Paul P. Leyssac

Renal tubular function in patients treated with high‐dose cisplatin

The effect of three cycles of high‐dose cisplatin (40 mg/m2 day for 5 days) on renal tubular function was evaluated in 30 patients. A significant impairment of proximal tubular salt and water reabsorption rates was observed, but also distal tubular function seemed to be affected. These changes were also present 6 months after termination of treatment. Sodium and magnesium clearance increased significantly during treatment. Magnesium clearance normalized shortly after treatment but sodium clearance was significantly elevated 6 months after treatment. Proteinuria, albuminuria, and amino aciduria, together with an increase of β2‐microglobulin and N‐acetyl‐β‐D‐glucosaminidase (NAG) excretion rates, were observed during each treatment cycle. A good correlation was registered between the increase in urinary excretion rates of protein, NAG, and magnesium and the decrease in proximal tubular salt and water reabsorption during cisplatin administration.

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.

Dopamine, Dobutamine, and Dopexamine A Comparison of Renal Effects in Unanesthetized Human Volunteers

BackgroundRecently, dopexamine(DX), which acts via adrenergic (β2and dopaminergic DA1 receptors, has been introduced in the treatment of low cardiac output states. However, the renal effects of DX have not been compared to those produced by equipotent inotropic doses of dopamine (DA), which predominantly stimulates DA1 and DA2 receptors, and of do-butamine (DB), which stimulates β, but not DA receptors. The current study tested the null hypothesis that, with equal increases in cardiac output, DX, DA, and DB would have similar effects on renal function. MethodsEach drug was given for 2 h on three different occasions to eight normal subjects in doses adjusted to produce a similar 30–35% Increase in cardiac output. Effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were measured as renal clearances of l31I-hippuran and 99mTc-DTPA, respectively. Lithium clearance (CLI) was used as an Index of proximal tubular outflow. ResultsDoses of DA, DX, and DB were 2.90 ± 0.19, 1–00 ± 0.02, and 4.92 ± 0.40 μg · kg−1 · min−1 respectively. Dopamine and DX increased ERPF by 23% and 10%, respectively, whereas ERPF remained unchanged during DB. The Increase in ERPF was smaller during DX compared with DA. The GFR remained unchanged during DA and DB, but increased during DX (7%). The CLi Increased by 35% and 30% during DA and DX, respectively, but was not changed by DB. Calculated absolute proximal reabsorption rate (APR = GFR – CLi) decreased by 13% during DA, but remained unchanged during DB and DX. Dopamine Increased sodium clearance (CNa) by 103%, but the changes during DX and DB were not significant. Only DA decreased fractional distal reabsorption (FDRNa = 1 – CNa/CLi). ConclusionsThe findings are consistent with a specific, renal-vasodilating effect of DA and DX. However, in the current doses, this effect of DX was of lesser magnitude compared with that of DA. Only DA significantly Increased CNa, and the decreases In APR and FDRNa indicate that an effect on tubular reabsorption rate contributed to the natriuresis.

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 (CLi) as an indicator for proximal tubular function, and absolute distal reabsorption of sodium (ADRNa) as an indicator for distal tubular function. The excretion rate of EGF was rather closely correlated with GFR, CLi and ADRNa (Spearman coefficients of variation 0.88, 0.69, and 0.74, respectively). The correlations between the excretion rate of THP and GFR, CLi and ADRNa 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 ADRNa but not with CLi. 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.

Functional and histopathological changes in dog kidneys after administration of cisplatin.

The nephrotoxic effect of cisplatin (5 mg/kg i.v.) was evaluated in 8 dogs 48-72 h after administration. The lithium clearance method was used for assessing the absolute and fractional reabsorption rates of sodium and water in proximal as well as in more distal segments of the total nephron population, before and during saline loading (infusion of 5 ml/kg of isotonic saline i.v.). Histological examinations of the kidney biopsies were used to evaluate the degree of renal tissue injury. During 48-72 h after administration of cisplatin blood urea nitrogen and plasma creatinine increased significantly from 3.9 +/- 0.2 to 11.7 +/- 1.4 mmol/l and 96 +/- 3 to 178 +/- 10 mumol/l, respectively. Mean values of renal blood flow, glomerular filtration rate, filtration fraction and lithium clearance in cisplatin-treated animals (143 +/- 14 ml/min, 10.7 +/- 1.1. ml/min, 0.14 +/- 0.01 and 6.3 +/- 0.6 ml/min, respectively) were significantly lower than in 6 control animals (212 +/- 8 ml/min, 49.0 +/- 2.0 ml/min, 0.36 +/- 0.001 and 10.1 +/- 1.3 ml/min, respectively). In contrast, urinary excretion rates of sodium, potassium and water were significantly higher, while fractional as well as absolute proximal and distal reabsorption rates were significantly lower in cisplatin-treated animals compared to controls. Saline loading caused an increase in the output of tubular fluid from the proximal tubules (lithium clearance) in the cisplatin-treated animals, while the fractional distal reabsorption rate of sodium decreased significantly. The histological changes are in agreement with the physiological data which point to the proximal tubules as the more severely damaged segment. In conclusion, the depressed renal function 48-72 h after administration of cisplatin can be attributed to impairment of proximal as well as distal tubular reabsorptive capacities associated with increased renal vascular resistance. The polyuria seems to be due to impaired reabsorption rates in the distal nephron segments, which will affect the concentration mechanism.

