Hyperuricaemia in cyclosporin-treated patients: a GFR-related effect

BACKGROUND: Hyperuricaemia is a well known side-effect of cyclosporin A(CsA) treatment. The pathogenic mechanisms, however, remaincontroversial. There is no convincing evidence that hyperuricaemiais due to CsA-induced, impaired tubular handling of uric acid.The impact of diminished GFR in this particular context hasnever been investigated. METHODS: We prospectively studied plasma uric acid, inulin clearances,and fractional clearances of uric acid in two groups of CsA-treatedpatients (bone-marrow transplant patients, n=50; renal transplantpatients, n=32), and one healthy control group without CsA (livingrelated kidney donors, n=28). Bone-marrow transplant patientswere examined before transplantation and 6, 12, 18, 24 monthsafter transplantation, renal transplant patients 1 year aftertransplantation, and living related kidney donors before and1 year after unilateral nephrectomy. RESULTS: After 1 year of CsA treatment, hyperuricaemia was found in 36%of bone-marrow transplant patients and in 53% of renal transplantpatients. Thirty per cent of living related kidney donors wereborderline hyperuricaemic 1 year after unilateral nephrectomy.The fractional clearance of uric acid, measured serially inbone-marrow transplant patients did not change significantlyover time; it was, however, slightly higher during CsA treatmentthan after CsA withdrawal. Moreover, the bone-marrow transplantpatients' fractional clearance of uric acid was not statisticallydifferent from the renal transplant patients' and the livingrelated kidney donors' (values 1 year after transplantation/unilateralnephrectomy: bone-marrow transplant patients, 15.3±2.3%;renal transplant patients, 11.9±0.9%; living relatedkidney donors, 11.1±0.8%). The GFR at 1 year, measuredby inulin clearance, was identical in the CsA-treated groupsand slightly higher in the living related kidney donors (bone-marrowtransplant patients, 51±6 ml/min per 1.73 m² renal transplantpatients, 49±3 ml/min per 1.73 m² living related kidneydonors, 61±2 ml/min per 1.73 min²). CONCLUSIONS: There is no evidence for impaired tubular handling of uric acid,induced by a CsA-specific tubulotoxic effect. Hyperuricaemiain CsA-treated transplant patients can therefore be attributedto the cyclosporin associated decrease of GFR.     

Fish oil and cyclosporin A-induced renal hypoperfusion in kidney-transplanted patients

BACKGROUND.: Dietary supplementation with fish oil has been said to improverenal function in cyclosporin A (CsA)-treated subjects. METHODS.: Renal function and the acute renal haemo-dynamic and tubularresponse to an oral CsA-dose (3 mg/kg) were investigated beforeand after 12 weeks of fish oil supplementation (6 g/day) in12 low-dose CsA-treated kidney-transplanted patients (s-creatinine,124 ± 24 µmol/l, mean ± SD). After an overnightfast, ten 1-h renal clearance periods were performed, two periodsbefore and eight after CsA-ingestion. An additional controlclearance study without CsA intake was performed in six subjects. RESULTS.: Fish oil did not change baseline values of the effective renalplasma flow (ERPF) or the glomerular filtration rate (GFR).Compared to the control study, CsA decreased GFR and ERPF significantlyon aver-age 20 ± 3% (P<0.01) and 23 ± 3% (P<0.01)respectively, 4–6 h after peak CsA blood concentrationwith no additional effect of fish oil. CsA also significantlydecreased the renal clearance of lithium, used as an index ofproximal tubular outflow, with no impact of dietary fish oil. CONCLUSION.: Fish oil supplementation had no effect on baseline renal functionor CsA-induced hypoperfusion in stable renal transplant recipientstreated with a low maintenance dose of CsA.     

A Prospective Randomised Comparative Study on the Influence of Cyclosporin and Azathioprine on Renal Allograft Survival and Function

To study the effectiveness and nephrotoxic side-effects of cyclosporinA (CsA) in renal transplant recipients, a prospective randomisedtrial was designed to compare CsA with azathioprine (Aza). Eachtreatment group consisted of 40 patients; in the CsA group,18 were randomly selected for conversion to Aza after 3 months.The 1-year graft survival for CsA-treated patients was 87% comparedwith 66% for the Aza group (P=0.033). Anti-rejection therapywas administrated to 78% of the patients in the Aza group and47% of those in the CsA group (P<0.01). There was no differencein the incidence of primary non-functioning kidneys, cytomegalovirusinfections, hypertension, or degree of proteinuria between thetwo treatment groups. At 3 months the mean creatinine clearance was 42±2 ml/min(mean±SEM) for the CsA group compared with 56±4ml/min for the Aza group (P<0.01), whereas the mean creatinineclearances at 6 months for both the converted and the non-convertedCsA-treated patients did not differ from that found in the Aza-treatedgroup. At 1 year, the mean creatinine clearance for CsA-treatedpatients who were converted to Aza was higher than that foundfor Aza treated patients (62±7 vs 50±6 ml/min;P<0.05). Furthermore, the increment in creatinine clearanceobserved after conversion from CsA to Aza at 3 months showeda linear relationship (r=0.9061) with the CsA trough levelsbefore discontinuation of the drug. This indicates that CsA treatment induces a dose-dependent,nephrotoxic side-effect which is probably reversible.     

