Mechanism of impaired urinary concentrating ability in normokalemic primary aldosteronism

Renal clearance studies were performed during anti-diuresis (before and after hypertonic saline infusion) and during water diuresis in three hypertensive patients with normokalemic primary aldosteronism (NPA) and in matched patients with normoreninemic essential hypertension (EH). The NPA patients showed an impaired ability to concentrate urine. By progressively increasing Cosm with saline loading, TcH2O plateaued both in NPA and in EH patients; in the former, however, the plateau occurred earlier and was lower than in the latter. In water diuresis, absolute values of CH2O were higher in NPA due to increased distal delivery secondary to impairment in proximal tubular reabsorption. Fractional CH2O (i.e. the ratio between CH2O and distal sodium delivery), however, was lower in NPA than in EH patients. Both in antidiuresis (after saline loading) and in water diuresis the NPA patients exhibited an enhanced fractional excretion of sodium. In one of NPA patients, clearance studies were repeated after adrenalectomy. In this patient, normalization of BP and reduction of body weight were associated with a rise in Uosm and a reduction in Cosm in antidiuresis; Uosm and Cosm were restored to pre-surgical values by expanding extracellular fluid volume (ECV) with saline loading. In summary our results suggest that ECV expansion is the mechanism by which urine concentration is impaired in patients with NPA.     

Decrease in urinary excretion of aquaporin-2 associated with impaired urinary concentrating ability in diabetic nephropathy

Aquaporin-2 (AQP-2) is known to be expressed in the renal collecting duct cells and participates in urinary concentration in response to arginine vasopressin (AVP). The present study was undertaken to determine whether progression of renal dysfunction affects urinary excretion of AQP-2 in diabetic nephropathy. The study was composed of 8 control subjects and 14 patients with type 2 diabetes classified into two groups according to serum creatinine level (cut-off point; 1.5 mg/dl). After an 8-hour water deprivation, both urinary osmolality (U(osm)) and urinary excretion of AQP-2 significantly decreased in the diabetic patients with chronic renal failure as compared to the control subjects (p < 0.0001, p < 0.05, respectively). After a water load (10 ml/kg), no differences were found in plasma osmolality (P(osm)), AVP levels and U(osm), whereas urinary excretion of AQP-2 significantly decreased in the patients with chronic renal failure as compared to the control subjects (p < 0.05). These results indicate that the decreased urinary excretion of AQP-2 in diabetic nephropathy is due to the impaired cellular signaling of AVP in collecting duct cells, which may be partly involved in the urinary concentrating defect in renal failure.     

Impaired urinary concentrating ability in genetically polyuric mice

Newly recognized strain of mice with hereditary polyuria (PUS mice) was characterized. Polyuria was inherited as a single autosomal-recessive trait. At 15 weeks, PUS mice excreted hypotonic (urine osmolality: PUS;270.8 +/- 15.5 vs. cont.; 3,228.6 +/- 163.6 mosm/kg) polyuria (urine volume: PUS; 25.0 +/- 1.5 vs. cont.; 1.1 +/- 0.1 ml/day). In PUS mice, plasma osmolality was slightly elevated as well as urinary excretion of vasopressin (AVP). Although PUS mice could concentrate urine after 24 h water deprivation, urine osmolality remained low. Blunted response to continuous infusion of dDAVP, a synthetic V2 agonist, was also observed. These in vivo studies indicated renal resistance to AVP contributed to the polyuria in this strain of mice. Microanalysis of isolated tubular segments revealed that AVP-induced cAMP accumulation in cortical collecting ducts (CCD) of PUS mice was significantly lower (60%) with or without a phosphodiesterase inhibitor, IBMX. Vasopressin induced similar cAMP accumulation in medullary ascending limbs of Henle (MAL), and medullary collecting ducts (MCD) between PUS and control mice. In CCDs, PUS mice had low basal adenylate cyclase (AdC) activity and responded less to AVP and forskolin stimulation than control mice. No difference in cyclic AMP phosphodiesterase activity was detected between control and PUS mice. These results indicate that impaired cAMP accumulation due to low AdC activity may be related to the impaired renal concentrating ability observed in this new strain of mice.     

