The influence of long-term infusion of the calcium antagonist diltiazem on postischemic acute renal failure in conscious dogs

Summary The influence of long-term infusion of the calcium-entry blocker diltiazem on postischemic acute renal failure was investigated in conscious dogs monitored by implanted instruments. In 18 uninephrectomized beagle dogs on a salt-rich diet, an electromagnetic flow probe and an inflatable plastic cuff were placed around the renal artery. Acute renal failure was induced by inflating the cuff for 180 min in the conscious animal. Group A (n=5, control) received an intraaortic injection of 0.9% NaCl (5 ml/day) from the 3rd day before until the 7th day after ischemia and group B (n=6, posttreatment) an intra-aortic injection of diltizem (5 µg·min^–1·kg^–1) beginning at the end of ischemia until the 7th day. Group C (n=7, pre- and posttreatment) received diltiazem from the 3rd day before until the 7th day after ischemia. In group A, renal blood flow dropped from 149±16 (preischemic) to 129±29 ml·min^–1 on the 1st day after ischemia. In contrast, renal blood flow increased on the 1st postischemic day in both treatment groups by 29±15% (group B,P 0.05) and 14±13% (group C). In the following days, there was no significant difference in renal blood flow between groups A, B and C. In group B, the reduction of the glomerular filtration rate was similar to that in the control group. In group C, the glomerular filtration rate was significantly less reduced than in group A (34±1.8 preischemically to 17±5.4 on day 1,P 0.05 and 20±4.1 ml·min^–1 on day 7,P 0.05). Plasma renin activity increased in both diltiazem groups, more pronounced so in group B (from 3.7±1.0 on day 1 to 16.2±7.9 ng ATI·ml^–1·h^–1 on day 7,P 0.05). In contrast to groups A and B, the increase in fractional sodium excretion was less pronounced in group C. Likewise, the decrease in free water-reabsorption was less marked than in groups A or B. It was apparent that diltiazem, when administered pre- and post-ischemically, preserved glomerular filtration rate and renal blood flow. When diltizem was given solely postischemically there was an improvement in renal blood flow, but no significant influence on glomerular filtration rate. We therefore conclude that mainly tubular factors, in addition to the attenuation of postischemic vasoconstriction, are involved in the protective effect of diltiazem on postischemic acute renal failure in conscious dogs.Abbreviations ARF acute renal failure - C_osmol clearance of osmolarity - E_Na urinary excretion rate of sodium - FE_Na fractional excretion rate of sodium - GFR glomerular filtration rate - HR heart rate - NE norepinephrine - PAM mean arterial blood pressure - PRA plasma renin activity - RBF renal blood flow - RVR renal vascular resistance - T_H2_O free water reabsorption - V_U urine volume     

Pharmacodynamic and kinetic considerations on diuretics as a basis for differential therapy

Summary Diuretics are classified according to their site of action in the nephron: loop diuretics, thiazides, and antikaliuretics. During peak diuresis the pattern of electrolyte excretion is constant and characteristic for a class of diuretics. The ratio of diuretic-induced excretion of K⁺ to Na⁺ is 0.12 for loop diuretics, 0.20 for thiazides, and –0.21 for antikaliuretics. The ratio of Ca²⁺ to Na⁺ is 0.02 for loop diuretics and 0.003 for thiazides. Mg²⁺ excretion follows K⁺ excretion in a ratio of 0.15. The natriuretic effect of a diuretic directly depends on the renal clearance of the drug and is proportionate to the number of intact nephrons. Not only loop diuretics but also thiazides and antikaliuretics were demonstrated to be effective natriuretic drugs down to end-stage renal disease. In renal failure FE_Na is doubled with every halfening of GFR. Loop diuretics increase FE_Na to a maximum of 24%, thiazides to 10–15%, and FE_Na is doubled by antikaliuretics. Comedication of loop diuretics with thiazides in renal failure may therefore be more effective than increasing monotherapy. In liver disease, nonrenal drug clearance is reduced the more the patient's direct bilirubin rises thus causing an increase in AUC and urinary excretion of parent drug and metabolites. Despite increased A_e, the cirrhotic patient may become resistant to diuretics as may patients with congestive heart failure or nephrotic syndrome. This is considered to be due to reduced Na⁺ load available at the diuretic's site of action following avid proximal Na⁺ reabsorption. In reduced EABV a short-term comedication of loop diuretics with carboanhydratase inhibitors is considered a more effective diuretic strategy than vigorously increasing monotherapy.Abbreviations GFR glomerular filtration rate (ml/min) - A_e amount of drug excreted into the urine (% of given dose) - AUC area under the plasma level time curve (g·h/ml) - Cl_pl total plasma clearance=Dose_i.v./AUC (ml/min) - Cl_r renal clearance=A_e/AUC (ml/min) - Cl_nr nonrenal clearance=Cl_pl-Cl_r (ml/min) - FE_Na fractional sodium excretion (%)=Na excreted x 100/Na filtered=urine sodium × urine volume per minute x 100/plasma sodium x GFR - CHF congestive heart failure - EABV effective arterial blood volume - RAA Renin angiotensin aldosterone system - NE Norepinephrin - NSAIDs Nonsteroidal anti-inflammatory drugs Gratefully dedicated to Prof. Dr. K.J. Ullrich     