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 µmol/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 µmol/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.

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.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.

Acute Effect of Cisplatin on Renal Hemodynamics and Tubular Function in Dog Kidneys

The present study was designed to investigate the early hemodynamic and tubular effects of cisplatin administration on dogs. To localize the nephrotoxic actions of cisplatin, we have taken advantage of the lithium clearance method. After infusion of 5 mg of cisplatin per kg, an immediate and significant increase in urinary flow rate (from 0.39 +/- 0.07 ml/min to 0.73 +/- 0.12 ml/min), sodium clearance (from 0.33 +/- 0.11 ml/min to 0.65 +/- 0.14 ml/min), potassium clearance (from 9.23 +/- 0.48 ml/min to 10.77 +/- 0.95 ml/min), lithium clearance (from 15.55 +/- 2.21 ml/min to 23.76 +/- 4.00 ml/min) and fractional lithium clearance (from 0.31 +/- 0.03 to 0.44 +/- 0.04) was seen. This occurred without measurable changes in glomerular filtration rate and renal blood flow. The calculated fractional as well as absolute rates of proximal reabsorption of sodium decreased significantly from 0.68 +/- 0.03 to 0.56 +/- 0.04 and from 4.76 +/- 0.32 mmol/min to 3.92 +/- 0.23 mmol/min, respectively. The results show that administration of cisplatin causes an acute, mainly proximal tubular impairment in dogs without alterations in renal hemodynamics.

Effect of dietary sodium content on renal handling of lithium

Previous studies have shown that the clearance of lithium (CLi) is a quantitative measure of the delivery of tubular fluid to Henles loop in rats given food with an ordinary or high sodium content but not in rats given food with a low sodium content, because under these circumstances lithium is also reabsorbed to some extent in the distal nephron segment. The present study examines CLi, CNa and urine flow in diabetes insipidus rats at various dietary sodium contents. The results showed that CLi was 120 μl/min/100 g b.w. when no distal reabsorption took place at a dietary sodium content of 300 mmol/kg. At a dietary sodium content of 5 mmol/kg the calculated distal lithium reabsorption reduced CLi by 55 μl/min/100 g b.w.; at 25 mmol/kg distal reabsorption was reduced to half this value; at 50 mmol/kg distal reabsorption was slight and barely significant, and at 75–300 mmol/kg there was no distal reabsorption of lithium. It is concluded that CLi can be used as a quantitative measure of the delivery of tubular fluid to the loop of Henle at dietary sodium contents higher than 50–75 mmol/kg in the rat.

Effects of acute volume loading on kidney function in patients with essential hypertension, as estimated by the lithium clearance method.

This study investigated the mechanism underlying the exaggerated natriuresis seen in patients with essential hypertension. The study used the lithium clearance method, which permits accurate determination of both proximal and distal sodium reabsorption in man. One litre of isotonic sodium chloride, intravenously (i.v.), produced a significant increase in sodium excretion in patients with essential hypertension, both during and after the infusion. This increase in sodium excretion was accompanied by a significant increase in the clearance of lithium, indicating an increased output of isotonic fluid from the proximal tubules. The calculated distal reabsorption of sodium increased during the natriuresis. In the normotensive controls, sodium excretion increased only after the infusion of 1 l isotonic saline. This was accompanied by a modest increase in absolute distal sodium reabsorption. However, when the amount of saline was increased to 2 l, similar changes to those seen in hypertensives given 1 l of saline occurred in normotensive subjects. Furthermore, chronic antihypertensive treatment abolished the phenomenon of exaggerated natriuresis. It is concluded that the exaggerated natriuresis represents the normal response to sodium loading being reset to a lower level. This resetting may be a secondary consequence of the high blood pressure, since lowering the pressure abolishes the phenomenon.