Role of urinary concentrating ability in the generation of toxic papillary necrosis

We studied the pathogenesis of chemically induced papillary necrosis in six groups of rats. Papillary necrosis was produced by a single injection of 2-bromoethylamine hydrobromide (BEA), 50 mg, i.v.; the animals were followed for 7 to 10 days after the administration of the compound. Following BEA, heterozygous Brattleboro rats developed all the functional and morphologic lesions of papillary necrosis that we previously described in Sprague-Dawley rats. They were unable to maintain sodium balance when dietary sodium was withdrawn. Homozygous Brattleboro rats, on the other hand, developed none of the manifestations of papillary necrosis (that is, animals with central diabetes insipidus were protected completely from the nephrotoxic effects of BEA). They adapted normally to a zero sodium diet. Chronic administration of vasopressin to homozygous Brattleboro rats fully restored the toxic effects of BEA. Lowering urinary concentrating ability by inducing a water diuresis in Sprague-Dawley rats completely protected against BEA-induced papillary necrosis. Decreasing papillary solute concentration by furosemide or increasing urine flow after abrupt withdrawal of vasopressin to homozygous Brattleboro rats did not protect against BEA-induced papillary necrosis. We conclude that the combination, but not either alone, of increased urine flow and decreased papillary solute concentration protects against the development of BEA-induced papillary necrosis.     

Lithium-induced reduction in urinary concentrating ability and urinary aquaporin 2 (AQP2) excretion in healthy volunteers

BACKGROUND: Lithium therapy is associated with the development of nephrogenic diabetes inspidus. Experimentally, lithium inhibits arginine vasopressin (AVP)-stimulated translocation of cytoplasmic aquaporin 2 (AQP2) to the apical membrane. Clinically, the actions of lithium on renal tubular function are less clearly established. This study examined the effects of four weeks of lithium therapy on desmopressin (dDAVP)-stimulated urinary concentrating ability in healthy volunteers. METHODS: Eleven healthy volunteers underwent baseline urinary concentrating ability studies which were repeated following 4 weeks therapy with lithium carbonate (250 mg twice a day). Urinary osmolality, urinary AQP2 and cyclic adenosine monophosphate (cAMP) levels were measured following overnight fluid deprivation and after the administration of 40 microg of dDAVP. Baseline values were compared with results after 4 weeks of lithium therapy. RESULTS: Four weeks of lithium therapy reduced dDAVP-stimulated urinary concentrating ability (996 +/- 27 to 945 +/- 26 mOsm/kg) (P < 0.05) and this was associated with significant reduction in urinary AQP2 excretion (99.2 +/- 10.0 to 77.8 +/- 7.4 fmol/micromol creatinine) (P < 0.05) and urinary cAMP excretion (3188 +/- 376 to 2212 +/- 378 units) (P < 0.01). CONCLUSION: Four weeks of lithium therapy in healthy volunteers produced a small but significant reduction in dDAVP-stimulated urinary concentrating ability, which appears to be mediated by the inhibition of AVP-stimulated translocation of cytoplasmic AQP2 to the collecting tubule apical membrane via inhibition of adenyl cyclase.     

Evidence for a defect in urinary concentrating ability in primary aldosteronism and its reversal by adrenal surgery

Of 15 patients with primary aldosteronism, 7 had idiopathic adrenal hyperplasia (IHA) and 8 had aldosterone-producing adenoma (APA). In order to determine any renal problems involved in the treatment, the renal clearance of these patients was analyzed and the results compared with those obtained from 12 patients with essential hypertension. With water diuresis or under antidiuresis status, levels of urine volume, Cosm and CH2O in patients with APA were greater (p less than 0.05-p less than 0.001) than those of patients with essential hypertension, while the fractional tubular sodium delivery of the former patients was lower than that of the latter patients (p less than 0.001 or less than 0.05). A similar tendency was observed in clearance studies in patients with IHA, although to a lesser extent. Adrenal surgery for patients with APA normalized these values, but administration of trilostane (3 beta-hydrosteroid dehydrogenase inhibitor) to patients with IHA failed to improve these values. These results indicate that impaired urinary concentrating ability as well as reduced urinary diluting capability is a common feature of primary aldosteronism. Such impaired renal function was improved only in patients with APA after adrenal surgery.     