Verhalten der renalen Funktionsreserve von Typ I Diabetikern: Einfluß der Konversionshemmung

Summary Renal functional reserve capacity was evaluated in 19 normotensive type I diabetics without microalbuminuria. All patients had normal basal renal function as assessed by 24-hour creatinine clearances higher than 120 ml/min. PAH, inulin, and creatinine clearances were carried out every hour before, during, and after infusion of an amino acid (AA) solution. The same experiment was repeated after ACE inhibition with captopril (25 mg). Two groups of patients were found: Group A (responders) showed a significant rise in GFR after AA infusion (inulin clearances from 117±8 to 138±10 ml/min) (p<0.05), whereas in Group B (non-responders) no significant change in GFR was observed. Groups were comparable in age, duration of diabetes, metabolic control, and mean arterial blood pressure.Group B, however, had a significantly higher basal inulin clearance (167±17 ml/min) than Group A (117±8 ml/min).In Group A ACE inhibition completely blocked the AA-induced rise in GFR, while basal GFR in Group B was significantly reduced (167±17 to 148±8 ml/min) after captopril administration. In both groups renal plasma flow was enhanced by ACE inhibition.A rise in glucagon was observed in all patients during AA infusion.It is concluded that type I diabetics with normal basal renal function already have reduced (Group A) renal functional reserve capacity, which is completely abolished (Group B) when concomitant hyperfiltration occurs. ACE inhibition reduces hyperfiltration and is capable of blocking the AA-induced rise in GFR in these patients.

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Abkürzungsverzeichnis ACE Angiotensin converting enzyme - ANP Atriales natriuretisches Peptid - AS Aminosäuren - BE Broteinheit - GFR Glomeruläre Filtrationsrate - PAH Paraaminohippursäure Herrn Prof. Dr. med. F. Scheler zum 65. Geburtstag gewidmet.     

Atrial natriuretic peptide in human urine

Summary A highly sensitive radioimmunoassay to measure atrial natriuretic peptide (ANP) concentration in urine has been established, and its clinical usefulness is presented. ANP in urine was stable at 4° C for several days and was easily measured by our radioimmunoassay. The average ANP excretion in 65 healthy persons was 25.0±1.4 ng/day (mean ± SEM) and the fractional excretion of ANP was 0.7±0.05%. In 14 patients with congestive heart failure, the average ANP excretion was 119.2±29.4 ng/day, which decreased to 53.3±11.0 after successful treatment.Abbreviations ANP atrial natriuretic peptide - hANP human atrial natriuretic peptide - RIA radioimmunoasay - NSB non specific bound - FE_ANP the fractional excretion of atrial natriuretic peptide - FE_Na the fractional excretion of sodium - SIADH the syngrome of inappropriate secretion of antidiuretic hormone     

Supersensitivity of the renal tubule to catecholamines in the chronically denervated canine kidney

