Renal blood flow, early distal sodium, and plasma renin concentrations during osmotic diuresis.

Inconsistencies in previous reports regarding changes in early distal NaCl concentration (ED(NaCl)) and renin secretion during osmotic diuresis motivated our reinvestigation. After intravenous infusion of 10% mannitol, ED(NaCl) fell from 42.6 to 34.2 mM. Proximal tubular pressure increased by 12.6 mmHg. Urine flow increased 10-fold, and sodium excretion increased by 177%. Plasma renin concentration (PRC) increased by 58%. Renal blood flow and glomerular filtration rate decreased, however end-proximal flow remained unchanged. After a similar volume of hypotonic glucose (152 mM), ED(NaCl) increased by 3.6 mM, (P < 0.01) without changes in renal hemodynamics, urine flow, sodium excretion rate, or PRC. Infusion of 300 micromol NaCl in a smaller volume caused ED(NaCl) to increase by 6.4 mM without significant changes in PRC. Urine flow and sodium excretion increased significantly. There was a significant inverse relationship between superficial nephron ED(NaCl) and PRC. We conclude that ED(Na) decreases during osmotic diuresis, suggesting that the increase in PRC was mediated by the macula densa. The results suggest that the natriuresis during osmotic diuresis is a result of impaired sodium reabsorption in distal tubules and collecting ducts.

Role of the renin-angiotensin system in regulation and autoregulation of renal blood flow.

The role for ANG II in renal blood flow (RBF) autoregulation is unsettled. The present study was designed to test the effect of clamping plasma ANG II concentrations ([ANG II]) by simultaneous infusion of the angiotensin-converting enzyme inhibitor captopril and ANG II on RBF autoregulation in halothane-anesthetized Sprague-Dawley rats. Autoregulation was defined as the RBF response to acute changes in renal perfusion pressure (RPP). Regulation was defined as changes in RBF during long-lasting changes in RPP. The results showed that a prolonged reduction of RPP reset the lower limit of autoregulation from 85 +/- 1 to 73 +/- 2 mmHg (P < 0.05) and regulated RBF to a lower level. Reduction of RPP to just above the lower limit of autoregulation (88 mmHg) induced regulation of RBF to a lower level within 10 min. Clamping [ANG II] per se reset the lower limit of autoregulation to 62 +/- 5 mmHg. In this case, reduction in RPP to 50 mmHg did not induce a downregulation of RBF. We conclude that ANG II plays an important role in the resetting of the autoregulation limits. The ability to regulate RBF to a new level as a response to changes in RPP also depends on changes in [ANG II].

Glomerular and tubular function in renal transplant patients treated with and without ciclosporin A.

The present study evaluated whether chronically administered low-dose (<5 mg/kg) ciclosporin A (CsA) affects renal haemodynamics and tubular function in renal transplant recipients (RTx) when studied at nadir CsA blood levels. The renal clearance of lithium was used as an index of proximal tubular outflow of sodium and water. Effective renal plasma flow, glomerular filtration rate, and renal clearance of lithium were studied in 67 stable non-diabetic RTx and 44 healthy controls. Forty-eight of the RTx were treated with CsA, prednisone, and azathioprine. Nineteen were treated exclusively with prednisone and azathioprine. In RTx with a good graft function (serum-creatinine <125 micromol/l), no specific CsA-induced renal haemodynamic and tubular dysfunctions were evident. In CsA-treated RTx with a slightly reduced renal function (serum creatinine 125-180 micromol/l) a decrease in fractional proximal tubular reabsorption was found. The renal clearances of urate and magnesium were comparable between RTx treated with or without CsA, and a significant correlation between glomerular filtration rate and renal clearance of urate was found. CsA-treated RTx had a significantly higher blood pressure, independent of glomerular filtration rate and segmental tubular function. In conclusion, at nadir CsA blood levels, no specific CsA-induced tubular dysfunction evaluated by the renal lithium clearance method could be demonstrated in RTx receiving chronically low-dose CsA. The hyperuricaemia commonly seen in RTx seems to be mainly caused by the reduced glomerular filtration rate.

Proximal tubular function in adult rats treated neonatally with enalapril.

