The effect of nifedipine on graft function in renal allograft recipients treated with cyclosporin A

The effect of the calcium channel antagonist nifedipine on renal allograft function was assessed in two groups of renal transplant recipients at least one year after transplantation. Group 1 comprised 10 patients receiving low-dose prednisolone and cyclosporin A, and Group 2 comprised 9 patients receiving low-dose prednisolone and azathioprine. Before commencing nifedipine, creatinine and sodium clearance rates and the fractional excretion of sodium were similar in both two groups. Lithium clearance rates and the fractional excretion of lithium were, however, significantly lower (p less than 0.01) in Group 1 than in Group 2. The absolute reabsorption of sodium from the distal nephron (p less than 0.01), the absolute reabsorption of water from the distal nephron segment (p less than 0.01) and the fractional reabsorption of sodium from the distal tubule relative to the delivery of sodium from the proximal tubule (p less than 0.05) were also lower in Group 1. After seven days of nifedipine treatment (10 mg/8 h) there was a significant fall in sodium clearance (p less than 0.01) and fractional sodium excretion (p less than 0.05), and an increase in the fractional distal reabsorption of sodium relative to the delivery of sodium from the proximal tubule (p less than 0.01), and the fractional distal reabsorption of water relative to the delivery of water from the proximal tubule (p less than 0.02), in Group 1 but not Group 2. The only alterations observed in Group 2 were an increase in fractional lithium excretion (p less than 0.05), and a significant fall in the absolute proximal tubular reabsorption of iso-osmotic fluids (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

An investigation of cyclosporine A (CyA) nephrotoxicity by lithium clearance]

It has been widely recognized that cyclosporine A (CyA) is useful in transplantation of the kidneys. On the other hand, the nephrotoxicity as one of its adverse effects is clinically important. There have been accumulated pieces of pathological evidence that CyA causes the renal proximal tubule damage. However, there are few reports available on the changes in the proximal tubular function. Recently, lithium clearance (CLi) has been employed to assess the proximal tubular function in CyA nephrotoxicity, because lithium ions are mainly reabsorbed throughout the proximal tubules in the same proportion as sodium and water. Several studies have already shown that long-term CyA administration results in a decrease in CLi reflecting enhanced lithium ion reabsorption. I studied, in male Sprague-Dawley rats, 1) whether short term and small dose of CyA administration which does not induce the renal tubular cell damage affects CLi and 2) the possibility that high salt intake influences CLi in CyA nephrotoxicity. Then, I divided rats into 6 groups: three groups were allowed the access to water, but the other three groups of rats were allowed to drink only saline. Group 2 and 3 were received 12.5 mg/kg and 25 mg/kg, respectively, of CyA intraperitoneally every day. As for creatinine clearance (Ccr), Ccr of group 3 (CyA 25) was the lowest, being significantly different from the other two groups. The most important result is fractional reabsorption of sodium and water in the proximal tubule. There is a significant difference between 1-A (vehicle, H2O) and 2-A (CyA 12.5, H2O), but no significant difference between 1-B (vehicle, saline) and 2-B (CyA 12.5, saline).(ABSTRACT TRUNCATED AT 250 WORDS)     

Does lithium affect renal sodium handling and renal haemodynamics in normal man?

Renal haemodynamics, sodium excretion, and free-water clearance were evaluated at baseline and after acute frusemide administration in nine moderately volume-expanded healthy volunteers receiving a single administration of either 750 mg lithium carbonate or placebo. Lithium plasma concentration under 0.29 mmol/l exerted no significant effect on renal haemodynamics, on absolute, fractional, or cumulative sodium excretion, or on free-water and chloride clearances at baseline or after frusemide administration. Despite previous volume expansion and presumably depressed proximal reabsorption, frusemide decreased the fractional reabsorption of lithium significantly, suggesting that a small but significant part of lithium may be reabsorbed in the thick ascending limb of Henle's loop. By contrast, frusemide did not change renal haemodynamics or plasma renin activity. Using combined free-water and lithium clearances at baseline and after frusemide administration, fractional reabsorption of sodium in the (FRTAL) was calculated as delta CH2O/CLi, where delta CH2O, the difference in free water clearance before minus after frusemide, is taken as an index of sodium reabsorption in the thick ascending limb, and lithium clearance as an estimation of sodium delivery to the thick ascending limb. FRTAL was calculated in these volume-expanded subjects to lie from 11% to 20% depending on whether some lithium is assumed to be in the thick ascending limb.     

