Abnormal Function of the Vasopressin-cyclic-AMP-aquaporin2 Axis During Urine Concentrating and Diluting in Patients with Reduced Renal Function. A Case Control Study

Erling B Pedersen; Ingrid M Thomsen; Thomas G Lauridsen

Disclosures

BMC Nephrology. 2010;11(26) 

In This Article

Discussion

Our study showed that patients with a renal function corresponding to chronic kidney disease stage III and IV, i. e. 15 ≤ e-GFR < 60 ml/min, have a reduced renal concentrating and diluting capacity compared to both patients with milder chronic kidney disease or hypertension, corresponding to stage I and II, i. e. GFR ≥ 60 ml/min, and healthy control subjects. Our analyses showed that these phenomena can be attributed, at least partly, to an abnormal function of the AVP-c-AMP-AQP2 axis.

In healthy subjects, AVP stimulates vasopressin receptors on the principal cells in the collecting ducts of nephron. This results in an increased production of c-AMP, which through a cascade of intracellular reactions upregulate the AQP 2 water channels, and thereby promotes water transport from the tubular lumen to the cell. Subsequently, water is further transported to the interstitial fluid through aquaporin 3 and 4 water channels.[2] In previous studies, we have demonstrated that u-AQP2 reflects the functional status of the aquaporin2 water channels during urine concentrating and diluting procedures.[13,16,17] Urinary excretion of u-c-AMP is a measure of the renal production of c-AMP. Thus, the function of the principal cells can be determined by measurements of u-AQP2 and u-c-AMP together with p-AVP.

The renal concentrating ability is a defense mechanism to prevent water depletion and hyperosmolarity in body fluids. A decrease in urinary concentrating ability can have several reasons. Firstly, the delivery of tubular fluid can be diminished due to a fall in GFR. Secondly, the ability to generate interstitial hypertonicity can be reduced due to decreased sodium and chloride absorption in the ascending limb of Henle, decreased urea accumulation, or a change in renal medullar blood flow. Thirdly, the response to vasopressin may be reduced or absent.[18,19]

After the urine concentrating test, we measured a significant increase in u-Osm in all groups, and UV and CH2O were clearly and significantly reduced in Groups 1 and 2. However, in Groups 3 and 4 CH2O was unchanged, and UV was unchanged or only borderline changed in Groups 3 and 4, respectively. Thus, the increase in u-Osm and the fall in UV and CH2O were smaller in patients with reduced renal function, which indicated a reduced concentrating ability. Our study also showed that u-c-AMP was decreased in patients with an e-GFR < 60 ml/min, and the correlation analyses showed a significantly, positive correlation between e-GFR and u-c-AMP. Thus, the kidneys' ability to synthesize c-AMP decreased with deteriorating renal function. This phenomenon might be attributed to a reduced sensitivity to AVP, because p-AVP was increased in patients with e-GFR < 60 ml/min and correlated inversely with e-GFR in the whole group of study subjects. The concentration of AQP2 was not significantly changed during the urine concentrating test in Groups 3 and 4, but increased significantly in the other two groups. This is in good agreement with the lack of increase in u-c-AMP in Groups 3 and 4. Thus, our study showed that the reduced renal concentrating capacity during decreasing renal function can be attributed, at least partly, to a lack of responsiveness to vasopressin of the principal cells in the distal tubules. Our results are in agreement with a previous small study of patients with diabetic nephropathy, in whom a decrease in u-AQP2 was associated with impaired urinary concentrating ability.[20] In addition, our results are in good accordance with animal experiments, which have demonstrated a vasopressin resistant down regulation in expression of AQP2, when urinary concentrating ability was impaired, i. e. in nephrogenic diabetes insipidus, post-obstructive polyuria, and renal failure.[1–3,9]

The renal diluting mechanism is a defense mechanism against water intoxication and hypoosmolarity.. An abnormal diluting capacity can be attributed to several factors. Firstly, a decrease of tubular fluid to the diluting segments of the nephron can be caused by a diminished GFR, an increased absorption of sodium and water in the proximal tubules or both. Secondly, an abnormally reduced absorption of sodium and chloride in the thick ascending limb of Henle or in the distal convoluted tubule can prevent establishment of sufficient interstitial hypertonicity.