Neonatal treatment with angiotensin-converting enzyme (ACE) inhibitors or the angiotensin II type-1 receptor antagonist losartan in rats induces irreversible renal histological abnormalities, mainly papillary atrophy, in association with an impairment in urinary concentrating ability. The aim of the present study was to assess proximal tubular function in adult rats treated neonatally with enalapril. Male Wistar rats received daily, intraperitoneal injections of either enalapril (10 mg kg-1) or isotonic saline vehicle from 3 to 24 days of age. In 15-week-old, hydropenic rats we analysed: (i) proximal tubular iso-osmotic fluid reabsorption using the method of lithium clearance; and (ii) maximal tubular D-glucose reabsorption (TmG), under pentobarbital anaesthesia. The main findings were that neonatally enalapril-treated rats showed: (i) reductions in absolute (APRH2O) and fractional (FPRH2O) iso-osmotic fluid reabsorption in the proximal tubules (APRH2O: 0.50 +/- 0.02 vs. 0.64 +/- 0.03 mL min-1 g KW-1, P < 0.05; FPRH2O: 58 +/- 3 vs. 68 +/- 2%, P < 0.05); and (ii) a normal TmG. In addition, during baseline clearance measurements neonatally enalapril-treated rats showed increases in urine volume and fractional excretion rates of sodium and potassium, a reduction in urine osmolality, whereas glomerular filtration rate and effective renal plasma flow were unaltered. These results suggest that neonatal ACE inhibition produces an irreversible, but differentiated, abnormality in proximal tubular function. Thus, the development of a normal proximal tubular function in the rat seems to be dependent on an intact renin-angiotensin system, (RAS) neonatally.

Urinary excretion of Tamm-Horsfall protein and epidermal growth factor in chronic nephropathy.

Tamm-Horsfall protein (THP) and epidermal growth factor (EGF) are both synthesized by tubular cells in the distal part of the nephron and excreted with the urine. The present study examines the urinary excretion rates of the two peptides in relation to functional tubular markers in patients with chronic nephropathy. Four groups of patients with moderate to severely reduced renal function were studied: glomerulonephritis (n = 10), diabetic nephropathy (n = 11), tubulointerstitial nephropathy (n = 13), and polycystic kidney disease (n = 8). The renal function was evaluated by glomerular filtration rate (GFR) as an indicator for the general renal function, lithium clearance (C(Li)) as an indicator for proximal tubular function, and absolute distal reabsorption of sodium (ADR(Na)) as an indicator for distal tubular function. The excretion rate of EGF was rather closely correlated with GFR, C(Li) and ADR(Na) (Spearman coefficients of variation 0.88, 0.69, and 0.74, respectively). The correlations between the excretion rate of THP and GFR, C(Li) and ADR(Na) were weaker (Spearman coefficients of variation 0.68, 0.42, and 0.44). When the effect of GFR had been accounted for by multiple variance analyses, the excretion rates of the two peptides were still associated with ADR(Na) but not with C(Li). In conclusion, the urinary excretion rates of especially EGF but also those of THP were correlated with renal function and distal tubular reabsorption of sodium in patients with chronic nephropathy.

Renal haemodynamics, sodium and water reabsorption during continuous intravenous infusion of recombinant interleukin-2.

1. Renal haemodynamics, lithium and sodium clearance were measured in 14 patients treated with recombinant interleukin-2 for metastatic renal cell carcinoma. 2. Patients were studied before and after 72 h of continuous intravenous infusion of recombinant interleukin-2 (18x10(6) i.u..24 h-1.m-2) and 48 h post therapy. Cardiac output was measured by impedance cardiography. Effective renal plasma flow and glomerular filtration rate were determined by the renal clearances of 131I-hippuran and 99mTc-diethylenetriaminepenta-acetic acid (DTPA) respectively. Renal clearance of lithium (CLi) was used as an index of proximal tubular outflow. 3. Treatment caused a transient decrease in mean arterial blood pressure and systemic vascular resistance, but cardiac output remained unchanged. Renal blood flow decreased and renal vascular resistance increased during and after treatment. Sodium clearance decreased from 1.10 (0.63/1.19) ml/min to 0.17 (0.18/0.32) ml/min (P=0.003). Glomerular filtration rate remained unchanged, whereas the median CLi decreased from 26 (17/32) ml/min to 17 (10/21) ml/min (P=0.008). Calculated absolute proximal reabsorption rate of water increased from 63 (40/69) ml/min to 71 (47/82) ml/min (P=0.04). The urinary excretion rate of thromboxane B2 and the ratio between excretion rates of thromboxane B2 and 6-keto-prostaglandin-F1alpha increased by 98% (P=0.022) and 175% (P=0.022) respectively. 4. The study suggests a specific recombinant interleukin-2-induced renal vasoconstrictor effect. Changes in renal prostaglandin synthesis may contribute to the decrease in renal blood flow. The lithium clearance data suggest that an increased proximal tubular reabsorption rate may contribute to the decreased sodium clearance during recombinant interleukin-2 treatment.

