Vasopressin-V2 receptor stimulation reduces sodium excretion in healthy humans

In addition to its effect on water permeability, vasopressin, through its V2 receptors (AVPR2), stimulates Na reabsorption in the collecting duct by increasing the activity of the amiloride-sensitive sodium channel ENaC. This study evaluated whether dDAVP (a potent AVPR2 agonist) reduces sodium excretion in healthy humans (n = 6) and in patients with central (C; n = 2) or nephrogenic (N) diabetes insipidus (DI) as a result of mutations of either the aquaporin 2 gene (AQP2; n = 3) or AVPR2 (n = 10). dDAVP was infused intravenously (0.3 microg/kg body wt in 20 min), and urine was collected for 60 min before (basal) and 150 min after the infusion. dDAVP markedly reduced both urine flow rate and sodium excretion in healthy individuals. A reduction in sodium excretion was also observed in CDI and NDI-AQP2 patients but not in NDI-AVPR2 patients. The magnitude of the fall in sodium excretion correlated with the rise in urine osmolality and the fall in urine output but not with the simultaneously observed fall in mean BP. These results suggest that the dDAVP-induced antinatriuresis is due to a direct V2 receptor-dependent stimulation of sodium reabsorption in the collecting duct and is not secondary to a hemodynamic effect. In conclusion, this study reveals a potent V2-dependent antinatriuretic effect of vasopressin in humans. The possibility that an inappropriate stimulation of ENaC by vasopressin might lead to significant sodium retention in chronic situations remains to be determined.     

Diabetes-induced albuminuria: role of antidiuretic hormone as revealed by chronic V2 receptor antagonism in rats.

BACKGROUND: Vasopressin, an antidiuretic hormone, is elevated in diabetes mellitus (DM). The aim of this study was to evaluate whether the V(2) receptor-mediated actions of vasopressin contribute to the albuminuria of diabetes. METHODS: Fourteen adult male Wistar rats with streptozotocin-induced DM were treated over 9 weeks with a selective, non-peptide, orally active V(2) receptor antagonist (SR 121463) and were compared to 14 untreated diabetic rats (control). The dose of antagonist was adapted in order to maintain urine osmolality close to plasma osmolality, but not to induce the formation of hypoosmotic urine. Every second week, urine was collected in metabolic cages for two 24 h periods. RESULTS: Urinary albumin excretion (UAE) rose regularly and significantly with time in the untreated control group, whereas it did not rise in treated rats. Interestingly, a variable pattern of UAE increase over time was observed in different rats of the control group. Some rats exhibited pronounced progression of albuminuria with time, while others showed no or only a very modest rise. An a posteriori partition of the control group into 'progressors' and 'non-progressors' revealed that progressors had more intense urinary concentrating activity, higher creatinine clearance and larger relative glomerular mesangial area than the other subgroup. CONCLUSIONS: This study shows that V(2) receptor-mediated actions of vasopressin play a critical role in the albuminuria of diabetes. It also reveals that individual rats, like humans, seem to exhibit an unequal susceptibility to diabetic nephropathy, or at least to albuminuria, a factor considered to be one of its early manifestations.     

Antidiuretic action of oxytocin is associated with increased urinary excretion of aquaporin-2.

BACKGROUND: The antidiuretic effect of oxytocin in humans is controversial. Urinary excretion of aquaporin-2 (AQP2) can be used as an index of the action of vasopressin on the kidney. We investigated whether exogenous oxytocin affects urinary concentration and urinary AQP2 excretion in human beings. METHODS: Oxytocin was administered intravenously at a rate of 20 mU/min in 10 healthy volunteers, seven patients with central diabetes insipidus (CDI) and three patients with nephrogenic diabetes insipidus (NDI). On the next day, 2 micro g of 1-desamino-8-d-arginine vasopressin (dDAVP) was injected subcutaneously. Two-hour urine was collected before and after the administration of oxytocin and dDAVP, and urinary AQP2 was measured semi-quantitatively by western analysis. RESULTS: Urine volume and free water clearance were decreased, and urine osmolality was increased by the administration of oxytocin or dDAVP in the normal volunteers and CDI patients. Urinary AQP2 excretion was increased by oxytocin infusion in the normal volunteers (from 34+/-12 to 326+/-120 densitometry unit (DU)/2 h) and in the CDI group (from 8+/-2 to 227+/-92 DU/2 h) (P<0.05), but not in the NDI group. dDAVP also had a similar but more potent effect on the urinary excretion of AQP2 in the normal and CDI groups. CONCLUSIONS: Oxytocin has an antidiuretic effect and increases the urinary excretion of AQP2 in humans whose urinary concentration mechanism is preserved. These results suggest that AQP2 might have a regulatory role in the antidiuretic action of oxytocin in humans.     