Presymptomatic detection of familial juvenile hyperuricaemic nephropathy in children

We studied 34 apparently healthy children and 2 propositi from kindreds with familial juvenile hyperuricaemic nephropathy (FJHN) – a disorder characterised by early onset, hyperuricaemia, gout, familial renal disease and a similarly low urate clearance relative to glomerular filtration rate (GFR) [fractional excretion of uric acid (FE_ur) 5.1±1.6%] in young men and women. In addition to the propositi, 17 asymptomatic children were hyperuricaemic – mean plasma urate (368±30 μmol/l), twice that of controls (154±41 μmol/l). Eight of them had a normal GFR (>80 ml/min per 1.73 m²), and 11 renal dysfunction, which was severe in 5. The FE_ur in the 14 hyperuricaemic children with a GFR >50 ml/min was 5.0±0.5% and in the 5 with a GFR ≤50 ml/min was still low (11.5±0.2%) compared with controls (18.4±5.1%). The 17 normouricaemic children (185±37 μmol/l) had a normal GFR (>80 ml/min) and FE_ur (14.0±5.3%). The results highlight the dominant inheritance, absence of the usual child/adult difference in FE_ur in FJHN and presence of hyperuricaemia without renal disease in 42% of affected children, but not vice versa. Since early allopurinol treatment may retard progression to end-stage renal failure, screening of all relatives in FJHN kindreds is essential. Received June 25, 1997; received in revised form and accepted December 1, 1997     

Substitution of conventional cyclosporin with a new microemulsion formulation in renal transplant patients: results after 1 year

BACKGROUND: A new galenic form of cyciosporin A has been developed, basedon microemulsion technology. The bioavailability of the compoundis reiativeiy independent of food intake and bile flow. It wasthe purpose of this prospective clinical trial to study thesafety of the microemulsion form of cyclosporin A. METHODS: Three hundred and two renal transplant patients, stratifiedaccording to transplant age, were switched from the conventionalto the new micro-emulsion formulation of cyclosporin A. A 1:1conversion ratio was used. Measurements included CsA levels,S-creatinine, liver enzymes, uric acid, and blood pressure.Measurements were performed at baseline and on days 4, 8, 15,29 and months 3, 6 and 12 after conversion. Dose adjustmentswere performed to achieve trough levels of 80–120 ng/ml. RESULTS: Within the 12-month observation period the cyclosporin dosewas reduced by 14.7% (from 204±60 mg/day at baselineto 174±51 mg/day after conversion, P<0.001). Acutely,i.e. by day 8, a 1:1 dose conversion resulted in a modest increaseof mean drug trough levels (from 114 ng/ml at baseline to 120ng/ml, P<0.01). This increase was accompanied by an increasein serum creatinine concentration, a decrease in calculatedcreatinine clearance, and an increase in uric acid values (P0.05).Liver enzymes remained unchanged while systolic and mean arterialblood pressure decreased (P<0.05). After 1 month, drug troughlevels had decreased to baseline (112 ng/ml) and remained thereuntil month 6. They were significantly lower after 12 months(102±33 ng/ml, P<0.001). Creatinine clearance valuesincreased to above baseline at 6 and 12 months. Within the 1-yearperiod there occurred 24 (=8%) episodes of biopsy-proven rejectionand seven episodes of cyclosporin-attributed nephrotoxicity. CONCLUSIONS: The 1:1 conversion from conventional cyclosporin A to the microemulsionformulation is efficacious and safe, but an initial dose reductionof 10% is advised in patients with trough levels in the high-normalrange.     

Amlodipine reduces cyclosporin-induced hyperuricaemia in hypertensive renal transplant recipients.