Experiments were performed on anesthetized dogs to study whether or not renal tubules of the chronically denervated kidney show supersensitivity toward circulating catecholamines. In one kidney the influence of plasma catecholamines was inhibited by intrarenal administration of the alpha adrenergic receptor blocker phenoxybenzamine (POB, 2 g/min), and renal parameters of the infused kidney were compared to those of the contralateral noninfused organ. Before POB infusion urine flow (V), urinary sodium and potassium excretion (U_NaV, U_KV) as well as clearance of inulin and PAH (GFR, C_PAH) were similar in infused and contralateral kidneys in all the groups studied. In dogs (n=8) with two innervated kidneys POB infusion elevated V and U_NaV by 53±13% and 102±34% (p<0.05). In dogs (n=8) with acute bilateral renal denervation POB administration failed to alter any of the measured parameters. In contrast, V and U_NaV from chronically denervated kidneys (n=7) were increased after POB infusion by 40±9% and 103±34% (p<0.05). Glomerular filtration rate, C_PAH and U_KV were not changed by alpha adrenoceptor blockade in any of the groups. In an additional group of animals (n=8) acute unilateral renal denervation increased V and U_NaV to a significantly higher extent (by 282±85% and 330±106%) than POB administration did in the innervated kidney and elevated U_KV (44±10%), too. It is concluded that supersensitivity to catecholamines developed in renal tubules of the chronically denervated dog kidney and, in consequence, circulating catecholamines at elevated plasma levels caused by surgery were capable of increasing tubular reabsorption of sodium and water.     

Effect of carbonic anhydrase inhibition on GFR and renal hemodynamics in adenosine-1 receptor-deficient mice

The reduction of glomerular filtration rate (GFR) caused by inhibitors of carbonic anhydrase (CA) is thought to be initiated by activation of the tubuloglomerular feedback (TGF) mechanism. We determined the effect of the CA inhibitor benzolamide (Bz) on renal hemodynamics in adenosine-1 receptor (A1AR) knockout mice that have been shown previously to lack a TGF response. In A1AR^+/+ mice, Bz (150 µg plus 2 µg/min) reduced RBF by 19.8% (from 829±42 to 666±44 µl/min; n=7), and GFR by 19.8% (from 396±43 to 324±46 µl/min; n=9, P=0.001). In A1AR^–/– mice, RBF fell by 15.9 % (from 809±24 to 680±40 µl/min; n=7), and GFR by 21.1% (from 358±27 to 287±32 µl/min; n=10, P=0.0003; NS compared with A1AR^+/+). The absence of TGF responses both before and during Bz infusion in A1AR^–/– mice was confirmed by micropuncture. Following angiotensin II-receptor blockade with candesartan, Bz did not alter RBF (1.4±0.2 vs. 1.4±0.15 ml/min in A1AR^+/+, and 1.4±0.22 vs. 1.39±0.2 ml/min in A1AR^–/–; n=5/genotype) while GFR changed by –8.9 % in A1AR^+/+ mice (n=7), and by –1% in A1AR^–/– mice (n=9; NS compared with A1AR^+/+). Bz caused a significant rise of plasma renin concentration in both A1AR^+/+ and A1AR^–/– mice. Our data show that the absence of a functional TGF mechanism does not prevent the reduction in GFR or RBF caused by CA inhibition. Acute angiotensin II receptor blockade, on the other hand, diminishes the effect of CA inhibition on GFR and RBF. The causes for the GFR reduction appear to be complex and include an effect of the renin-angiotensin system.     

Effect of somatostatin on kidney function and vasoactive hormone systems in healthy subjects

Summary The acute effects of i.v. somatostatin (250 mcg bolus followed by 250 mcg/h continuous infusion for two hours) on renal hemodynamics, renal electrolyte and water handling, and urinary excretion of catecholamines and prostaglandins, as well as on plasma concentrations of arginine vasopressin, atrial natriuretic factor, norepinephrine, epinephrine, dopamine, glucagon, and plasma renin activity were studied in seven normal subjects. Somatostatin decreased effective renal plasma flow and glomerular filtration rate, osmotic and free water clearances, urine volume, and sodium and potassium excretion, while urinary osmolality, fractional excretion of sodium, and phosphate excretion increased significantly. Plasma concentrations of arginine vasopressin, atrial natriuretic factor, norepinephrine, epinephrine, and dopamine remained unchanged, while plasma renin activity (3.0±0.25 vs 2.4±0.2 ng AngI/ml/h;p}<0.01) and glucagon levels (40±11 vs 20±16 pg/ml;p}<0.01) decreased. Urinary excretion of norepinephrine, epinephrine, dopamine, PGE₂, and PGF_2alpha was suppressed under somatostatin. A significant positive correlation was found between urinary dopamine and sodium excretion (r=0.7;p}<0.001) and urinary postaglandin E₂ and glomerular filtration (r=0.52;p}<0.01). Without accompanying changes in plasma osmolality and vasopressin concentration significant antidiuresis occurred, suggesting a direct tubular effect of somatostatin. However, the hormone-induced changes are due mainly to the decrease in renal plasma flow. The results demonstrate that somatostatin at supraphysiological doses exerts significant effects on the kidney.Abbreviations PAH paraaminohippuric acid - ANF atrial natriuretic factor - AVP arginine vasopressin - PRA plasma renin activity - ERPF effective renal plasma flow - GFR glomerular filtration rate - TRP tubular reabsorption of phosphate - NE norepinephrine - E epinephrine - DA dopamine - GH growth hormone     