Converting enzyme inhibition and the glomerular hemodynamic response to glycine in diabetic rats.

GFR normally increases during glycine infusion. This response is absent in humans and rats with established diabetes mellitus. In diabetic patients, angiotensin-converting enzyme inhibition (ACEI) restores the effect of glycine on GFR. To ascertain the glomerular hemodynamic basis for this effect of ACEI, micropuncture studies were performed in male Wistar-Froemter rats after 5 to 6 wk of insulin-treated streptozotocin diabetes. The determinants of single-nephron GFR (SNGFR) were assessed in each rat before and during glycine infusion. Studies were performed in diabetics, diabetics after 5 d of ACEI (enalapril in the drinking water), and weight-matched controls. Diabetic rats manifest renal hypertrophy and glomerular hyperfiltration but not glomerular capillary hypertension. ACEI reduced glomerular capillary pressure, increased glomerular ultrafiltration coefficient, and did not mitigate hyperfiltration. In controls, glycine increased SNGFR by 30% due to increased nephron plasma flow. In diabetics, glycine had no effect on any determinant of SNGFR. In ACEI-treated diabetics, the SNGFR response to glycine was indistinguishable from nondiabetics, but the effect of glycine was mediated by greater ultrafiltration pressure rather than by greater plasma flow. These findings demonstrate that: (1) The absent response to glycine in established diabetes does not indicate that renal functional reserve is exhausted by hyperfiltration; and (2) ACEI restores the GFR response to glycine in established diabetes, but this response is mediated by increased ultrafiltration pressure rather than by increased nephron plasma flow.     

Salt-losing nephrogenic diabetes insipidus caused by fetal exposure to angiotensin receptor blocker

The administration of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin type 1 receptor blockers (ARBs) to pregnant women has been reported to cause ACEI/ARB fetopathy, including oligohydramios, pulmonary hypoplasia, renal insufficiency, limb contracture, and fetal hypotension in the child. Most of the patients die or develop end-stage renal failure during the neonatal period. The long-term prognosis of renal dysfunctions of patients with ARB fetopathy has not been reported. We report two pediatric cases, a 6- and 2-year-old boy, respectively, with ARB fetopathy whose renal functions were thoroughly evaluated after recovery from neonatal renal failure. Both patients showed (1) mildly decreased glomerular filtration rate, (2) no significant proximal tubular dysfunctions, and (3) salt-losing nephrogenic diabetes insipidus, while the excretion of arginine vasopressin and urine level of cyclic AMP were increased. The data on these two patients indicate that the administration of ARB to the fetus profoundly impairs the urine concentrating ability, probably due to papillary atrophy and the disturbed formation of the osmotic gradient in the medulla, which have been confirmed in neonatal rats administered with ACEIs or ARBs. ACEIs/ARBs must not be administered to pregnant women.     

Selective blockade of vasopressin V2 receptors reveals significant V2-mediated water reabsorption in Brattleboro rats with diabetes insipidus.