BACKGROUND: Hypertension and hyperuricaemia are common side-effects of cyclosporin A (CsA) treatment in renal transplant recipients. While it is well established that the calcium channel blocker amlodipine can control CsA-induced hypertension effectively in this patient population, recent evidence suggests amlodipine might also reduce hyperuricaemia. The present study was designed to compare the effects of the calcium channel blocker amlodipine (5-10 mg/day) and the beta-adrenoceptor antagonist tertatolol (5-10 mg/day) on CsA-induced hyperuricaemia in post-renal transplant recipients with hypertension. METHODS: Forty-eight hypertensive renal transplant recipients on a stable dose of CsA were randomized in a double-blind, parallel-group manner to receive either amlodipine (n = 24) or tertatolol (n = 24) for 60 days. The primary outcome measure was the change from baseline in serum uric acid concentration. Secondary analyses of efficacy were based on changes in renal function and blood pressure. RESULTS: Amlodipine significantly decreased serum uric acid levels from 483 +/- 99 to 431 +/- 110 microM/l (P < 0.001), while tertatolol significantly increased uric acid from 450 +/- 98 to 476 +/-84 microM/l (P = 0.006). Amlodipine also significantly increased glomerular filtration rate (P = 0.0048) and the clearance rate of uric acid (P = 0.023) and it reduced the fractional proximal tubular reabsorption of sodium (P < 0.001), compared with tertatolol. Renal plasma flow and filtered fraction were unaffected by both treatments, as was trough CsA blood concentration. Amlodipine lowered systolic blood pressure to a significantly greater extent than did tertatolol (P = 0.007). The time-dependent profile of diastolic blood pressure did not differ significantly between treatment groups. Both drugs were well tolerated. CONCLUSIONS: Amlodipine could be more appropriate than tertatolol for CsA-induced hypertension and hyperuricaemia in renal transplant recipients.     

Renal effects of maintenance low-dose cyclosporin A treatment in psoriasis

The renal effects of low-dose cyclosporin A (CsA) treatmentin severe psoriasis was investigated in 10 patients treatedwith a mean CsA dose of 3.23 (range 1.94–4.10) mg/kg/dayfor 12 months. The psoriasis area and severity index was reducedby 63–76%. Ambulatory GFR (iothalamate-¹²⁵I) ERPF (hippuran-¹³¹),RVR and MAP were examined at 3-months intervals. A control renalbiopsy was performed shortly before treatment start and a secondbiopsy was taken after 12 months of therapy. GFR was slightlybut significantly reduced after 6 and 9 months; after 12 monthsthe decrease was not significant (121.0±7.6 versus 115.2±7.8ml/min/l.73M P>0.10). After 12 months serum creatinine increasedfrom 82±4 to 94±7 µmol/litre (P<0.05while an insignificant increase of ERPF was seen and FF decreasedfrom 0.29±0.01 to 0.26±0.01 (P<0.05). MAP remainedunchanged. GFR and serum creatinine correlated significantlywithin each 3-month interval. A slight de novo interstitialfibrosis was seen in the second biopsy in 4 of 10 patients receivinga mean CsA dose of 3.2–4.1 mg/kg/day. In three of thesepatients a concomitant rise in serum creatinine was seen. In conclusion, low-dose CsA was associated with reversible fallin GFR and potentially progressive structural changes not alwaysaccompanied by corresponding functional alterations. One shouldconsider reducing the daily dose of CsA to 3.0 mg/kg body- weightor less in CsA therapy up to 1 year.     

Concentration of dimethyl-L-arginine in the plasma of patients with end-stage renal failure

Abstract. N^GN^Gdimethyl-L-arginine (asymmetric dimethyl-L-arginineADMA) and N^GN^G dimethyl-L-arginine (symmetric dimethyl-L-arginine;SDMA) are naturally occurring analogues of L-arginine, the substratefor nitric oxide (NO) synthesis. ADMA is a potent inhibitorof NO synthesis, and accumulates in the plasma of patients withrenal failure. However the precise concentration of ADMA andSDMA in renal patients is still controversial. This study wasperformed to measure plasma ADMA and SDMA concentrations bytwo different HPLC techniques in nine healthy controls and 10uraemic subjects, and to investigate the effects of haemodialysis.In controls, the mean (±SEM) plasma concentrations ofADMA and SDMA were 0.36±0.09 and 0.39±0.05 µmol/lrespectively, yielding an ADMA/SDMA ratio of 1.2± 0.17.In uraemic patients, the plasma concentrations of ADMA and SDMAwere 0.9±0.08 µmol/l (P<0.001 compared to controls)and 3.4±0.3 µmol/l (P<0.001 compared to controls)with an ADMA/SDMA ratio of 0.27±0.015 (P<0.001). Inthe course of one 4 h haemodialysis session, ADMA concentrationsdecreased from 0.99±0.13 to 0.77±0.3 µmol/land SDMA concentrations from 3.38±0.44 to 2.27±0.21µmol/l. The plasma ADMA/creatinine ratio tended to increasefrom 1.26±0.20 x 10^–3 to 2.01±0.41 x 10^–3It is concluded that there is a modest (3-fold) but definiteincrease in plasma ADMA concentration in uraemic patients comparedto controls. SDMA accumulates to a greater degree (8-fold increase)and more closely parallels creatinine concentration than ADMA.The change in the ADMA/SDMA ratio is not accounted for by greaterrenal or dialysis clearance of ADMA, and, even though alternativeexplanations are not excluded, greater metabolism of ADMA thanSDMA is the most likely explanation. Although small in magnitude,the increase in ADMA concentration might be biologically significant.     

