when drinking volume dropped). Total kidney weight (TKW) and cyst ratio were investigated and compared to non-treated Pkd1-deletion mice. Treatment was started early or late (21 or 42 days postnatal). RESULTS: Water intake was significantly higher throughout the experiment in the TD compared to the FD group. FD treatment that was initiated early reduced TKW and cyst ratio but lost its renoprotective effect later during the experiment. In contrast, TD treatment was able to maintain the renoprotective effect. TD treatment, however, was also associated with a higher early termination rate in comparison with FD treatment. Late start of treatment (FD or TD) did not show a renoprotective effect. CONCLUSIONS: Titration of a V2RA aimed to maintain aquaresis at a high level showed a better renoprotective effect compared to FD administration. However, this treatment regimen was poorly tolerated and did not overcome treatment unresponsiveness when started later in the disease.

Urine and plasma osmolality in patients with autosomal dominant polycystic kidney disease: reliable indicators of vasopressin activity and disease prognosis?

BACKGROUND: Vasopressin plays an essential role in osmoregulation, but has deleterious effects in patients with ADPKD. Increased water intake to suppress vasopressin activity has been suggested as a potential renoprotective strategy. This study investigated whether urine and plasma osmolality can be used as reflection of vasopressin activity in ADPKD patients. METHODS: We measured urine and plasma osmolality, plasma copeptin concentration, total kidney volume (TKV, by MRI) and GFR ((125)I-iothalamate). In addition, change in estimated GFR (eGFR) during follow-up was assessed. RESULTS: Ninety-four patients with ADPKD were included (56 males, age 40 ± 10, mGFR 77 ± 32 ml/min/1.73 m(2), TKV 1.55 (0.99-2.40) l. Urine osmolality, plasma osmolality and copeptin concentration were 420 ± 195, 289 ± 7 mOsmol/l and 7.3 (3.2-14.6) pmol/l, respectively. Plasma osmolality was associated with copeptin concentration (R = 0.54, p < 0.001), whereas urine osmolality was not (p = 0.4). In addition, urine osmolality was not associated with TKV (p = 0.3), in contrast to plasma osmolality (R = 0.52, p < 0.001) and copeptin concentration (R = 0.61, p < 0.001). Fifty-five patients were followed for 2.8 ± 0.8 years. Baseline plasma and urine osmolality were not associated with change in eGFR (p = 0.6 and p = 0.3, respectively), whereas baseline copeptin concentration did show an association with change in eGFR, in a crude analysis (St. ß = -0.41, p = 0.003) and also after adjustment for age, sex and TKV (St. ß = -0.23, p = 0.05). CONCLUSIONS: These data suggest that neither urine nor plasma osmolality are valid measures to identify ADPKD patients that may benefit from increasing water intake. Copeptin appears a better alternative for this purpose.

Dialysis hypotension: a role for inadequate increase in arginine vasopressin levels? A systematic literature review and meta-analysis.

BACKGROUND: Intradialytic hypotension is a common complication of hemodialysis (HD). Some studies have suggested that inadequate arginine vasopressin (AVP) increase could play a role in the pathogenesis of intradialytic hypotension. However, AVP levels during HD and its relation to hypotension has never been systematically studied. SUMMARY: PubMed and Embase were searched (1970-2013, search terms 'vasopressin' and 'hemodialysis') for studies reporting on AVP levels during standard HD or other dialysis techniques. Observational studies reporting on AVP levels pre- and postdialysis were additionally included in a meta-analysis. Thirty-seven studies were included in the systematic literature review, of which 26 studies were eligible for meta-analysis. The main findings were that pretreatment AVP levels were higher in dialysis patients compared with healthy controls (6.4 ± 3.5 vs. 2.5 ± 1.3 pg/ml, p = 0.003) and that plasma AVP levels showed little or no increase during HD (from 7.0 ± 4.9 to 8.8 ± 9.3, p = 0.433). Significant heterogeneity was found between studies. Meta-regression analysis revealed no significant associations between AVP and patient or study characteristics. Studies on other dialysis techniques showed mixed results regarding the AVP course. The eight studies that addressed the relation between intradialytic hypotension and AVP also showed inconsistent results. KEY MESSAGES: Plasma AVP levels are higher in dialysis patients compared with healthy controls, but show little or no increase during HD. The lack of a rise in AVP levels during HD may be pathophysiologically involved in the onset of intradialytic hypotension, but firm conclusions are not possible from our review of the literature.