Tubuloglomerular feedback in Dahl rats.

We have previously demonstrated a loss of autoregulation in Dahl salt-sensitive (Dahl-S) rats rendered hypertensive on a high-salt diet. To determine whether this was due to a decreased activity of either the myogenic or the tubuloglomerular feedback (TGF) response, we tested the TGF response in both Dahl-S and salt-resistant Dahl rats on high- and low-salt diets. TGF was investigated in the closed-loop mode with a videometric technique, in which the response in late proximal flow rate to perturbations in Henle flow rate was measured. All Dahl rats showed a similar compensatory response to perturbations around the natural operating point, with a TGF response that was more efficient than in normotensive Sprague-Dawley rats. No evidence of decreased TGF responsiveness in hypertensive Dahl-S rats was found. The results suggest that the loss of autoregulation in hypertensive Dahl-S rats is due to a compromised myogenic response. We also measured the free-flow proximal intratubular pressure in Dahl rats. Perfectly regular oscillations were demonstrated in all Dahl series, including the hypertensive Dahl-S rats. This is the first demonstration of regular oscillations in an experimental rat model of hypertension.

Dynamic autoregulation and renal injury in Dahl rats.

The Dahl salt-sensitive (Dahl S) rat develops hypertension and renal injuries when challenged with a high salt diet and has been considered to be a model of chronic renal failure. Renal injuries appear very early in life compared with the spontaneously hypertensive rat (SHR). During the course of hypertension, a gradual impairment of autoregulatory control of renal blood flow might expose the glomerular circulation to periods of elevated pressure, resulting in renal injuries in Dahl S rats. Dynamic autoregulatory capacity was assessed in Dahl S and Dahl salt-resistant (Dahl R) rats, SHR, and Sprague-Dawley rats by inducing broad-band fluctuations in the arterial blood pressure and simultaneously measuring renal blood flow. Dynamic autoregulation was estimated by the transfer function using blood pressure as the input and renal blood flow as the output. Renal morphological injuries were evaluated in Dahl S rats and SHR and were scored semiquantitatively. Dynamic autoregulation was efficient and comparable in the low-frequency range (<0.015 Hz) in Dahl R rats, SHR, and Sprague-Dawley rats. The response in Dahl S rats depended strongly on the initiation time of the high salt diet. Autoregulation was preserved during a low salt diet and in rats exposed to a late-onset hypertension of short duration, only partly preserved if the late-onset hypertension was of a longer duration, and abolished in early-onset hypertension. All Dahl S rats on a high salt diet showed severe morphological changes in the kidney. In conclusion, autoregulatory capacity in the kidney of Dahl S rats is gradually impaired when rats are rendered hypertensive with a high salt diet. Renal morphological injuries develop before loss of dynamic autoregulation. Impaired autoregulation appears to be the result, not the cause, of the process that ultimately leads to renal failure in the Dahl S rat.

Effect of angiotensin II receptor blockade on proximal tubular fluid reabsorption.

The effect of physiological concentrations of angiotensin II on proximal tubular fluid reabsorption remains controversial. To investigate the effect of blockade of intratubular AT1 receptors on tubular reabsorption, losartan (10(-5) M) was administered by microperfusion into an early proximal convolution of halothane-anesthetized Sprague-Dawley rats. Four parameters that depend on the rate of proximal fluid reabsorption were measured: proximal intratubular pressure (Pprox), early and late proximal flow rate, and early distal NaCl concentration. Pprox decreased by 0.5 +/- 0.1 mmHg, late proximal flow rate decreased by 2.0 +/- 0.8 nl/min, and early distal NaCl concentration decreased by 4.3 +/- 0.8 mM (mean +/- SE). No changes were observed after microperfusion with saline. Because the tubuloglomerular feedback mechanism was operating in the closed-loop mode, the decreased NaCl load to the macula densa will be compensated by an increase in the single-nephron glomerular filtration rate. In agreement with this, the early proximal flow rate, measured proximal to the site of losartan administration, increased by 5.7 +/- 1.3 nl/min. The increase in the rate of proximal reabsorption between the early and late proximal convolutions was estimated to be 7.8 nl/min (approximately 36%). It is concluded that a decrease in local luminal angiotensin II levels and/or AT1 receptor activity under free flow conditions increases the rate of proximal tubular fluid reabsorption.