BACKGROUND: In a previous study we observed that acute administration of the selective antagonist of vasopressin (AVP) V2 receptors, SR 121463A (SR), aggravated the symptoms of diabetes insipidus (DI) in homozygous Brattleboro rats (an AVP-deficient strain). The present study investigates in more details the acute and chronic effects of SR in DI rats. METHODS AND RESULTS: In experiment A, different groups of rats received acute i.p. injections of SR (0.001-10 mg/kg) or vehicle alone, and urine was collected for the next 24 h. SR dose-dependently increased urine flow rate and decreased urine osmolality with no significant change in solute excretion, thus confirming a pure 'aquaretic' effect. In experiments B and C, the chronic effects of orally administered SR were evaluated over 8 days in Brattleboro DI rats (experiment B, 1 mg/kg/day) and in adult Sprague-Dawley rats with normal AVP secretion (experiment C, 3 mg/kg/day). In DI rats, the aquaretic effects of SR persisted with the same intensity over the 8 days. In Sprague-Dawley rats, SR induced a sustained, stable aquaretic effect and also increased non-renal water losses, suggesting an effect of AVP on water conservation in extrarenal sites. Because oxytocin (OT) synthesis is elevated in DI rats and OT is known to bind to V2 receptors, we evaluated the antidiuretic effects of OT in DI rats in experiment D. Chronic infusion of OT (3 microg/kg/h, i.p.) induced a marked antidiuresis, and acute SR (1 mg/kg) in OT-treated DI rats completely abolished this antidiuretic effect, thus indicating that it was due to binding of OT to V2 receptors. CONCLUSION: (i) SR is a potent orally active aquaretic and induces stable effects during 1 week in rats with or without endogenous AVP secretion. (ii) Significant V2 receptor-mediated water reabsorption occurs in collecting ducts of Brattleboro DI rats because their usual urine osmolality is about twofold higher than the minimum observed during SR-induced maximum diuresis. (iii) This V2 agonism could be mediated in part by OT binding to V2 receptors. Small amounts of endogenous AVP, known to be produced by adrenal and testis in DI rats, could also contribute to this V2 agonism, as well as a possible constitutive activation of the V2 receptors. (iv) In normal rats, AVP probably reduces water losses through extrarenal sites, probably the lungs.     

Diabetes insipidus in pregnancy

Diabetes insipidus (DI) and pregnancy may coexist and, when they do, present challenging diagnostic and therapeutic problems. Women with preexisting central DI usually experience increased thirst and require additional hormone replacement. Women with nephrogenic DI have an increased water turnover. Of interest is a group of women with transient DI of gestation. In some of these patients, central DI is brought to the fore by increases in water turnover during pregnancy as well as increments in the metabolic clearance of arginine vasopressin (AVP), especially near term. Others have a "vasopressin-resistant" form of the disease, which in one case followed by us appeared to be due to marked increments in circulating cystine-aminopeptidase (vasopressinase). This patient's DI was resistant to pitressin, but she concentrated her urine when given dDAVP. Her vasopressinase levels 2 weeks postpartum were still several-fold those of normal term gravidas. Her DI remitted, and she concentrated her urine appropriately 2 months postpartum. This article reviews the different forms of DI peculiar to pregnancy.     

Therapeutic approaches in lowering albuminuria: travels along the renin-angiotensin-aldosterone-system pathway

Achieving optimal blood pressure and albuminuria control is a major therapeutic treatment goal in patients with renal insufficiency. Angiotensin-converting enzyme-inhibitors (ACEIs) and angiotensin-receptor blockers (ARB) are the mainstay of therapy in these patients. However, despite these therapies many patients remain at high risk of renal or cardiovascular disease that shows a relationship with albuminuria. Various approaches have been tested to maximize the efficacy of ACEI and ARB. Increasing the dose of an ACEI or ARB beyond the maximal registered antihypertensive dose causes a distinct decrease in albuminuria without additional effects on blood pressure. The combination of an ACEI and ARB is another possibility to further reduce albuminuria. However, the alleged beneficial effects on hard renal and cardiovascular outcome are not unambiguously demonstrated. Adding a direct renin inhibitor to an ACEI or ARB has been shown to lower albuminuria in patients with and without diabetes. Long-term trials are currently under way to determine the effects of direct renin inhibition on clinical outcomes. Volume excess has been shown to blunt the blood pressure and albuminuria response to ACEI or ARB therapy. Intervening in volume status by means of restricting dietary sodium intake or diuretic therapy has convincingly been shown to lower blood pressure and albuminuria. Whether this strategy translates into a reduction in the risk of renal or cardiovascular events has not (yet) been investigated in prospective randomized trials. Various options are at hand which have been shown to maximize the blood pressure and albuminuria response to ACEI and ARB treatment. However, long-term studies supporting the benefits of these strategies on hard renal and cardiovascular outcomes are warranted.     