Copeptin, a surrogate marker for vasopressin, is associated with kidney function decline in subjects with autosomal dominant polycystic kidney disease.

BACKGROUND: Experimental studies have suggested that vasopressin plays a detrimental role in autosomal dominant polycystic kidney disease (ADPKD). It is, however, unknown whether endogenous vasopressin concentration is associated with kidney function decline in subjects with ADPKD. METHODS: We measured plasma copeptin (a marker of vasopressin) in 79 ADPKD subjects with renal function assessed during short-term follow-up by inulin clearance measured glomerular filtration rate (mGFR) and during long-term follow-up by Modification of Diet in Renal Disease (MDRD) equation estimated GFR (eGFR). RESULTS: In these subjects (43% male, age 36.8 ± 10.1 years, GFR 96.8 ± 18.2 mL/min/1.73 m(2)), median copeptin concentration at baseline was 2.71 [interquartile ranges (IQR) 1.63-5.46] pmol/L. Baseline copeptin concentration was inversely associated both with change in mGFR during follow-up for 3.3 (3.1-3.5) years, (R = -0.300, P = 0.01), as well as with change in eGFR during follow-up for 11.2 (4.5-14.3) years, (R = -0.302, P < 0.01). These associations were independent of age, gender and baseline GFR. Nine subjects started renal replacement therapy during follow-up of which eight had at baseline a copeptin concentration above the median in this population. CONCLUSION: In ADPKD subjects, a higher copeptin concentration is associated with kidney function decline during follow-up, suggesting that copeptin may be a new marker to predict kidney outcome in ADPKD.

Use of the Urine-to-Plasma Urea Ratio to Predict ADPKD Progression.

BACKGROUND AND OBJECTIVES: Predicting disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) poses a challenge, especially in early-stage disease when kidney function is not yet affected. Ongoing growth of cysts causes maximal urine-concentrating capacity to decrease from early on. We therefore hypothesized that the urine-to-plasma urea ratio, as a reflection of the urine-concentrating capacity, can be used as a marker to predict ADPKD progression. DESIGN: The urine-to-plasma urea ratio was calculated by dividing concentrations of early morning fasting spot urine urea by plasma urea. First, this ratio was validated as surrogate marker in 30 patients with ADPKD who underwent a prolonged water deprivation test. Thereafter, association with kidney outcome was evaluated in 583 patients with ADPKD with a broad range of kidney function. Multivariable mixed-model regression was used to assess association with eGFR slope, and logarithmic regression to identify patients with rapidly progressive disease, using a cutoff of -3.0 ml/min per 1.73 m2 per year. The urine-to-plasma urea ratio was compared with established predictors, namely, sex, age, baseline eGFR, Mayo Clinic height-adjusted total kidney volume class, and PKD gene mutation. RESULTS: The maximal urine-concentrating capacity and urine-to-plasma urea ratio correlated strongly (R=0.90; P<0.001). Next, the urine-to-plasma urea ratio was significantly associated with rate of eGFR decline during a median follow-up of 4.0 (interquartile range, 2.6-5.0) years, both crude and after correction for established predictors (ß=0.58; P=0.02). The odds ratio of rapidly progressive disease was 1.35 (95% confidence interval, 1.19 to 1.52; P<0.001) for every 10 units decrease in urine-to-plasma urea ratio, with adjustment for predictors. A combined risk score of the urine-to-plasma urea ratio, Mayo Clinic height-adjusted total kidney volume class, and PKD mutation predicted rapidly progressive disease better than each of the predictors separately. CONCLUSIONS: The urine-to-plasma urea ratio, which is calculated from routine laboratory measurements, predicts disease progression in ADPKD in addition to other risk markers. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_01_27_CJN10470620_final.mp3.