Dopamine natriuresis in salt-repleted, water-loaded humans: a dose-response study.

AIMS: The purpose of the present study was to define the dose-response relationship between exogenous dopamine and systemic haemodynamics, renal haemodynamics, and renal excretory function at infusion rates in the range 0 to 12.5 microg kg(-1) min(-1) in normal volunteers. METHODS: While undergoing water diuresis, eight subjects were infused with 0, 1, 2, 3, 5, 7.5, 10 or 12.5 microg of dopamine kg(-1) min(-1) over 2 h in a randomized and double-blind fashion. On each study day, renal clearance studies were performed during a 1 h baseline period and subsequently during the second 1 h infusion period. Lithium clearance (CL(Li)) was used to estimate proximal tubular outflow. RESULTS: Cardiac output increased with the four highest doses. Mean arterial pressure followed a biphasic pattern with a decrease during the two lowest doses and a dose-dependent increase from the 7.5 microg kg(-1) min(-1) dose onwards. Effective renal plasma flow increased with all doses of dopamine, but peaked with the 3 microg kg(-1) min(-1) infusion rate [from 617 (585-649) ml min(-1) with placebo to 915 (824-1006) ml min(-1) (means with 95% CI, P<0.001)]. None of the doses changed glomerular filtration rate (GFR). Sodium clearance (CL(Na)) and CL(Li) were elevated with the four lowest doses but increased further from 7.5 microg kg(-1) min(-1) onwards. Compared with placebo, the percentage increase in CL(Na) with increasing dose was 77 (5-159), 93 (13-172), 107 (24-190), 121 (60-181), 253 (65-441), 284 (74-494), and 212 (111-312) %, respectively. There were only small, inconsistent decreases in absolute proximal reabsorption rate (APR = GFR-CL(Li)). Fractional distal reabsorption of sodium (FDR(Na) = (CL(Li)-CL(Na))/CL(Li)) decreased with all doses, reaching its nadir with 7.5 microg kg(-1) min(-1) [from 95.9 (94.6-97.2) % with placebo to 91.5 (90.0-93.0) % (P<0.01)] whereafter a flat dose-response curve was observed. CONCLUSIONS: In conclusion, the renal vasodilating effect of dopamine was maximal with 3 microg kg(-1) min(-1). The dose-dependent attenuation seen with higher doses is consistent with an increased alpha-adrenergic stimulation opposing the effect on dopaminergic receptors. The present CL(Li) studies confirm that dopamine increases proximal tubular outflow. The results suggest that the natriuretic effect of depressor doses of dopamine was primarily caused by attenuation of the increase in distal sodium reabsorption normally seen after an increase in proximal tubular outflow. Pressor doses further increased sodium excretion, indicating the presence of pressure natriuresis at these high doses.

The influence of angiotensin-converting enzyme inhibition on renal tubular function in progressive chronic nephropathy.