Glomerular filtration changes during renal artery infusion of various hypertonic solutions in the dog

Summary Effects of renal artery infusion of hypertonic equiosmolar solutions of NaCl, Na₂SO₄, urea, glucose and mannitol on the glomerular filtration rate (GFR) were studied in anesthetized dogs. GFR was determined as a product of the renal plasma flow—calculated from directly measured renal blood flow and hematocrit—and the extraction ratio of exogenous creatinine (RPF·E _cr).Hypertonic solutions of urea, glucose and mannitol depressed GFR while NaCl and Na₂SO₄ were without significant effect. The change in filtration was a linear function of the inhibition of the net absolute tubular reabsorption of water (T _{H 2}O) caused by hypertonic infusions. This relation was observed with all the infusates except Na₂SO₄ which depressed totalT _{H 2}O but did not affect GFR. It is suggested that a definite inhibition of proximal reabsorption, probably absent with Na₂SO₄ infusion, determines the fall in GFR in osmotic diuresis.     

Renal handling of norepinephrine and epinephrine in the pig

To investigate the renal handling of catecholamines in the pig, intravenous infusions of⁵¹Cr-EDTA and PAH were performed in 7 animals, and samples for simultaneous measurement of norepinephrine (NE), epinephrine (E),⁵¹Cr-EDTA and PAH were obtained through catheters placed into the aorta, left renal vein and both urethers. For both kidneys together,⁵¹Cr-EDTA clearance [GFR] averaged 48±14 (±SD) ml/min (2.23±0.66 ml/kg/min). In the left kidney, GFR averaged 22±9 ml/min, arteriovenous PAH extraction 0.87±0.09, and calculated total renal plasma flow 91±30 ml/min. Plasma NE and E were lower in renal venous than arterial blood (P<0.005), extraction ratios averaging 0.36 and 0.77, respectively. NE excretion rate in final urine (8.9±4.3 ng/min) exceeded transrenal NE extraction rate (5.2±3.9 ng/min) by 3.7±4.4 ng/min. In contrast, urinary E excretion rate (2.9±2.0 ng/min) was slightly lower than transrenal E extraction rate (3.6±3.8 ng/min). These observations suggest that in pig kidneys, plasma PAH extraction rate and GFR related to body weight are quite similar to values in man. Three quarters of circulating E are extracted for the most part by tubular secretion, and the slightly smaller amount appearing in urine is consistent with some intrarenal metabolism. NE, presumably originating from intrarenal neuronal release and/or de novo production, is secreted into the urine.This study was supported by the Swiss National Science Foundation     

Roles of estrogen and progesterone in modulating renal nerve function in the rat kidney

The maintenance of extracellular Na⁺ and Cl^- concentrations in mammals depends, at least in part, on renal function. It has been shown that neural and endocrine mechanisms regulate extracellular fluid volume and transport of electrolytes along nephrons. Studies of sex hormones and renal nerves suggested that sex hormones modulate renal function, although this relationship is not well understood in the kidney. To better understand the role of these hormones on the effects that renal nerves have on Na⁺ and Cl^- reabsorption, we studied the effects of renal denervation and oophorectomy in female rats. Oophorectomized (OVX) rats received 17β-estradiol benzoate (OVE, 2.0 mg·kg^-1·day^-1, sc) and progesterone (OVP, 1.7 mg·kg^-1·day^-1, sc). We assessed Na⁺ and Cl^- fractional excretion (FE_Na⁺ and FE_Cl^-, respectively) and renal and plasma catecholamine release concentrations. FE_Na⁺, FE_Cl^-, water intake, urinary flow, and renal and plasma catecholamine release levels increased in OVX vs control rats. These effects were reversed by 17β-estradiol benzoate but not by progesterone. Renal denervation did not alter FE_Na⁺, FE_Cl^-, water intake, or urinary flow values vs controls. However, the renal catecholamine release level was decreased in the OVP (236.6±36.1 ng/g) and denervated rat groups (D: 102.1±15.7; ODE: 108.7±23.2; ODP: 101.1±22.1 ng/g). Furthermore, combining OVX + D (OD: 111.9±25.4) decreased renal catecholamine release levels compared to either treatment alone. OVE normalized and OVP reduced renal catecholamine release levels, and the effects on plasma catecholamine release levels were reversed by ODE and ODP replacement in OD. These data suggest that progesterone may influence catecholamine release levels by renal innervation and that there are complex interactions among renal nerves, estrogen, and progesterone in the modulation of renal function.     