The Effect of Renal Function and Hemodialysis Treatment on Plasma Vasopressin and Copeptin Levels.

INTRODUCTION: Copeptin is increasingly used in epidemiological studies as a substitute for vasopressin. The effect of renal function per se on copeptin and vasopressin concentrations as well as their ratio have, however, not been well described. METHODS: Copeptin and vasopressin levels were measured in 127 patients with various stages of chronic kidney disease, including 42 hemodialysis patients and 16 healthy participants in this observational study. Linear (segmental) regression analyses were performed to assess the association between renal function and copeptin, vasopressin and the C/V ratio. In addition, clearance of copeptin and vasopressin by hemodialysis was calculated. RESULTS: Both copeptin and vasopressin levels were higher when renal function was lower, and both showed associations with plasma osmolality. The C/V ratio was stable across renal function in subjects with an eGFR >28 ml/min per 1.73 m2. In contrast, the C/V ratio increased with worsening renal function in patients with eGFR ≤28 ml/min per 1.73 m2. During hemodialysis, the initial decrease in vasopressin levels was greater compared with copeptin and, consequently, the C/V ratio increased. This was, at least in part, explained by a greater dialytic clearance of vasopressin compared with copeptin. DISCUSSION: Our data indicate that copeptin is a reliable substitute for vasopressin in subjects with an eGFR >28 ml/min per 1.73 m2, whereas at an eGFR ≤28 ml/min per 1.73 m2, that is, CKD stages 4 and 5, a correction for renal function is required in epidemiological studies that use copeptin as a marker for vasopressin. Intradialytic copeptin levels do not adequately reflect vasopressin levels because vasopressin clearance by hemodialysis is higher than that of copeptin.

Urine Concentrating Capacity, Vasopressin and Copeptin in ADPKD and IgA Nephropathy Patients with Renal Impairment.

BACKGROUND: Autosomal Dominant Polycystic Kidney Disease (ADPKD) patients have an impaired urine concentrating capacity. Increased circulating vasopressin (AVP) concentrations are supposed to play a role in the progression of ADPKD. We hypothesized that ADPKD patients have a more severely impaired urine concentrating capacity in comparison to other patients with chronic kidney disease at a similar level of kidney function, with consequently an enhanced AVP response to water deprivation with higher circulating AVP concentrations. METHODS: 15 ADPKD (eGFR<60) patients and 15 age-, sex- and eGFR-matched controls with IgA nephropathy (IgAN), underwent a water deprivation test to determine maximal urine concentrating capacity. Plasma and urine osmolality, urine aquaporin-2 (AQP2) and plasma AVP and copeptin (a surrogate marker for AVP) were measured at baseline and after water deprivation (average 16 hours). In ADPKD patients, height adjusted total kidney volume (hTKV) was measured by MRI. RESULTS: Maximal achieved urine concentration was lower in ADPKD compared to IgAN controls (533±138 vs. 642±148 mOsm/kg, p = 0.046), with particularly a lower maximal achieved urine urea concentration (223±74 vs. 299±72 mmol/L, p = 0.008). After water deprivation, plasma osmolality was similar in both groups although change in plasma osmolality was more profound in ADPKD due to a lower baseline plasma osmolality in comparison to IgAN controls. Copeptin and AVP increased significantly in a similar way in both groups. AVP, copeptin and urine AQP2 were inversely associated with maximal urine concentrating in both groups. CONCLUSIONS: ADPKD patients have a more severely impaired maximal urine concentrating capacity with a lower maximal achieved urine urea concentration in comparison to IgAN controls with similar endogenous copeptin and AVP responses.