Impaired phosphate handling of renal allografts is aggravated under rapamycin-based immunosuppression.

BACKGROUND: Impaired phosphate handling of the renal allograft is a common problem and of multifactorial origin. The aim of the study was to elucidate whether a rapamycin- or a mycophenolate-based immunosuppressive therapy aggravates the renal phosphate leak in kidney transplant recipients. METHODS: Renal phosphate handling was determined in thirty-eight cadaveric allograft recipients, with good renal function at 8, 12, 20 and 28 weeks after transplantation. Nineteen patients (group 1) received triple immunosuppression with rapamycin, cyclosporine and prednisolone, nineteen other transplant recipients received mycophenolate mofetil, cyclosporine and prednisolone immunosuppression (group 2), and six healthy subjects (group 3) served as controls. After 12 weeks of stable graft function, group 1 patients were divided further into two subgroups. Ten patients were kept on their immunosuppressive regimen (group 1A), whereas the remaining nine randomly chosen subjects had their cyclosporine withdrawn; they were thus maintained on a dual immunosuppression regimen with prednisolone and a higher dosage of rapamycin (group 1B). RESULTS: Renal phosphate reabsorption was significantly lower in group 1 at 8 and 12 weeks after transplantation as compared with groups 2 and 3. At 20 weeks after transplantation, patients with rapamycin-based immunosuppression (groups 1A and 1B) continued to exhibit hypophosphataemia and impaired renal phosphate handling. Group 1B had the lowest TmP/ GFR compared with all groups. At 28 weeks, renal phosphate reabsorption and plasma phosphate levels were no longer different between patient groups and controls. CONCLUSION: These data suggest that rapamycin-based immunosuppression prolongs the phosphate leak of the allografted kidney, leading to low serum phosphate levels during the first weeks after transplantation.     

The effect of cyclosporine on early graft function in human renal transplantation

The effect of cyclosporine and steroids on early renal allograft function and eventual graft outcome was analyzed in 100 recipients; 33 recipients of living related donor (LRD) and 67 recipients of cadaveric donor (CAD) allografts were studied. A concurrent population of 47 CAD recipients treated with azathioprine and steroids was used for comparison. Recipients received oral cyclosporine (14 mg/kg) 48 hours (LRD) or 6-12 hours (CAD) pretransplant. No cases of acute tubular necrosis (ATN) were observed in the LRD recipients. The incidence of posttransplant ATN was similar in the cyclosporine-treated (41%) and in the azathioprine-treated (45%) CAD recipients (P = ns). Cyclosporine-treated CAD kidneys preserved less than 24 hr experienced a lower rate of ATN (P less than .01) using simple cold storage (31%), as compared with hypothermic pulsatile perfusion (57%). One-month creatinine nadirs were higher in cyclosporine-treated than in azathioprine-treated recipients, using median values for each group. One-year actuarial patient survival for cyclosporine-treated LRD recipients was 97%; CAD recipients, 94%, and azathioprine-treated CAD recipients, 91%. Graft survival rates in the same groups were 91%, 76%, and 55%, respectively. The major causes of graft loss in cyclosporine-treated patients were nonimmunologic. It is concluded that cyclosporine and prednisone are a safe, efficacious combination for LRD and CAD renal transplantation. The possibility of nephrotoxicity leading to impaired graft function in the early posttransplant period should not preclude the administration of cyclosporine prior to alloantigen presentation.     