Subacute effects of thiazide administration on renal hemodynamics and calcium metabolism

Summary To elucidate the renal effects of thiazides as a function of sodium intake, 8 healthy volunteers without renal disease were studied at baseline and 1 day as well as 4 days after the administration of 100 mg hydrochlorothiazide/day. The subjects were compared on two different dietary sodium intakes (120 mmol/day and 220 mmol/day). Measurements comprised inulin clearance (Cin) and paraaminohippurate clearance (Cpah) by infusion clearance technique, total and ionised calcium, immunoreactive parathyroid hormone (1,84 iPTH), 1.25 (OH)₂ vitamin D₃, and indices of hemoconcentration. Acute administration of hydrochlorothiazide (HCTZ) caused no change in Cin (before 111 ± 3 ml/min 1.73 m² ; 24 h after, 107 ± 2 ml/min 1.73 m²) or Cpah (before, 579 ± 9 ml/min 1.73 M²; after, 584 ± 12 ml/min 1.73 m²), while a significant (P < 0.01) decrease was noted on the 4th day after 100 mg HCTZ/day and normal sodium intake. No significant change of creatinine clearance (Ccr) was seen with either manouever. Renal hemodynamic changes after HCTZ administration were marginal when hemoconcentration was prevented by a high salt intake. Acute administration (1 h) of HCTZ caused suppression of 1,84 iPTH (before, 2.3 ±0.5 pmol/l; after, 1.9 ± 0.2 pmol/l; P < 0.01), but after 4 days a lower ionised calcium (baseline, 1.25 ± 0.01 mmol/l; day 5, 1.20 ± 0.02 mmol/l; P < 0.01) was noticed in parallel with hemoconcentration, metabolic alkalosis, and reduced 1,25 (OH)₂ vitamin D₃ concentrations. The level of 1,84 iPTH was elevated. We conclude that (i) hydrochlorothiazide does not affect the renal hemodynamics if hemoconcentration is avoided and (ii) hydrochlorothiazide acutely lowers PTH, while subacutely metabolic alkalosis and decreased ionised calcium may occur with concomitant increase in 1,84 iPTH and decrease in 1,25 (OH)₂ vitamin D₃ concentrations unless hemoconcentration is prevented.Abbreviations GFR glomerular filtration rate - PTH parathyroid hormone - iPTH immunoreactive PTH - PAH paraaminohippurate - HCTZ hydrochlorothiazide - FF filtration fraction - cAMP cyclic adenosine monophosphate - Cin inulin clearance - Cpah PAH clearance - Ccr creatinine clearance - CV coefficient of variation - HPLC high performance liquid chromatography - PRA plasma renia activity     

Binding sites of atrial natriuretic peptide in human renal tissue — Quantification by in vitro receptor autoradiography

Summary Specific binding sites for atrial natriuretic peptide (99–126) in different areas of normal human renal tissue were quantified by in vitro autoradiography. Our data represent the first characterization of ANP binding sites in different structures of the human kidney. Characterization of ANP binding revealed by Scatchard plot analysis a single class of high affinity binding sites in the glomeruli (K _d 0.53±0.11 nM;B _Max 74.4±17.86 fmol/mg protein), the vasculature (K _d 0.18±0.014 nM;B _Max 91.6±25.02 fmol/mg protein), and the medulla (K _d 0.34±0.13 nM;B _Max 106.0±30.61 fmol/mg protein). These sites may play a key role in the actions of the cardiac hormone in human kidney and in the ameliorating effects of ANP in the recovery from acute renal failure.Abbreviations ANP Atrial natriuretic peptide - cGMP Cyclic guanosine monophosphate     