Microalbuminuria and urinary albumin excretion: clinical practice guidelines

Measurement of urinary albumin excretion (UAE) may be done on a morning urinary sample or on a 24 hours-urine sample. Values defining microalbuminuria are: 24 hour-urine sample: 30-300 mg/24 hours; morning urine sample: 20-200 mg/ml or 30-300 mg/g creatinine or 2.5-25 mg/mmol creatinine (men) or 3.5-35 mg/mol (women). Timed urine sample: 20-200 microg/min. The optimal use of semi-quantitative urine test-strip is not clearly defined. It is generally believed that microalbuminuria reflects a generalized impairment of the endothelium; however, no definite proof has been shown in humans. IN DIABETIC SUBJECTS: Microalbuminuria is a marker of increased risk of cardiovascular (CV) and renal morbidity and mortality in type 1 and type 2 diabetic subjects. The increase in UAE during follow-up is also a marker of CV and renal risk in type 1 and type 2 diabetic subjects; its decrease during follow-up is associated with lower risks. IN NO DIABETIC SUBJECTS: Microalbuminuria is a marker of increased risk for diabetes mellitus, deterioration of the renal function, CV morbidity and all-cause mortality. It is a marker of increased risk for the development of hypertension in normotensive subjects, and is associated with unfavorable outcome in patients with cancer and lymphoma. Persistence or elevation of UAE overtime is associated with deleterious outcome in some hypertensive subjects. Measurement of UAE may be recommended in hypertensive subjects with one or two CV risk factors in whom CV risk remains difficult to assess, and in those with refractory hypertension: microalbuminuria indicates a high CV risk and must lead to strict control of arterial pressure. Studies focused on microalbuminuria in non-diabetic non-hypertensive subjects are limited; most of them suggest that microalbuminuria predicts CV complications and deleterious outcome as it is in diabetic or hypertensive subjects. Subjects with a history of CV or cerebrovascular disease have an even greater CV risk if microalbuminuria is present than if it is not; however, in all cases, therapeutic intervention must be aggressive regardless of whether microalbuminuria is present or not. It is not recommended to measure UAE in non-diabetic non-hypertensive subjects in the absence of history of renal disease. Monitoring of renal function (UAE, serum creatinine and estimation of GFR) is annually recommended in all subjects with microalbuminuria. MANAGEMENT: In patients with microalbuminuria, weight reduction, sodium restriction (<6 g/day), smoking cessation, strict glucose control in diabetic subjects, strict arterial pressure control are necessary; in diabetic subjects: use of maximal doses of ACEI or ARB are recommended; ACEI/ARB and thiazides have synergistic actions on arterial pressure and reduction of UAE; in non diabetic subjects, any of the five classes of antihypertensive medications (ACEI, ARB, thiazides, calcium channel blockers or betablockers) can be used.     

Epinephrine and dDAVP administration in patients with congenital nephrogenic diabetes insipidus. Evidence for a pre-cyclic AMP V2 receptor defective mechanism

We recently showed that the administration of the antidiuretic V2 specific agonist, 1-desamino[8-D-arginine]vasopressin (dDAVP), to seven male patients with congenital nephrogenic diabetes insipidus (CNDI) did not cause a decrease in blood pressure nor an increase in plasma renin activity or factor VIIIc or von Willebrand factor release. In normal subjects, plasma renin activity, coagulation factors and plasma cyclic AMP are stimulated not only by dDAVP but also by the administration of epinephrine. In the present study, we measured tissue plasminogen activator (activity and antigenicity), von Willebrand factor multimers, plasma and urinary cyclic AMP concentrations following dDAVP or epinephrine administration. We infused epinephrine into three male patients with CNDI. Factor VIIIc and tissue plasminogen activator augmented by 75 to 100% and von Willebrand Factor multimers were increased; plasma renin activity and plasma cyclic AMP concentration increased by 200%. None of these values changed when the same subjects as well as eleven other male patients with CNDI received dDAVP. Furthermore, dDAVP administration increased plasma cyclic AMP concentrations in normal subjects, but not in 14 male patients with CNDI. These results demonstrate the specificity of the extrarenal V2 receptor defect expressed in our patients. The lack of a plasma cyclic AMP response to the administration of dDAVP would suggest an altered pre-cyclic AMP stimulation mechanism.     