The influence of angiotensin-converting enzyme (ACE) inhibition on renal tubular function in progressive chronic nephropathy was investigated in 69 patients by the lithium clearance (C(Li)) method. Studies were done repeatedly for up to 2 years during a controlled trial on the effect of enalapril on progression of renal failure. The pattern of proteinuria was followed over the first 9 months. At baseline, the glomerular filtration rate (GFR) was 5 to 68 mL/min. Absolute proximal tubular reabsorption rate of fluid (APR), estimated as the difference between GFR and C(Li), was 1 to 54 mL/min. Calculated fractional proximal reabsorption (FPR) was moderately subnormal. During the study, GFR decreased and sodium clearance was unchanged; fractional excretion of sodium therefore increased. In the group of patients randomized to treatment with enalapril (n = 34), GFR at 1 month was 83% (P < 0.001) and C(Li) was 88% (P < 0.01) of the baseline values, APR and FPR had not changed significantly, and potassium clearance was significantly decreased. Through the rest of the study period, APR remained nearly unchanged and FPR even increased in the enalapril group. In the group of patients randomized to treatment with conventional antihypertensive drugs (n = 35), C(Li) was unchanged until severe reduction in GFR, APR and FPR decreased gradually, and potassium clearance was almost unchanged. These differences in tubular function between the two treatment regimens were significant (P < 0.05). An unchanged or increased APR in either treatment regimen was associated with a long-term slower progression of renal failure. Over 9 months, the 24-hour fractional clearance of albumin decreased in the ACE inhibitor group (P < 0.01), whereas the clearances of immunoglobulin G and retinol-binding protein were unchanged in this group. In the conventional group, the fractional clearances of these three plasma proteins all increased. It is concluded that in progressive chronic nephropathy ACE-inhibitor treatment was associated with different adaptive tubular changes in the handling of sodium, water, and protein compared with conventional antihypertensive therapy. During ACE inhibition, the reabsorptive capacity of the proximal tubule appeared to be better preserved, which might be of importance for the beneficial effect of this treatment in chronic renal disease.

Renal effects of amino acids and dopamine in renal transplant recipients treated with or without cyclosporin A.

1. The nephrotoxic effects of cyclosporin A may diminish the ability of the transplanted kidney to increase the glomerular filtration rate and effective renal plasma flow during infusion of dopamine or amino acids. 2. The present study included 16 renal transplant recipients transplanted for more than 6 months. Eight of the patients were on immunosuppressive treatment including cyclosporin A [cyclosporin A group; cyclosporin A dose, 2.7 +/- 0.4 mg/kg; S-creatinine, 105 +/- 12 mumol/l (means +/- SEM)], whereas eight patients had never received cyclosporin A (non-cyclosporin A group; S-creatinine, 89 +/- 6 mumol/l). The renal response to infusion of dopamine and of amino acids was investigated on two separate days. All clearance measurements were carried out at nadir cyclosporin A blood levels. 3. Effective renal plasma flow increased significantly in the non-cyclosporin A group and cyclosporin A group by 31.0 +/- 4.1% and 35.9 +/- 6.6%, respectively, during infusion of dopamine, and by 18.7 +/- 6.7% and 13.9 +/- 5.3%, respectively, during infusion of amino acids. Glomerular filtration rate increased significantly in the non-cyclosporin A group and cyclosporin A group by 15.7 +/- 3.3% and 18.3 +/- 4.7%, respectively, during infusion of dopamine, and by 18.9 +/- 4.5% and 15.0 +/- 3.7%, respectively, during infusion of amino acids. 4. Furthermore, the amino acid- and dopamine-induced increases in proximal tubular outflow (renal clearance of lithium) and calculated changes in renal proximal and distal tubular handling of sodium (and water) were comparable between the two groups of patients. Dopamine caused significant natriuresis in both groups. 5. In conclusion, low-dose cyclosporin A seems not to attenuate the renal haemodynamic and tubular response to infusions of amino acids and of dopamine in renal transplant recipients with a good graft function.

Endogenous versus exogenous lithium clearance for evaluation of dopamine-induced changes in renal tubular function.