Renal tubular responses to low-dose infusion of angiotensin II in type 1 diabetes mellitus; relation to chronic glycaemic control

Renal responses to low-dose infusion of angiotensin II (ANGII,1.25 and 2.5 ng.kg^–1 min^–1) were examined in 15patients with type 1 diabetes and in 10 control subjects afterpretreatment with lithium carbonate (750 mg, 20 mmol). Meanarterial pressure rose during ANGII infusion in both groups.The renal haemodynamic response to angiotensin II was not abnormalin the diabetic patients. Absolute proximal reabsorption ofsodium was increased at baseline in the diabetic group, andfell during ANGII. Fractional lithium excretion was reducedin the diabetic patients at baseline (P<0.05), and the fallin fractional lithium excretion during ANGII was less than inthe control group (P=0.012). In the diabetic group correlationsexisted between glycated haemoglobin and baseline glomerularfiltration rate (P<0.05), baseline fractional lithium excretion(P=0.03), and the fall in fractional lithium excretion duringangiotensin II infusion (P=0.013). There was no correlationbetween glycated haemoglobin and absolute lithium clearance.Some indices of sodium reabsorption by the proximal renal tubulein diabetic patients correlate with prevailing chronic glycaemiccontrol, largely reflecting changes in glomerular filtrationrate. Reduced fractional proximal tubular responsiveness toexogenous angiotensin II is consistent with a role for endogenousangiotensin II as one mediator of increased tubular reabsorptionof sodium in type I diabetes, but the data does not excludealternative mechanisms.     

Clinical experience of mycophenolate mofetil in the treatment of chronic allograft nephropathy in kidney transplantation: three-year follow-up

BACKGROUND: Mycophenolate mofetil (MMF) in conjunction with calcineura antagonists has been shown to prevent acute rejection in renal allograft recipients. Its role in treatment of chronic rejection or allograft nephropathy is still controversial. We initiated the study to investigate the effect of adding MMF to a cyclosporine plus prednisolone regimen in renal recipients with chronic allograft nephropathy. MATERIALS AND METHODS: We retrospectively studied 36 patients with chronic allograft nephropathy, defined clinically as increased of serum creatinine, proteinuria, and hypertension. Renal function, cyclosporine level, renal biopsy, and renal scan were regularly done as indicated. MMF was added to 20 recipients after initial treatment with cyclosporine and prednisolone. The other 16 recipients were managed without adding MMF. Serum creatinine was monitored for 3 years. RESULTS: The demographic characteristics of the patients in the two groups were comparable. The average dose of prednisolone was unchanged throughout the study and the trough level of cyclosporine was maintained in the range of 100 to 150 ng/mL. The serum creatinine decreased initially in the group on MMF, but renal function deteriorated progressively after 6 months. There was a difference in serum creatinine between the two groups but this did not reach statistical significance. CONCLUSION: MMF therapy tender to improve renal function initially but did not attenuate significantly the impairment in chronic allograft nephropathy.     

Cyclosporine-induced acute renal dysfunction in the rat. Evidence of arteriolar vasoconstriction with preservation of tubular function

Dose-related cyclosporine-induced renal dysfunction is the most frequent adverse effect noted with this exciting immunosuppressive drug. To investigate pathogenetic factors involved, we studied renal tubular function and afferent arteriolar morphology during severe experimental cyclosporine-induced reduction in glomerular filtration rate. Pair-fed male rats were given cyclosporine 50 mg/kg or olive oil vehicle alone by gavage for periods of 3-14 days. Glomerular filtration rate declined progressively, reaching a nadir of 0.18 +/- .05 ml/min/100 g vs. .86 +/- .03 ml/min/100 g in controls at 14 days (P less than 0.001). Despite the severe reduction in glomerular filtration rate there was no difference in fractional sodium excretion, fractional lithium excretion, enzymuria, or in vitro renal cortical slice uptake of tetraethylammonium in cyclosporine and vehicle-treated animals. Light microscopy showed vacuolar changes without evidence of tubular necrosis at 7 and 14 days in cyclosporine-treated rats. Progressive decline in the diameter of the afferent arteriole was noted by scanning electron microscopy. By day 14 the lumenal diameter of afferent arterioles from cyclosporine-treated animals was 8.9 +/- 0.4 micron vs. 13.5 +/- 0.4 micron in controls (P less than 0.05). We conclude that afferent arteriolar vasoconstriction rather than direct tubular injury is a major pathogenetic factor in experimental cyclosporine nephrotoxicity.     