Kidney function and plasma copeptin levels in healthy kidney donors and autosomal dominant polycystic kidney disease patients.

BACKGROUND AND OBJECTIVES: Plasma copeptin, a marker of arginine vasopressin, is elevated in patients with autosomal dominant polycystic kidney disease and predicts disease progression. It is unknown whether elevated copeptin levels result from decreased kidney clearance or as compensation for impaired concentrating capacity. Data from patients with autosomal dominant polycystic kidney disease and healthy kidney donors before and after donation were used, because after donation, overall GFR decreases with a functionally normal kidney. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data were obtained between October of 2008 and January of 2012 from healthy kidney donors who visited the institution for routine measurements predonation and postdonation and patients with autosomal dominant polycystic kidney disease who visited the institution for kidney function measurement. Plasma copeptin levels were measured using a sandwich immunoassay, GFR was measured as (125)I-iothalamate clearance, and urine concentrating capacity was measured as urine-to-plasma ratio of urea. In patients with autosomal dominant polycystic kidney disease, total kidney volume was measured with magnetic resonance imaging. RESULTS: Patients with autosomal dominant polycystic kidney disease (n=122, age=40 years, men=56%) had significantly higher copeptin levels (median=6.8 pmol/L; interquartile range=3.4-15.7 pmol/L) compared with donors (n=134, age=52 years, men=49%) both predonation and postdonation (median=3.8 pmol/L; interquartile range=2.8-6.3 pmol/L; P<0.001; median=4.4 pmol/L; interquartile range=3.6-6.1 pmol/L; P<0.001). In donors, copeptin levels did not change after donation, despite a significant fall in GFR (from 105 ± 17 to 66 ± 10; P<0.001). Copeptin and GFR were significantly associated in patients with autosomal dominant polycystic kidney disease (ß=-0.45, P<0.001) but not in donors. In patients with autosomal dominant polycystic kidney disease, GFR and total kidney volume were both associated significantly with urine-to-plasma ratio of urea (ß=0.84, P<0.001; ß=-0.51, P<0.001, respectively). CONCLUSIONS: On the basis of the finding in donors that kidney clearance is not a main determinant of plasma copeptin levels, it was hypothesized that, in patients with autosomal dominant polycystic kidney disease, kidney damage and associated impaired urine concentration capacity determine copeptin levels.

Vasopressin, copeptin, and renal concentrating capacity in patients with autosomal dominant polycystic kidney disease without renal impairment.

BACKGROUND AND OBJECTIVES: Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary renal disease, characterized by cyst formation in the kidneys leading to end stage kidney failure. It is clinically acknowledged that ADPKD patients have impaired urine concentrating capacity, but the mechanism behind this observation is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fifteen ADPKD patients (estimated GFR ≥60 ml/min per 1.73 m(2)) and 15 age- and sex-matched healthy controls underwent a standard prolonged water deprivation test in which urine and plasma osmolality, vasopressin, and copeptin were measured. The effect of a synthetic vasopressin analog (desmopressin) injected at the moment of maximal urine concentrating capacity was also studied. RESULTS: After 14 hours of water deprivation, ADPKD patients tended to have higher plasma osmolality (P=0.07) and significantly higher vasopressin and copeptin levels (both P<0.05), whereas urine osmolality was similar in ADPKD patients and controls (710 versus 742 mOsmol/kg; P=0.61). Maximal urine concentrating capacity was lower in ADPKD patients (758 versus 915 mOsmol/kg in controls; P<0.001). At maximal urine concentrating capacity, plasma osmolality, vasopressin, and copeptin levels were significantly higher in ADPKD patients. The median increase in urine osmolality after desmopressin administration in ADPKD patients was less than in healthy controls. CONCLUSIONS: Already early in their disease, ADPKD patients have impaired maximal urine concentrating capacity brought out upon dehydration, with no evidence of impaired hypothalamic response. To maintain fluid balance, vasopressin concentration increases, which is hypothesized to play a role in ADPKD disease progression.