A novel splicing mutation in the V2 vasopressin receptor

In order to elucidate the molecular basis and the clinical characteristics of X-linked recessive nephrogenic diabetes insipidus (CNDI) in a kindred of Danish descent, we performed direct sequencing of the arginine vasopressin receptor 2 (AVPR2) gene in five members of the family, as well as clinical investigations comprising a fluid deprivation test and a 1-deamino-8-D-arginine- vasopressin (dDAVP) infusion test in the study subject and his mother. We found a highly unusual, novel, de novo 1447A→C point mutation (gDNA), involving the invariable splice acceptor of the second intron of the gene in both the affected male (hemizygous) and his mother (heterozygous). This mutation is likely to cause aberrant splicing of the terminal intron of the gene, leading to a non-functional AVP receptor. The clinical studies were consistent with such a hypothesis, as the affected subject had a severe insensitivity to both the antidiuretic and the coagulation factors stimulatory actions of AVP and its analogue dDAVP. Direct sequencing of the AVPR2 is an accurate and rapid diagnostic tool for CNDI and early referral of patients for AVPR2 sequencing is therefore strongly suggested. Received: 15 December 1999 / Revised: 24 May 2000 / Accepted: 25 May 2000     

Involvement of renal nerves and endothelins in the regulation of renal water excretion in diabetes insipidus rats

The interaction between renal nerves, endothelins acting via endothelin-A receptors and vasopressin in the regulation of renal excretory function was investigated. In conscious intact and renal denervated diabetes insipidus (DI) Brattleboro rats, as well as their controls, Long-Evans (LE) rats, an infusion of 16.4 nmol/kg/min ET(A) receptor antagonist BQ-123 was performed in the course of 50 min. Femoral artery blood pressure, heart rate, Ccr, V x U(Na), V x U(K) and V x U(Cl) did not alter in any of the groups. Urine flow rate diminished by 38.1% (p < 0.02), while urine osmolality increased by 30.3% (p < 0.05) as a result of BQ-123 infusion in the intact LE rats but neither urine flow rate nor urine osmolality changed in the DI rats. In contrast to intact LE rats, BQ-123 infusion in renal denervated LE rats did not alter urine flow rate or urine osmolality. However, urine flow rate in renal denervated DI rats surprisingly decreased by 71.1% (p < 0.01) while urine osmolality increased by 161% (p < 0.001) as a result of BQ-123 infusion. Endogenous endothelins can regulate renal water excretion through ET(A) receptor activation. Renal sympathetic nerves participate in the modulation of renal water excretion influencing the ET(A) receptor-mediated effects of endothelins in the kidney.     

Renoprotective and anti-hypertensive effects of combined valsartan and perindopril in progressive diabetic nephropathy in the transgenic (mRen-2)27 rat.

BACKGROUND: We have previously reported that severe glomerulosclerosis progressively develops in the streptozotocin (STZ) diabetic transgenic (mRen-2)27 rat. In this diabetic model, monotherapy with either angiotensin converting enzyme inhibition (ACEI) or angiotensin type 1 (AT(1)) receptor blockade is largely renoprotective. The objective of the present study was to determine if a combination therapy at lower doses than monotherapy would confer greater renoprotection. METHODS: At 6 weeks of age, non-diabetic control and STZ diabetic female heterozygous Ren-2 rats were randomized to receive vehicle, the AT(1) receptor blocker valsartan (V, 20 mg/kg/day), the ACEI perindopril (P, 6 mg/kg/day), or a combination of low-dose V+P (V, 3 mg/kg/day plus P, 0.5 mg/kg/day) for 12 weeks. RESULTS: Systolic blood pressure was lowered with all treatments, but the greatest reductions were observed with V monotherapy and combination V+P therapy. All treatments reduced albuminuria, the decline in glomerular filtration rate, and cortical collagen staining, to the same extent. The glomerulosclerotic index was increased with diabetes and reduced with V and P monotherapy. However, the low-dose combination therapy was more effective than single therapy and reduced severe glomerulosclerosis to levels observed in non-diabetic controls. CONCLUSIONS: Monotherapy with either V or P reduced blood pressure and retarded the decline in renal function and glomerulosclerosis in the diabetic Ren-2 rat. Combination therapy has the additional benefit of requiring only low doses of AT(1) receptor blockade and ACEI to achieve superior renoprotective effects in this diabetic nephropathy model.     