Calcium channel blockade and preservation of renal graft function in cyclosporine-treated recipients: a prospective randomized placebo-controlled 2-year study

BACKGROUND: Studies have provided conflicting results as to the protective role of calcium channel blockers (CCB) in cyclosporine-treated patients with regard to blood pressure control and preservation of renal graft function. Lacidipine is a dihydropyridine CCB that possesses antioxidative, anti-atherosclerotic, and anti-adhesion properties and was shown to prevent cyclosporine-induced nephrotoxicity in a rat model. METHODS: We conducted a multicenter prospective, randomized, placebo-controlled study in 131 de novo recipients of a cadaveric renal allograft on cyclosporine therapy. The aim of this 2-year study was to assess the effects of lacidipine on graft function (plasma iohexol clearance), renal plasma flow, anastomotic arterial blood flow, deterioration of renal function, blood pressure, acute rejection, and hospitalization rate. RESULTS: A total of 118 recipients were available for intention-to-treat analysis on efficacy (lacidipine: n=59; placebo: n=59). Graft function assessed by serum creatinine concentration and glomerular filtration rate measured as plasma iohexol clearance, was persistently better in lacidipine-treated patients from 1 year onwards (respectively, P<0.01 and P<0.05). Renal plasma flow and anastomotic blood flow were not significantly higher in lacidipine-treated patients. Three patients on lacidipine therapy and four on placebo experienced treatment failure defined as an increase in serum creatinine from baseline of more than 60% (log-rank test: P=0.57). Study groups did not differ in acute rejection rate, trough blood cyclosporine concentrations, blood pressure, number of antihypertensive drugs, hospitalization rate, and adverse event rate. CONCLUSIONS: The use of calcium channel blockers in cyclosporine-treated renal recipients results in a significantly better allograft function at 2 years and this effect is independent of blood pressure lowering.     

Early and late forms of cyclosporine nephrotoxicity: studies in cardiac transplant recipients

To characterize the two forms of cyclosporine nephrotoxicity, we examined renal function in the immediate and late postoperative periods after cardiac transplantation. Moderate azotemia occurred during the first postoperative week in 58% of 43 cyclosporine-treated recipients, but in only 34% of 41 azathioprine-treated recipients, and 4% of 25 patients undergoing cardiopulmonary bypass for nontransplant surgery (both P less than .01 v cyclosporine). Acute renal failure developed in an additional 12% of the cyclosporine-treated group. Late postoperative renal dysfunction also occurred with a high prevalence. Life-table analysis indicated that at 6 months 55%, at 12 months 17%, at 24 months 4%, and at 36 months no cyclosporine-treated recipients retained normal renal function. Three renal biopsies performed in subjects with late nephrotoxicity demonstrated prominent interstitial fibrosis. Although one patient subsequently required chronic dialysis, reduction of cyclosporine dosage from a mean of 5.3 +/- 0.7 mg/kg/d to a mean of 2.3 +/- 0.3 mg/kg/d 9 to 21 months after transplantation with concurrent initiation of azathioprine therapy to prevent rejection led to an improvement of renal function in the five patients so treated. These data indicate that there are two distinct forms of cyclosporine nephrotoxicity. Although both occur with high prevalence, the early form does not appear to be a specific risk factor for the late form.     

Long-term effects of cyclosporine on renal function in liver transplant recipients

The long-term effects of cyclosporine on renal function were evaluated in eleven liver transplant recipients over a 6-26-month follow-up period. Renal hemodynamic function (glomerular filtration rate [GFR], effective renal plasma flow [ERPF]) fell 60% postoperatively, subsequently improved, and stabilized at 45-60% of normal despite continued drug administration. Tubular sodium transport studies during water diuresis suggested that the proximal tubule is a major site of cyclosporine nephrotoxicity. In contrast to the acute effects of cyclosporine on renal function, the fraction of glomerular filtrate reabsorbed in the proximal tubule was less in the patient group while the fractional excretion of sodium, potassium, and phosphate was increased. When the fraction of filtered sodium reabsorbed in the diluting segment was examined as a function of sodium delivery, functional impairment occurred in the diluting segment as well. Eight renal biopsies performed in six patients 4-29 months posttransplantation showed only mild to moderate changes, predominantly vascular, which correlated poorly with corresponding renal function. These data showed that long-term cyclosporine administration produced early and persistent depression of both hemodynamic and tubular function. A functional rather than structural mechanism appears to be more significant during this period of observation.     