Thirdly, plasma level of vasopressin may be increased due to drug treatment or primary diseases outside the kidneys as heart failure, liver cirrhosis with fluid retention, hypothyroidism and adrenal insufficiency.[3] Treatment with a vasopressin receptor antagonist reversed the consequence of non-osmotic increase in vasopressin release in these conditions and improved urinary dilution, and animal studies showed that AQP2 expression was increased.[4,6]

Our study showed that urine diluting capacity was decreased in patients with moderately reduced renal function. Thus, the amount of excreted water represented more than 80% of the load during the first four hours after the load was given in Groups 1, 2 and 3, but only half of the load was excreted in Group 4. This corresponded very well with the increase in both UV and CH2O in all groups and a much lower increase in Group 4 than the other three groups. During urine dilution, p-AVP was reduced in all groups, but the level was significantly higher in patients with e-GFR < 60 ml/min, and p-AVP correlated significantly and inversely with e-GFR during all periods of the test. In addition, u-c-AMP was lower in Group 4 than in Groups 1, 2 and 3 and correlated significantly and positively with e-GFR during the whole test. Thus, our results showed that the high level of p-AVP in Group 4 failed to control c-AMP, presumably due to a defect function of the principal cells induced by the chronic kidney disease. This leaves the function of the AQP2 water channels without regulatory influence of the AVP-c-AMP-axis. U-AQP2 was reduced during urine dilution in all groups, but the level was higher in Group 4 that in the other three groups during the whole test. This is in accordance with a deficiency in regulatory influence on the formation of AQP2 water channels by the AVP-u-c-AMP-axis. Our results suggest that the abnormal urine dilution capacity in chronic kidney disease stage III and IV is due to a lower ability of the principal cell in the distal part of the nephron to down regulate the expression of the AQP2 water channels and in that way promote water excretion. However, it is likely that the reduced GFR and a reduced hypertonicity in the renal interstitial tissue contributed to the reduced urine diluting capacity in chronic kidney disease.

Among several variables, the multiple regression analysis demonstrated that e-GFR was the most important factor to determine the extent of disturbance in the AVP-AMP-AQP2-axis, and thus the degree of deterioration in urine concentrating and diluting ability in chronic kidney disease.

We have used established procedures to test urinary concentrating and diluting capacity.[21] Several different formulas have been suggested for estimation of GFR using p-creatinine, gender, body weight, height and ethnicity in various combinations.[22] Each of these estimates of GFR has weaknesses and strengths. In the present study, we have chosen the Hull-equation to estimate GFR.[15] We have also calculated e-GFR according to the MDRD-equations.[23–25] Using correlation analyses, we found a highly significant correlation between e-GFR estimated by the Hull-equation and both the original MDRD equation from 1999 (r = 0.978, n = 51, P < 0.000) and the new MDRD equation from 2009 (r = 0.985, n = 51, P < 0.000). Thus, it is unlikely that small differences in e-GFR from different formula would have changed the conclusions of our study, even if we had used either older or newer equations.[23–25]

Urine concentrating ability is decreased in the aging mammalian kidney.[26] A functional impairment of renal concentrating ability was demonstrated in aged rats.[27] This phenomenon appeared to be related to decreased responsiveness of the kidney to vasopressin caused by a down regulation of the renal vasopressin 2 receptor and AQP2 abundance.[27] We measured a marked difference in urine concentrating and diluting ability between the three groups of patients in the present study, in spite of a rather narrow age range between the groups with medians between 49 and 59 years. Thus, it is unlikely that differences in age between the three groups of patients could explain our findings.

We studied different types of renal diseases. During progressive deterioration in renal function urinary concentrating and diluting ability may be affected differently depending on the nature of the disease, i.e. in primarily glomerular, tubular, interstitial or vascular pathogenesis. However, we demonstrated clear abnormalities in urine concentrating and diluting ability during progression to Stage III and IV despite differences in etiology of the disease.

A large proportion of the patients in the present study received antihypertensive treatment, which might influence the activity in the renin-angiotensin-aldosterone system, natriuretic peptide system, and sympathetic nervous activity. In addition to vasopressin, these homeostatic systems have a modulating influence on the transport in the aquaporin2 water channels.[28–32] It would have been ideal to perform studies after withdrawal of all antihypertensive treatment. This was not done, since we did not find it ethically justified to discontinue antihypertensive therapy. The prostaglandin system can also modulate the transport via aquaporin2 water channels, but none of the patients in the present study received non-steroid-anti-inflammatory drugs.

The present study comprised three patients with polycystic kidney disease. Animal studies indicated that vasopressin regulates cystogenesis,[33] which has been basis for ongoing clinical trials regarding the effect of vasopressin antagonists on cyst growth and deterioration of renal function in patients with PKD.[34] Other ongoing trials study the effect of statins, blockade of the renin-angiotensin system, sirolimus, and somatostatins in PKD.[35] At the time being, it is far from clarified, whether these therapeutic aspects will be effective regarding cyst growth and preservation of renal function in patients with PKD or have influence on the abnormal urine concentrating and diluting ability in progressive renal disease. Neither is it known whether polycystic kidney per se will change urine concentrating and diluting ability. However, we have analyzed our data with exclusion of the three patients with PKD, and the results and conclusions were unchanged.

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