Elevated plasminogen activator inhibitor levels in cyclosporin-treated renal allograft recipients

Atherosclerosis and thrombosis, two major causes of morbidityand mortality in renal transplant recipients, share the sameclinical risk factors including decreased fibrinolysis and lipiddisturbances. In a crosssectional study we have determined parametersof fibrinolysis in control subjects (n=23) and stable renalallograft recipients without cyclosporin CsA (n=10) and withCsA (n=87) in their immunosuppressive treatment. In CsA-treatedpatients, tissue-type plasminogen activator was moderately increasedcompared to patients without CsA (8.4±3.3 vs 5.5±2.8ng/ml). The plasminogen activator inhibitor (PAI) activity inplasma was clearly increased in CsA-treated patients: 14.5±8.8vs 7.2±3.2 in normal controls and 8.5±2.4 AU/mlin patients without CsA. Total cholesterol and LDL cholesterollevels were higher in CsA-treated patients (256±62 and169±60 mg/dl) than in patients without CsA (209±45and 136±44 mg/dl). The two groups did not differ in HDLcholesterol, triglycerides, and lipoprotein(a). Hypercholesterolaemia,obesity, and steroid-induced diabetes could be identified asrisk factors for elevated plasma PAI activity in CsA-treatedpatients. Hypofibrinolysis induced by elevated PAI levels andincreased LDL cholesterol may contribute to the increased thrombogenicityand accelerated atherosclerosis observed in cyclosporin-treatedpatients.     

Monitoring of iron requirements in renal patients on erythropoietin

We studied 38 patients (9 haemodialysis, 18 peritoneal dialysis,11 advanced renal failure) over the first 12 weeks of erythropoietintherapy. In 14 iron-overloaded patients (ferritin >500 µg/l)the haemoglobin (±SEM) increased from 6.74±0.27to 9.85±0.36 g/dl (P<0.0001) entirely by mobilizingiron reserves (reduced from 1,220±73 to 739±111mg, P<0.0001). In the 24 non-overloaded patients (ferritin<500µg/l) the haemoglobin rose similarly from 7.04±0.18to 10.70±0.36 g/dl (P<0.0001), partly from iron reserves(depleted from 200±74 to –44±77mg, P=0.016)and partly from oral iron supplements (305±110 mg). Inthe overloaded patients the ferritin declined from 1057 µg/l(geometric mean, range 504–3699) to 317 µg/l (42–1505,P<0.0001). In the non-overloaded patients it declined from82 µg/l (8–461) to 45 µg/l (5–379, P=0.016).The transferrin saturation (TS) in the overloaded patients appearedto decline from 38.3±7.2% to 24.0±3.7% but thiswas not statistically significant. In the non-overloaded theTS was unchanged (23.3±2.4 before and 28.1±3.6%after treatment). Considering all 38 patients together, thehaemoglobin correlated negatively with the ferritin (r=0.3731,P<0.001) but not with the TS. The TS correlated with theserum ferritin initially (r=0.75, P<0.001) but not afterthe first 4 weeks. At 12 weeks, eight of 15 patients with irondeficiency (ferritin<50 µg/l) had a TS >20%, whereastwo of five patients with persistent iron overload (ferritin>500 µg/l) had a TS <20%. We conclude that (a) inpatients with iron overload, stored iron is utilizable for erythropoiesis;(b) oral iron supplements are necessary and sufficient for mostpatients without iron overload; (c) the serum ferritin is abetter indicator of iron status than the TS for renal patientson erythropoietin.     