Kidney transplantation without calcineurin inhibitor drugs: a prospective,randomized trial of sirolimus versus cyclosporine

BACKGROUND: Progressive nephrotoxicity caused by calcineurin inhibitor drugs contributes to the long-term decline in renal function in kidney transplant patients. METHODS: We conducted a randomized, prospective trial of calcineurin inhibitor drug avoidance in 61 adult primary kidney transplant recipients. Each patient received induction therapy with 20 mg basiliximab on days 0 and 4, and maintenance therapy with mycophenolate mofetil 1 g two times per day and steroids. Thirty-one patients received sirolimus, 5 mg daily after a 15-mg loading dose. Doses were then concentration-controlled to keep 24-hr trough levels at 10 to 12 ng/mL for 6 months and 5 to 10 ng/mL thereafter. Thirty patients began cyclosporine therapy at 6 to 8 mg/kg per day in divided doses and were then concentration-controlled to keep 12-hr troughs of 200 to 250 ng/mL. RESULTS: Mean follow-up is 18.1 months (range, 12-26 months). The percentages of 1-year patient survival, graft survival, and biopsy-confirmed acute rejection rates were not significantly different between the sirolimus-treated patients (96.7%, 96.7%, and 6.4%, respectively) and the cyclosporine-treated patients (100%, 95.4%, and 16.6%, respectively). At 6 and 12 months, respectively, the sirolimus-treated patients enjoyed significantly better (P=0.008 and P=0.004) mean serum creatinine levels (1.29 and 1.32 mg/dL) and calculated creatinine clearances (77.8 and 81.1 mL/min) than cyclosporine-treated patients (1.74 and 1.78 mg/dL, and 64.1 and 61.1 mL/min, respectively). Sirolimus-treated recipients have significantly (P=0.001) higher 1-year trough levels of mycophenolic acid (4.16 ng/mL) than cyclosporine-treated patients (1.93 ng/mL). Sirolimus also delays the repopulation of basiliximab-depleted CD25 T cells compared with cyclosporine. CONCLUSIONS: Calcineurin inhibitor drug avoidance with basiliximab induction and sirolimus provides comparable 1-year transplant outcomes, with significantly better renal function in primary renal allograft recipients.     

Site of the action of a synthetic atrial natriuretic peptide evaluated in humans

The renal site of the natriuretic effect of human, atrial natriuretic peptide (hANP) was studied using clearance techniques in eight salt-loaded normal volunteers undergoing maximal water diuresis. Lithium was used as a marker of proximal sodium reabsorption. According to a two-way, single blind, crossover design, hANP (Met12-(3-28)-eicosahexapeptide, (2 micrograms/min) or its vehicle (Ve) were infused for two hours, followed by a two-hour recovery period. Blood pressure, heart rate and insulin clearance remained unchanged. During hANP infusion, the filtration fraction increased slightly from 19.6 to 24.3% (P less than 0.001), fractional water excretion rose transiently at the beginning of the infusion. Fractional excretion of sodium increased markedly from 2.2% to 7.4% (P less than 0.001) but remained unchanged with Ve. ANP increased fractional excretion of lithium slightly from 46 to 58% (P less than 0.01), while it remained stable at 47% during Ve. The distal tubular rejection fraction of sodium calculated from sodium and lithium clearances rose markedly from 4.7 to 13% (P less than 0.001) and returned to 6.2% at the end of the recovery period. Thus, under salt loading and water diuresis conditions, hANP infusion did not alter GFR, but reduced proximal reabsorption of sodium, and markedly enhanced the fraction of sodium escaping distal tubular reabsorption, suggesting that hANP-induced natriuresis is due, for an important part, to inhibition of sodium reabsorption in the distal nephron.     