1. The present randomized, double-blind cross-over study compared endogenous and exogenous lithium clearance (CLi) for estimation of the effect of dopamine on tubular sodium reabsorption. Twelve normal, salt-repleted male subjects were investigated on three different occasions with either placebo or 450 mg or 600 mg of lithium given in random order at 22.00 hours. After an overnight fast, renal clearance studies were performed during a 1 h baseline period and subsequently during the second hour of an infusion of 3 micrograms min-1 kg-1 of dopamine. 2. Baseline values of endogenous CLi and fractional excretion of lithium (FELi) [27.0 (23.5-30.5) ml/min and 24.2 (20.3-28.2)% (means with 95% confidence interval)] were lower than exogenous values [lithium, 450 mg: 32.7 (29.9-35.4) ml/min (P < 0.05) and 27.4 (25.2-29.6)% (P < 0.05); lithium, 600 mg: 33.4 (29.2-37.6)ml/min (P < 0.05) and 28.6 (26.3-31.0)% (P < 0.01)]. Both test doses of lithium increased the baseline sodium clearance (CNa), but glomerular filtration rate and urine flow rate remained unchanged. 3. Dopamine increased CNa to similar values on the three study days. CLi increased to 40.9 (35.5-46.5) ml/min (endogenous lithium, P < 0.001), 43.2 (40.8-45.6) ml/min (450 mg of lithium, P < 0.01) and 44.9 (41.3-48.4) ml/min (600 mg of lithium, P < 0.001), respectively. FELi increased to 32.2 (27.5-37.0)% (P < 0.01), 35.4 (33.0-37.7)% (P < 0.01) and 35.9 (32.8-38.9)% (P < 0.01), respectively. Values during dopamine infusion did not differ significantly. 4. The lower baseline values of endogenous CLi and FELi compared with exogenous values suggest that CLi in humans depends on the plasma concentrations of lithium. However, the effect of dopamine on CLi and FELi was expressed to the same extent with endogenous and exogenous lithium, indicating that the two methods are interchangeable for estimation of dopamine-induced changes in tubular function.

Proximal tubular lithium/plasma concentration ratio depends on tubular fluid flow rate.

Previous studies have given slightly different values of proximal tubular fluid/plasma lithium concentration ratios (TF/P)Li. The aim of the present study was to investigate whether the technique of tubular fluid collection by micropuncture might contribute to this difference. Early distal and late proximal tubular fluid was collected by micropuncture during recording of early proximal hydrostatic pressure with varying pressures applied to the collection pipette. Distal fluid collection with 2-3 mmHg suction was unable to influence distal flow, proximal tubular pressure, nephron filtration rate (SNGFR), (TF/P)Li or (TF/P)Na significantly, as compared with values obtained without suction. In contrast, during late proximal collections, tubular pressure could be controlled. Within the range 2 mmHg below to 6 mmHg above free flow pressure maintained during collection, proximal flow rate varied from 9 to 44 nL min-1. (TF/P)Li was positively and significantly correlated to late proximal flow rate (P < 0.005, r = 0.65), independent of tubular pressure. (TF/P)Na was 1.03 and independent of flow rate and pressure. With collection adjusted to a late proximal flow of 24 nL min-1. (TF/P)Li would be about 1.15. At the more physiological flow rate of 12-14 nL min-1, (TF/P)Li was not significantly different from 1.00. It is concluded that proximal Li transport is distinct from Na transport and lags behind Na and water transfer only when flow rate is increased above normal. The result emphasizes the importance of the micropuncture fluid collection technique for estimates of proximal (TF/P)Li.

A re-evaluation of the determinants of glomerular filtration rate.

Several factors are potentially able to change the glomerular filtration rate (GFR) and thereby participate in its regulation, but only a few factors seem to be physiologically important. The variable nature of proximal tubular pressure should be recognized as important in the regulation of GFR. It is argued that a distinction should be made between the terms 'autoregulation of GFR' and 'regulation of GFR'. The tubuloglomerular feedback mechanism (TGF) is an important factor for autoregulatory control of GFR. When perturbations result in major increases in tubular flow, the TGF saturates. Proximal tubular pressure then increases and becomes the major factor responsible for the stabilization of GFR. Changes in the proximal reabsorption rate (APR) are important for long-term variations in GFR (regulation of GFR). Small changes in the APR cause near parallel changes in the GFR mainly through the TGF mechanism, while larger changes in the APR cause near parallel changes in the GFR mainly because of the effect on tubular pressure. The hydraulic resistance in the distal nephron segments is an additional factor in regulating GFR, through its effect on proximal tubular pressure. The stimulus to the TGF mechanism also depresses renin release. The resulting local angiotensin II concentration has effects both on the arteriolar resistances and on the APR. The renin-angiotensin system and TGF are therefore considered to be integrated parts of a common control system regulating GFR. According to the hypothesis advocated here, TGF-mediated changes in afferent arteriolar resistance and angiotensin-mediated changes in efferent arteriolar resistance and APR cooperate in counteracting perturbations in proximal tubular pressure and Henle loop flow. However, because of the biphasic proximal effect of angiotensin II, a major unresolved question is whether physiological increases in endogenous local angiotensin II concentrations stimulate or inhibit proximal reabsorption.