The effect of aldosterone blockade in patients with Alport syndrome

Recent studies indicate that adding the mineralocorticoid receptor antagonist spironolactone (SP) to angiotensin converting enzyme inhibitors (ACEI) or ACEI and angiotensin receptor blocker (ARB), which is known as a triple blockade, enhances the more beneficial effects on urinary protein excretion of patients with chronic kidney diseases. In this study, we explored the effects of SP on urinary protein excretion in patients with Alport syndrome featuring persistent proteinuria in spite of the long-term use of ACEI (lisinopril) or both ACEI and ARB (candesartan). Five patients with Alport syndrome were enrolled and SP treatment (25 mg/day) was started. At the start of SP administration, all patients showed good renal function and none of them suffered from hypertension. We decided to assess the effect of SP by determining the morning urinary protein/creatinine ratio (U-P/C) and estimated glomerular filtration rate (EGFR). After SP treatment was started, U-P/C was significantly reduced at 3, 6, 12 and 18 months, while EGFR did not change. The drop in systolic and diastolic blood pressure was statistically significant and serum potassium level was slightly elevated. None of the patients showed signs of severe hyperkalemia (>5.0 mEq/l). These results suggest that aldosterone receptor blockade combined with ACEI and ARB therapy offers a valuable adjuvant treatment for the reduction of proteinuria in patients with Alport syndrome as in those with other chronic kidney diseases. SP can thus be expected to constitute a good renoprotective agent for Alport syndrome. These preliminary data indicate that large-scale trials of this therapy should be done.     

Treatment strategies in patients with chronic renal disease: ACE inhibitors,angiotensin receptor antagonists,or both?

We discuss the evidence supporting the use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II type 1 receptor blockers (ARB), or the combination of both in children with chronic renal disease. Several large-scale, prospective, randomized studies with clinical end points have been performed in adult patients, but studies in children are relatively scarce. In adult patients with chronic renal diseases, ACEI clearly delay the progression of chronic non-diabetic renal diseases, and nephropathy in patients with type 1 diabetes. The benefits of ACEI are most apparent in glomerular diseases with marked proteinuria but extend also to kidney diseases with lower proteinuria. This notion is also supported by several smaller or retrospective trials in children. Therefore, ACEI should be given to children with chronic renal diseases, particularly if high blood pressure and/or proteinuria are present. In adults, large-scale trials have documented that ARB exert similar effects as ACEI but tend to exert fewer undesired side effects. Data on ARB in children with chronic renal disease are still very scarce, but these substances offer an alternative for patients who cannot tolerate ACEI due to unwarranted side effects. Combination therapy with ARB plus ACEI may be more effective than either drug class alone. However, we will need the results of further long-term prospective clinical studies, as well as a better understanding of the role of the AT₂ receptor, before combination therapy can be widely recommended. A trial of ARB plus ACEI is justified in selected patients if blood pressure and/or proteinuria cannot adequately be lowered by ACEI or ARB alone.     

Increased abundance of distal sodium transporters in rat kidney during vasopressin escape