Renal tubular sodium and water excretion in antibiotic-induced nephrotoxicity. Renal function in antibiotic nephrotoxicity

Clearance techniques were used to evaluate renal tubular sodium and water excretion in 4 patients with antibiotic-induced acute renal failure (ARF). Creatinine clearances and maximal urine flow rates of patients with ARF (22.6 and 5.23 ml/min, respectively) were significantly lower than control values during hypotonic volume expansion (125.5 and 13.71 ml/min, respectively, both p less than 0.01). During the period of maximal hydration, fractional sodium excretion (CNa/Ccr) and maximal urine osmolality (11.4% and 171 mosm/kg H2O, respectively) were increased compared to controls (1.04% and 53 mosm/kg H2O, respectively, both p less than 0.05). The increased CNa/Ccr observed in patients with ARF was consistent with reduced proximal sodium reabsorption as reflected by increased (CH2O + CNa)/Ccr and reduced fractional distal sodium reabsorption as indicated by decreased CH2O/(CH2O + CNa). The reduction in proximal and distal sodium reabsorption cannot be explained on the basis of an osmotic effect of urea as fractional clearances of BUN (CBUN/Ccr) were similar in patients with ARF and controls.     

Effect of angiotensin II on proximal tubular reabsorption in normal humans.

The effects of angiotensin II (AII) on proximal tubular reabsorption have been evaluated in 6 healthy volunteers under normal salt and water balance. One-hour clearance periods were performed before, during and after the infusion of pressor doses of AII; in 3 of the 6 subjects, the study was repeated with lower doses of AII. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were determined by the clearances of inulin and PAH, and the fractional excretion of lithium (FELi) was considered as an index of proximal sodium reabsorption. The effects of AII on the fractional excretion of beta 2 microglobulin (FE beta 2M) were also studied. Both doses of AII decreased GFR and RPF and increased the filtration fraction (FF); the modifications of these parameters, as well as the reduction of FELi and the fractional excretion of sodium (FENa) and the increase of plasma aldosterone and of plasma atrial natriuretic peptide (ANP), were more evident with pressor doses of AII, which increased the blood pressure from 129/83 to 142/95 mm Hg (p less than 0.01). AII did not modify FE beta 2M in either study. During AII, FELi decreased less than FENa and both were closely and inversely related to the variations of FF, whilst no relationship was present between FE beta 2M and FF. These results suggest that, in normal humans, the AII-induced rise of FF may be an important factor, even if not the only one, in enhancing the proximal reabsorption of lithium and thus of sodium, whilst it does not affect the absorption of beta 2M.     

Does H2-receptor antagonist alter the renal function of cyclosporine-treated kidney grafts?

Histamine-type 2 antagonists (H2-blockers) as represented by cimetidine have been shown to adversely affect renal allograft function, particularly when coadministered with cyclosporine, currently a major immunosuppressant. To determine whether or not a newer and more powerful H2-blocker, famotidine, would produce similar adverse effects, we assessed seven cyclosporine-treated renal allograft recipients with regard to changes in their renal function on or off the H2-blocker over a one-week period. Neither the administration nor withdrawal of famotidine (20-40 mg/day) resulted in any significant changes in serum creatine, BUN, urine output or cyclosporine trough levels, suggesting that famotidine can be safely administered as an H2-blocker to cyclosporine-treated renal allograft recipients.     

Increased serum beta 2 microglobulin during rejection, cyclosporine-induced nephrotoxicity, and cytomegalovirus infection in renal transplant recipients

In 83 renal transplant recipients, serum beta 2 microglobulin (beta 2m) levels were significantly elevated during pretransplant uremia, rejection, cyclosporine-induced nephrotoxicity, and infections. In patients with normal serum creatinine, 74% had elevated serum beta 2m levels. None of the cyclosporine-treated patients had normal levels of beta 2m. Patients with stable renal allograft function receiving cyclosporine showed significantly higher serum beta 2m (P less than 0.001) and serum creatinine (P less than 0.01) levels than azathioprine treated patients. Patients with an irreversible rejection showed significantly higher serum concentrations of beta 2m than patients experiencing a reversible rejection (P less than 0.001). During cytomegalovirus (CMV) infection the serum beta 2m levels were elevated compared with other infections (P less than 0.001), while the serum creatinine was not. However, infected patients had higher serum levels of beta 2m and creatinine than patients with stable renal allograft function (P less than 0.001). Serum beta 2m may therefore be useful in the early diagnosis of CMV infection. To conclude, serum beta 2m levels cannot distinguish between rejection, cyclosporine nephrotoxicity, or infection.     