Urinary sodium excretion in renal stone formers

Summary In the present investigation 238 randomly selected male individuals of the general population (age 19–41 years) and 42 age-matched male patients with recurrent renal stone formation (calcium oxalate and/or calcium phosphate) were studied under outpatient conditions without dietary restrictions. Urinary Na excretion was 207 ± 82 mmol/24 h (range 55–570) in controls and 208 ± 100 (range 76–575) in recurrent renal stone formers. Both in controls (r=0.36;p < 0.01) and in stone formers (r=0.4;p < 0.01) a significant correlation was observed between urinary excretion of sodium and calcium.Urinary sodium excretion was unrelated to systolic or diastolic blood pressure in normotensive or hypertensive individuals. This finding indicates that factors other than sodium are involved in the maintenance of hypertension. Urinary sodium, presumably an index of intake of nutrients, was significantly correlated to several coronary risk factors, e.g. fasting glucose, cholesterol and overweight. There existed a significant inverse relationship between fasting plasma phosphate and urinary sodium, but not between fasting plasma phosphate and serum iPTH or urinary cAMP. This finding points to some function of sodium excretion as one determinant of plasma phosphate.

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Abbreviations UV_Ca rate of urinary calcium excretion (mmol/24 h) - UV_Na rate of urinary sodium excretion (mmol/24 h) - TMP/GFR tubular threshold for phosphate (mg/dl) - C_Cr endogenous creatinine clearance (ml/min × 1.73 m²) - 25(OH)D serum level of 25-hydroxy-vitamin D - ECV extracellar fluid volume     

Resetting of renal autoregulation in conscious dogs: angiotensin II and alpha1-adrenoceptors

It has recently been shown, that common carotid occlusion (CCO) impairs autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR). This study was designed to investigate the mechanisms by which a moderate sympathetic stimulus influences RBF and GFR autoregulation. CCO provided a moderate sympathetic stimulus, and impaired autoregulation by increasing the lower autoregulatory limit of RBF and GFR by 21–30 mmHg. Basal RBF and GFR were not affected. A low-dose intrarenal infusion of the ₁-adrenoceptor agonist methoxamine (which did not change total RBF or GFR) induced a similar shift as CCO (n=5, RBF: +31±11 mmHg, P<0.05; GFR: +24±4 mmHg, P<0.01). In another group it was shown, that a combination of CCO with an intrarenal angiotensin II (A II) blockade (saralasin) did not significantly alter the response to CCO (n=7). These data suggest an ₁-adrenergic pathway for the sympathetic resetting of autoregulation. An augmented A II formation does not play a major role in mediating this effect.     

The effects of chronic papillary necrosis on acid excretion

Complete papillary necrosis in rats can be induced within 1 month following a single injection of 2-bromoethylamine hydrobromide (BEA) (50 mg, i.v.). Utilizing a combination of clearance and balance techniques the effects of complete absence of the papilla was examined as regards urinary acidification, whole kidney glomerular filtration rate (GFR), single nephron GFR, and morphology. Whole kidney GFR was not different from control, however, the percent filtering juxtamedullary nephrons was markedly diminished (87.2±2.1 vs. 31.5±3.6% filtering, control vs. BEA, respectively,P<0.001) and significantly reduced in the superficial nephrons (80.6±3.6 vs. 62.2±6.1% filtering, control vs. BEA, respectively,P<0.05). There was a significant decrease in juxtamedullary single nephron GFR and an increase in the superficial single nephron GFR as assessed by the quantitative Hanssen's technique in the animals with chronic papillary necrosis. Complete papillary necrosis was associated with normal arterial bicarbonate concentration, pH, and plasma electrolyte concentrations. At the same degree of acidemia (induced by NH₄Cl administration) minimal urinary pH, ammonium excretion, and titratable acid excretion were not different than seen in age matched controls. The response to Na₂SO₄ infusion and phosphate infusion was the same in both groups of animals. The urineblood (U-B)pCO₂, an index of urinary acidification, was identical in BEA and control animals. Scanning electron microscopy showed scarring of the juxtamedullary glomeruli one month after BEA. The papilla was sloughed and lying free in the renal pelvis in every experimental animal. These data demonstrate that complete papillary necrosis is not associated with acidosis nor a defect in urinary acidification.     