Impaired renal concentrating ability during resuscitation from shock

Renal concentrating ability was tested in 20 severely injured patients who received an average of 21 blood transfusions. Timed measurements were made of urine output (UO), and the clearance of creatinine glomerular filtration rate (GFR), sodium (CNa), osmols (COsm), and free water (CH2O) during operation and were repeated at 12 and 18 hours postoperatively, and on postoperative days 2 and 4. During operation the GFR was markedly reduced (36 mL/min), while UO, CNa, and COsm were all markedly increased (8.5, 5.9, and 8.1 mL/min, respectively). The CH2O was positive (0.4 mL/min). Following operation the rate of renal excretion of water and solutes was still high: UO, 4.0 mL/min; CNa, 4.3 mL/min; and COsm, 6.0 mL/min. Five hours postoperatively the CH2O had returned to normal. By day 2 the excretion rate of water had returned closer to normal: UO, 2.1 mL/min; CNa, 2.6 mL/min; COsm, 4.0 mL/min; the CH2O was normal. Subsequent study results were normal. These data demonstrate a renal concentrating impairment during and following operation. An osmotic diuresis, transient tubular ischemia, a washout of interstitial inner medullary osmoles, or some cryptic factor may be causative.     

Impaired urine concentrating ability in Itai-itai (ouch-ouch) disease

A case of Itai-itai (ouch-ouch) disease with reduced urinary kallikrein excretion and slightly enhanced renin-angiotensin-aldosterone system is described. Although it is well known that cadmium toxicity frequently affects the renal tubular lesions, this report is the first to demonstrate the impaired urine concentrating ability in this disease.     

Experimental tests of three-dimensional model of urinary concentrating mechanism.

Recently, a new model of the urinary concentrating process has been proposed that takes into account the three-dimensional architecture of the renal medulla. Under the assumptions of the model, computer simulations predicted significant axial osmolality gradients in the inner medulla without active transport by the inner medullary loop of Henle. Two of the model assumptions (which constitute hypotheses for this study) were: (1) the osmotic water permeability of the initial part of the inner medullary collecting duct (initial IMCD) is very low even in the presence of vasopressin; and (2) there is significant lateral separation of structures such that thin descending limbs are far from the collecting ducts at the same inner medullary level. The first hypothesis was addressed by perfusing rat initial IMCD segments in vitro and measuring osmotic water permeability. With the osmotic gradient oriented as predicted by the model (lumen greater than bath), vasopressin increased the osmotic water permeability from 286 to 852 microns/s. Three additional series of experiments confirmed the high water permeability in the presence of vasopressin. The second hypothesis was addressed by morphometric analysis of histologic cross-sections of the rat renal medulla. Mean distances of descending limbs to the nearest adjacent collecting duct were very small throughout the inner medulla (less than 6 microns) and substantially less than in the outer medulla (28 microns). It was concluded that the data are inconsistent with both hypotheses and therefore do not support the feasibility of the "three-dimensional" model of the renal inner medulla. The axial distributions of loops of Henle and collecting ducts in the rat renal medulla are also reported.     

Nephrotoxicity of an ellipticine derivative (N2-methyl-9-hydroxyellipticinium acetate) in rat: a defect of urinary concentrating ability.

The antitumor drug celiptium (N2-methyl-9-hydroxyellipticinium) is an ellipticine derivative effective in experimental tumors and in man. The major side effect is nephrotoxicity. The impairment of renal function is studied in rats following a single i.v. dose of 20 mg/kg celiptium and a long-term study (day 2 to day 60). A loss of body weight is noted in celiptium-treated animals between day 4 and day 15, and recovery occurs between day 15 and day 60. Histologic study shows cortical lesions characterized by focal necrosis of proximal tubules without any glomerular, interstitial, and vascular alterations on day 8. It is to be noted that any medullary lesions were not shown. A polyuria and a decreased creatinine clearance are reported on day 8. We were interested in a special study of this polyuria. For this study, rats were water deprived between day 6 and day 8 following celiptium administration. The decrease of urinary osmolality is not recovered after dehydration and exogenous vasopressin derivative (dD AVP) does not correct the renal concentration defect. AVP plasma levels increase after dehydration. These results suggest a pitressino-resistant urinary concentrating inability in celiptium-treated rats.