Stimulatory effect of insulin on tubular sodium reabsorption in normotensive subjects with a positive family history of hypertension

BACKGROUND: Insulin resistance and hyperinsulinaemia has been suggestedas a pathogenetic mechanism in hypertension. METHODS: In this investigation the renal response to insulin was studiedin normotensive subjects with a positive family history of hypertensionin two generations (n = 14), in one weight-matched (n = 11)and one lean (n = 13) control group. During hyperinsulinaemia(euglycaemic hyperinsulinaemic clamp technique) we determinedrenal haemodynamics (clearances of ⁵¹Cr-EDTA and PAH) and urinarysodium excretion. Lithium clearance was used to estimate thesegmental tubular reabsorption of sodium. RESULTS: In subjects with a positive family history of hypertension,hyperinsulinaemia did not influence renal plasma flow (RPF)or glomerular filtration rate (GFR) but urinary sodium excretiondecreased by 50%. Estimated proximal tubular sodium reabsorptionwas unaffected by insulin while estimated distal fractionalsodium reabsorption increased, P<0.01. At the end of theclamp a low-dose infusion of angiotensin II (0.1 ng/kg per min)was superimposed. GFR and RPF then decreased significantly concomitantwith urinary excretion of sodium. In control subjects hyperinsulinaemia caused an unchanged GFRin both groups, increased RPF in the lean control group and15–25% reduction in sodium excretion. No alteration wasseen in estimated proximal tubular sodium reabsorption, butestimated distal tubular sodium reabsorption increased (P<0.05)in the lean control group. Angiotensin II elicited a furtherincrease in distal fractional tubular sodium reabsorption inboth control groups (P<0.05). CONCLUSIONS: In normotensive subjects with a positive family history of hypertension,in contrast to control subjects without such history, hyperinsulinaemiacaused a marked decrease in urinary sodium excretion in presenceof unchanged RPF and GFR indicating a renal tubular effect ofinsulin located at a distal site of the renal tubules. AngiotensinII caused further sodium retention, probably due to an effecton renal haemodynamics.     

The effect of converting enzyme inhibition on the enhanced proximal sodium reabsorption induced by chronic diuretic treatment in patients with essential hypertension

During chronic chlorthalidone treatment of patients with essential hypertension, distal tubular sodium reabsorption is continuously inhibited. At the same time, sodium balance is maintained by an increase of the proximal tubular sodium reabsorption. In the present study, we investigated whether this increase is caused by a stimulated renin-angiotensin system (RAS). For this purpose, the renal effects of converting enzyme inhibition (CEI) were evaluated in 12 patients with essential hypertension who remained hypertensive despite chronic chlorthalidone treatment. After 6 weeks of chlorthalidone, an intravenous injection of 10 mg enalaprilic acid decreased the mean arterial pressure (MAP) from 110 to 102 mm Hg. The effective renal plasma flow (ERPF) increased. However, glomerular filtration rate (GFR) and the fractional excretions of sodium, lithium and free water did not change significantly. After 2 additional weeks of chlorthalidone combined with enalapril 20 mg b.i.d., MAP fell to 90 mm Hg, ERPF remained elevated and plasma aldosterone concentration decreased. As in the acute study, no significant changes were detected in the GFR and the fractional excretions of sodium, lithium or free water. Extracellular fluid volume was not diminished during these 2 weeks. Fractional proximal sodium reabsorption during chronic chlorthalidone therapy was higher when calculated from free water clearance (91%) than from the lithium clearance (71%), but neither of the two were affected by acute or chronic CEI. The results of this study suggest that during chronic diuretic treatment, maintenance of sodium balance by increased proximal reabsorption is not dependent on the stimulated RAS, or alternatively, that this function of the RAS is exactly counterbalanced by another effect of CEI, possibly by the fall in blood pressure.