Increased brain natriuretic peptide and atrial natriuretic peptide plasma concentrations in dialysis-dependent chronic renal failure and in patients with elevated left ventricular filling pressure

Brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) plasma concentrations were measured in patients with dialysis-dependent chronic renal failure and in patients with coronary artery disease exhibiting normal or elevated left ventricular end-diastolic pressure (LVEDP) (n = 30 each). Blood samples were obtained from the arterial line of the arteriovenous shunt before, 2 h after the beginning of, and at the end of hemodialysis in patients with chronic renal failure. In patients with coronary artery disease arterial blood samples were collected during cardiac catheterization. BNP and ANP concentrations were determined by radioimmunoassay after Sep Pak C₁₈ extraction. BNP and ANP concentrations decreased significantly (P < 0.001) during hemodialysis (BNP: 192.1 ± 24.9, 178.6 ± 23.0, 167.2 ± 21.8 pg/ml; ANP: 240.2 ± 28.7, 166.7 ± 21.3, 133.0 ± 15.5 pg/ml). The decrease in BNP plasma concentrations, however, was less marked than that in ANP plasma levels (BNP 13.5 ± 1.8%, ANP 40.2 ± 3.5%; P < 0.001). Plasma BNP and ANP concentrations were 10.7 ± 1.0 and 60.3 ± 4. 0 pg/ml in patients with normal LVEDP and 31.7 ± 3.6 and 118.3 ± 9.4 pg/ml in patients with elevated LVEDP. These data demonstrate that BNP and ANP levels are strongly elevated in patients with dialysis-dependent chronic renal failure compared to patients with normal LVEDP (BNP 15.6-fold, ANP 2.2-fold, after hemodialysis; P < 0.001 or elevated LVEDP (BNP 6.1-fold, ANP 2.0-fold, before hemodialysis; P < 0.001), and that the elevation in BNP concentrations was more pronounced than that in ANP plasma concentrations. The present results provide support that other factors than volume overload, for example, decreased renal clearance, are also involved in the elevationin BNP and ANP plasma levels in chronic renal failure. The stronger elevation in BNP concentrations in patients with chronic renal failure and in patients with elevated LVEDP and the less pronounced decrease during hemodialysis suggest a different regulation of BNP and ANP plasma concentrations.[/ p]Abbreviations ANP atrial natriuretic peptide - BNP brain natriuretic peptide - LVEDP left ventricular end-diastolic pressure Correspondence to: C. Haug     

The effect of streptozotocin-induced diabetes mellitus on urinary excretion of sodium and renal Na+−K+-ATPase activity

Renal sodium handling and microsomal Na⁺–K⁺-ATPase activity in kidney cortex, medulla and papilla of rats with streptozotocin-induced diabetes mellitus (DM) was studied.During 7 days following the administration of streptozotocin GFR, urinary excretion, filtered load and tubular reabsorption of Na⁺ averaged (mean±SE) 1.18±0.016 ml/min, 1.74±0.14, 177.3±8.9 and 175.6±8.9 mEq/min respectively in experimental rats as compared to corresponding rates of 0.85±0.04 (P<0.001), 0.85±0.03 (P<0.001), 129.8±5.8 (P<0.001) and 129±5.8 (P<0.001) respectively in the control rats.The activity of microsomal Na–K-ATPase in the kidney cortex, medulla and papilla of the control group was (mean±SE) 44.7±1.7, 150±7.5 and 37.4±3.6 (moles Pi/mg prot/h) respectively. 24 h after DM induction Na–K-ATPase activity in the cortex rose to 59.3±2.4 (P<0.001) and remained high after 3 and 7 days. Medullary Na–K-ATPase activity was unchanged 24 h after streptozotocin administration but was markedly increased to 260±9 (P<0.001) after 3 days and remained high after 7 days.These findings show that stretozotocin-induced DM in rats causes a substantial increase in GFR which is associated with a net increase in filtered and reabsorbed load of Na⁺ and natriuresis. These alterations are accompanied by a marked increase in Na–K-ATPase activity in renal medulla and in the cortex.This study was supported by the Morton S. Kaufman Hemodialysis Foundation and by the Joint Research Fund of the Hebrew University and Hadassah     

Serum cystatin C level is a useful marker for the evaluation of renal function in patients with cirrhotic ascites and normal serum creatinine levels

Background/Aims

Several studies suggested that serum cystatin C (CysC) is more useful than serum creatinine (Cr) for the assessment of renal function in patients with liver cirrhosis. This study evaluated the clinical significance of CysC in patients with cirrhotic ascites and normal Cr level.

