Vasopressin in chronic kidney disease, in particular ADPKD:Causal factor or innocent bystander?

Vasopressin is an important hormone for water regulation of the body. When dehydration occurs, vasopressin secretion leads to water reabsorption in the kidney to prevent water loss. However, vasopressin seems to have deleterious effects on the kidney as well. In autosomal dominant polycystic kidney disease (ADPKD), vasopressin increases cyst growth and disease progression. Detrimental effects of vasopressin on chronic kidney disease in general have been described as well. In the first part of this thesis, copeptin was validated as marker for vasopressin because vasopressin is difficult to measure. Copeptin was stable outside the body, easy to measure and was a reliable marker for vasopressin in patients with impaired kidney function. In the second part of this thesis vasopressin release during thirsting was investigated in ADPKD and IgA nephropathy patients. Already in an early stage of disease, ADPKD patients had an impaired urine concentrating capacity which lead to an increase in vasopressin. IgA nephropathy patients had an impaired concentrating capacity as well although less profound in comparison to ADPKD patients. Vasopressin levels were increased in IgA nephropathy patients as well. The following hypothesis was formulated: when kidney function deteriorates, urine concentrating capacity decreases leading to an increase in vasopressin. This increase in vasopressin leads to kidney damage and creates a vicious circle resulting in disease progression. Part three of this thesis showed that copeptin predicts disease progression of both ADPKD and IgA nephropathy. These results support the hypothesis that dehydration is harmful to the kidney

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

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 alpha 1 microglobulin (alpha 1m), beta 2 microglobulin (beta 2m), 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: 42613 years, mean arterial pressure (MAP): 101612mmHg, proteinuria: 1.4 (0.7-2.3) g/day, estimated glomerular filtration rate (eGFR): 48621mL/min/1.73m(2)] median copeptin was 9.4 (5.3-18.4) pmol/L. At baseline, copeptin was associated with alpha 1m [standardized beta (St. beta) = 0.34, P = 0.009], beta 2m (St. beta = 0.33, P = 0.01) and proteinuria (St. beta = 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

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 (I-125-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. beta = -0.41, p = 0.003) and also after adjustment for age, sex and TKV (St. beta = -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. (C) 2015 S. Karger AG, Base