[51Cr]EDTA for measuring total and single nephron glomerular filtration rate in the rat.

Clearance and micropuncture experiments were performed in halothane anaesthetized rats. The aim was a comparison of paired estimates of glomerular filtration rate (GFR) from the renal clearance of [51Cr]EDTA (C[51Cr]EDTA) with simultaneous estimates of polyfructosan ((Inutest) CIn), 3H,-and 14C-labelled inulin clearance (C[3H]In and C[14C]In, respectively) and proximal tubular fluid/plasma concentration ratios (TF/P) of [51Cr]EDTA and TF/P ratios of 14C-labelled inulin measured in the same samples. C[51Cr]EDTA correlated well with, but underestimated CIn by approximately 10%. The correlation coefficient (r) was 0.92. C[51Cr]EDTA also correlated with, and underestimated C[14C]In by 6%, r = 0.88, whereas it overestimated C[3H]In by 5%, still with a close correlation (r = 0.92). Paired data on proximal (TF/P) ratios of [51Cr]EDTA and [14C]inulin were collected from early, mid and late proximal convolutions. The data were scattered around the line of identity, r = 0.91. It is concluded that [51Cr]EDTA is a valid alternative for estimates of total renal and single nephron GFR in rats and has the advantage of being less expensive than [14C]inulin.

Nephrotoxicity of FK-506 in the rat. Studies on glomerular and tubular function, and on the relationship between efficacy and toxicity.

Recent studies in liver and kidney transplant recipients revealed a nephrotoxic adverse effect of the new macrolide immunosuppressant FK-506. Therefore the effect of FK-506 0.1 to 0.8 mg per kg per day was investigated in rats using clearance methods including lithium clearance. In rats given FK-506 or placebo during 1 week the nephrotoxicity of FK-506 was characterized by a slight reduction of inulin clearance. The end proximal delivery as measured by the lithium clearance was decreased by FK-506. In rats treated for 4 weeks with FK-506 0.8 mg/kg/day the glomerular filtration rate (GFR) had decreased to 23% of the GFR found in controls (P < 0.001), while end proximal delivery was only 8% of normal. Renal histopathological investigation showed a slight but statistically significant increase of tubular basophilia and atrophy in FK-506-treated rats. Skin transplantation studies in the same rat strain showed a dose-dependent immunosuppressive effect of FK-506. FK-506 0.8 mg/kg was significantly more immunosuppressive than 0.2 or 0.4 mg/kg, so it was concluded that the lower doses of FK-506 did not fully exploit the drug's immunosuppressive potential. Thus in a dosage inside the therapeutic range defined from skin transplantations, FK-506 generated a number of toxic effects including a considerable nephrotoxic effect. The FK-506 induced changes in glomerular and tubular function was a close match to the changes found in cyclosporin A nephrotoxicity. The present study suggests that FK-506 nephrotoxicity is caused by constriction of preglomerular vessels.

Late outcome of a controlled trial of enalapril treatment in progressive chronic renal failure. Hard end-points and influence of proteinuria.

An earlier controlled trial showed that over an average of 26 months, enalapril slowed the progression of chronic renal failure. Following completion of the trial, the patients continued to receive antihypertensive treatment according to ordinary clinical criteria. All but four patients in the enalapril group remained on that drug, and two patients in the control group were switched to an angiotensin-converting enzyme (ACE) inhibitor. In the present study the fate of the 70 patients 44 months after termination of the trial was investigated, with a total follow-up of around 7 years. In the original enalapril group, 12 of the 35 patients (34%) were alive without renal replacement therapy versus five of the 35 patients (14%) in the control group. This difference of 20% in favour of having been in the enalapril group in the original trial was significant (P = 0.05; 95% confidence limits 0.5-39.5%). The influence of baseline proteinuria on clinical outcome was analysed. In the original control group, baseline renal clearances of albumin (Calb) and immunoglobulin G (CIgG) were significantly lower in patients surviving without renal replacement therapy at follow-up than in patients who ultimately developed end-stage renal failure (ESRF) (P < 0.05). In the original enalapril group, these baseline clearances were equal in the two renal outcome groups. In all patients, baseline Calb and CIgG were negatively correlated with the rate of change in GFR during the controlled trial (r = -0.37, P < 0.01 and r = -0.28, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)