Methods

We enrolled patients with cirrhotic ascites and a normal serum Cr level (<1.2 mg/dL). GFR was measured by ^99mTc-DTPA renal scan. Serum Cr, CysC, and Cr clearance (CCr) were measured on the same day. Significant renal impairment and severe renal impairment were defined as GFR <60 mL/min and GFR <30 mL/min, respectively.

Results

Eighty-nine patients with cirrhotic ascites were enrolled in the study (63 men and 26 women; age, 55±11 years). Forty-seven (52.8%) and 42 (47.2%) patients were in Child-Pugh grade B and C, respectively. Serum Cr and CysC levels and GFR were 0.8±0.2 mg/dL, 1.1±0.3 mg/L, and 73.4±25.5 mL/min, respectively. Significant and severe renal impairment were noted in 28 (31.5%) and 2 (2.2%) patients, respectively. GFR was well correlated with serum Cr, CysC, and e-GFR_MDRD, while it was not correlated with e-GFR_C&G. In multivariate analysis, only CysC was significantly correlated with GFR (β, 45.620; 95% CI, 23.042-68.198; P<0.001). Serum CysC level was the only independent predictor for significant renal impairment.

Conclusions

Significant renal dysfunction was not rare in patients with cirrhotic ascites, even their serum Cr level is normal. Serum CysC is a useful marker for detecting significant renal dysfunction in these patients.     

Renal glycosuria in renal homograft recipients

Summary Transient renal glycosuria was observed in eight renal transplant patients during the recovery phase from initial tubular necrosis or acute rejection. In these subjects and three homograft recipients without glycosuria we performed glucose titration experiments. Three patients were found to have type A glycosuria, two had type B and three type C. The titration curve was normal in the three patients without glycosuria. In addition, most subjects presented with hypophosphataemia and hyperphosphaturia. Apart from a direct correlation between the point of splay of the glucose titration curves and the fractional clearance of phosphate, there was no clear-cut relationship between the handling of glucose and phosphorus. Mild hyperchloraemic acidosis was observed in six subjects, but this was unrelated to the type and grade of glycosuria. It is concluded that in homograft recipients the tubular alterations have a patchy and unpredictable distribution and may cause a variety of symptoms which do not necessarily occur in close association.Abbreviations GFR Glomerular filtration rate - C_PAH Sodium p-aminohippurate clearance - FF Filtration fraction - T_G Rate of glucose reabsorption - Tm_G Maximal rate of glucose reabsorption - C_Na Sodium clearance - P_Ca Serum calcium - P_{PO 4} Serum phosphate - C_{PO 4} Phosphate clearance - FE_{PO 4} Fractional phosphate excretion - PEI Phosphate excretion index - P_G Plasma glucose     

Renal intracortical blood flow distribution,function and sodium excretion in response to saline loading of anesthetized and unanesthetized dogs

Summary In order to study the effect of anesthesia on the canine response to saline loading, experiments were performed on 10 dogs, first while awake and then during pentobarbital anesthesia. Individual kidney function and intrarenal blood flow response to saline loading (7.5% body weight) were measured in each condition and all data are reported as the average of a single kidney. C_IN is considerably reduced under anesthesia (24.7±3.2 vs. 43.2±3.9 ml/min,P<0.01). A directionally similar reduction of PAH clearance was noted (89±17 vs. 122±13 ml/min). The natriuretic response to saline loading of the dogs reached 290±61 Eq/min while awake, but only 70±27 Eq/min while anesthetized. No measurable increase of C_IN or C_PAH occurred in response to saline loading either in the anesthetized or unanesthetized state. The natriuresis was entirely due to a rise of C_NA/GFR in both circumstances. The change of C_NA/GFR in response to saline load was also appreciably larger while awake (1.24.7% vs. 0.71.8%). Although the fraction of blood flow to the outermost quarter of the kidney was initially the same (31±3 vs. 29±3%) awake or anesthetized, the changes with saline loading were in the opposite direction and the values reached were significantly different (37±3, awake, vs. 27±3%,P<0.05). We conclude that while increased outer cortical blood flow is not necessary for natriuresis, it may occur during sodium loading and may facilitate sodium excretion.Supported by VA Program 3385-01