Hyponatremia is associated with inappropriately elevated vasopressin levels. A brisk natriuresis precedes the escape from this antidiuresis. Thus, the hypothesis was that the abundance of one or more of the sodium transporters of the distal tubule (a site for fine tuning of sodium balance) would be altered during vasopressin escape. Semiquantitative immunoblotting was used to examine the regulation of abundance of several sodium transporters/channels of the thick ascending limb through the collecting duct in the rat model. Osmotic minipumps to infuse dDAVP, the V2-selective vasopressin agonist (5 ng/h) for the entire experiment, were implanted in Male Sprague-Dawley rats. After 4 d, rats were divided into a control (dry AIN-76 diet/ad libitum water) or a water-loaded (gelled-agar-AIN-76 diet/ad libitum water) group. Rats were killed after 1, 2, 3, or 7 additional days. The water-loaded rats were hyponatremic (plasma Na+, 98 to 122 mmol/L) and manifested the expected early natriuresis and diuresis of vasopressin escape. Water loading (with dDAVP infusion) resulted in increased whole-kidney abundances of the thiazide-sensitive Na-Cl co-transporter, the alpha-subunit of the epithelial sodium channel (ENaC), and the 70-kD dimer of the gamma-subunit of ENaC. No changes were observed for the ss-subunit of ENaC. Similar protein changes have recently been associated with elevated aldosterone levels in rats. However, plasma aldosterone levels were significantly suppressed in this model. These data suggest that several distal sodium reabsorptive mechanisms are upregulated during vasopressin escape; this may help to attenuate the developing hyponatremia resulting from water loading when vasopressin levels are inappropriately elevated.     

Management of Renin-Angiotensin-Aldosterone System Blockade in Kidney Transplant Recipients

Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are the cornerstone treatment in chronic kidney disease patients. Despite facilitating a reduction in blood pressure and albuminuria, there are insufficient data in kidney transplant recipients (KTRs). They are often administered for hypertension and polycythemia treatment. The aim of this study was to investigate the frequency and route of administration of ACEIs and ARBs and their early clinical effects in the KTR population. In a cross-sectional, retrospective study we analyzed 874 medical records of all KTRs treated in our unit in 2014. A total of 391 KTRs (44.7%) using ARBs or ACEIs were qualified for the study. The primary reasons for renin-angiotensin-aldosterone system antagonist administration were hypertension (59.1%), polycythemia (19.2%), and proteinuria (18.2%). Among the studied KTRs, 86.7% of patients were treated with ACEIs and 12.2% were treated with ARBs. The majority of patients treated with ACEIs and ARBs received these agents in a dose range below 25% and between 25% and 49% of their maximal dose, respectively. Both the mean serum creatinine level and estimated glomerular filtration rate (chronic kidney disease epidemiology collaboration) remained fairly stable and urine protein excretion (g/24 hours) was significantly reduced after 3 months of ACEI and ARB therapy. The serum potassium level increased significantly, while hemoglobin concentration dropped significantly.In KTRs, renin-angiotensin-aldosterone system antagonists were applied mainly due to hypertension, proteinuria, and polycythemia. ACEIs and ARBs were effective in the reduction of proteinuria and hemoglobin, but graft function was stable and the increase of serum potassium was not of clinical significance.     

Reduction of albuminuria by angiotensin receptor blocker beyond blood pressure lowering: evaluation in megsin/receptor for advanced glycation end products/inducible nitric oxide synthase triple transgenic diabetic nephropathy mouse model

Aim: Antihypertensive agents inhibiting the renin-angiotensin system (RAS), such as angiotensin II type 1 receptor blockers (ARB), are now part of the standard treatment of patients with diabetic nephropathy, regardless of the presence of systemic hypertension. Whether ARB achieve better renoprotection than other RAS-independent antihypertensive drugs has been an issue of controversy. Several lines of large clinical studies provided better renoprotection of ARB. However, a recent meta-analysis argued against additional benefits of ARB beyond blood pressure. We generated a novel mouse model of diabetic nephropathy; that is, megsin/receptor for advanced glycation end products/inducible nitric oxide synthase triple transgenic mice. This model is normotensive but progressively develops severe diabetic nephropathy that resembles those observed in humans. Methods: In the present study, we tested whether olmesartan (ARB) achieves better renoprotection than amlodipine (calcium channel blocker). Drug treatment was initiated at the age of 6 weeks and lasted for 12 weeks. Results: This model develops significant glomerular lesions and albuminuria even at the age of 5 weeks. Despite equal blood pressure lowering, only olmesartan suppressed the progression of albuminuria. Neither olmesartan nor amlodipine modified histological lesions. Conclusion: Proteinuria and its reduction are known to predict the progression of diabetic nephropathy. Our results support the additional benefit of ARB beyond blood pressure lowering.