Survey of Blood Lead and Plasma Aluminium Concentrations in Patients of a Renal Unit

Blood lead and plasma aluminium concentrations have been measuredin patients with end-stage chronic renal failure treated byhaemodialysis (HD) or by continuous ambulatory peritoneal dialysis(CAPD) and in a control group of non-dialysed patients withchronic renal failure (CRF). Data on a group of subjects withnormal renal function is included for comparison. We have foundsignificantly increased mean blood lead and plasma aluminiumconcentrations in all patients with chronic renal failure comparedto a group with normal renal function. All blood lead concentrations were within the accepted safeexposure range of less than 1.8 µmol/l (380 µg/l)).There were significant differences among the patient groups:home HD, 0.60±0.25 µmol/l (124±52 µg/l);hospital HD, 0.39±0.31 µmol/l (81±64 µg/l);CAPD, 0.32±0.17 µmol/l (66±35 µg/l);CRF, 0.38±0.20 µmol/l (79±41 µg/l);normal, 0.24±0.11 µmol/l (50±23 µg/l).Correction of the blood lead results for haemoglobin accentuatesthese differences (i.e. hospital HD, 4.61±3.25 nmol/g(0.96±0.67 µg/g); CRF, 3.05±1.46 nmol/g(0.63±0.30 µg/g); normal, 1.65±0.70 nmol/g(0.34±0.14 µg/g). Plasma aluminium concentrations show a similar pattern: homeHD, 1.09±0.70 µmol/l (29.4±18.9 µg/l);hospital HD, 0.81±0.58 µmol/l (21.9±15.7µg/l); CAPD, 0.34±0.34 µmol/l (9.2±9.2µg/l); CRF, 0.18±0.09 µmol/l (4.9±2.4µg/l); normal, 0.09±0.07 µmol/1 (2.4±1.9µg/l). The duration of dialysis treatment is an important determinantof metal accumulation: there is a significant positive correlationbetween the duration of dialysis treatment and both blood lead:haemoglobinratio (r=0.48, P<0.01) and plasma aluminium (r=0.61, P<0.01)concentrations. There is also a significant negative correlation(r= –0.59, P<0.01) between urine volume and plasmaaluminium for haemodialysis patients, but not for peritonealdialysis patients. Urine volume shows no relationship to bloodlead. Age has no effect on lead accumulation in any of the patientgroups, but there is a significant correlation of age to bloodlead in the normal renal function group (r=0.47, P<0.01).The effect of sex and hypertension on metal concentrations isalso discussed. It is considered probable that the dialysate is a major factorcontributing to the accumulation of both elements. The possiblelong-term clinical significance of these findings remains tobe determined.     

Prevention of acute cyclosporin nephrotoxicity by verapamil and atrial natriuretic factor in the rat

Nephrotexicity is the most common and important side-effectof cyclosporin (CsA) therapy. CsA alters renal haemodynamicswith a reduction in renal blood flow (RBF) and glomerular filtrationrate (GFR) and a significant increase in renal vascular resistances(RVR). The present experimental study investigates whether verapamilor atrial natriuretic factor (ANF) are able to prevent the nephrotoxicityof CsA. All studies were conducted in an in-situ autoperfused rat kidneymodel which allows continuous measurement of renal blood flowwithout dissection of the renal artery. CsA as a 40 mg/kg bolus dose significantly decreased RBF (from2.15±0.1 and 2.19±0.1 before CsA, to 1.29±0.16ml/min/100 g BW, 60 mm after CsA administration) (P<0.05),and GFR (from 0.14±0.1 and 0.13±0.01 before CsA,to 0.08±0.01 ml/min/100 g BW, 60 min after CsA administration)(P<0.05). CsA significantly increased RVR (from 9.5±0.73and 9.8±0.78 before CsA, to 16.7±2.9 mmHgxmin/ml60 min after CsA administration) (P<0.05). Verapamil pretreatment(as continuous intrarenal infusion at the rate of 1.25 µg/kg/min)attenuated the fall in GFR (from 0.16±0.01 and 0.19±0.03ml/min/100 g before CsA to 0.20±0.05 ml/min/100 g BW,60 mm after CsA administration) (NS) and in RBF (from 2.42±0.2and 2.6±0.22 ml/min/100 g before CsA to 1.79±0.17ml/min/100 g BW, 60 min after CsA administration (P<0.05).Pretreatment with ANF (as continuous intrarenal infusion atthe rate of 2.5 µg/kg/min) protected GFR (from 0.11±0.02and 0.18±0.03 ml/min/100 g before CsA, to 0.11±0.03ml/min/100 g BW, 60 min after CsA administration) (NS) and RVR(from 9.53±0.6 and 8.95±0.74 mmHgxmin/ml beforeCsA to 11.93±1.19 minHgxmin/ml, 60 min after CsA administration)(NS)and attenuated the fall in RBF (from 2.17±0.11 and 2.2±0.14ml/min/100g before CsA to 1.56±0.25 ml/min/100 g BW 60mm after CsA administiation)(P<0.05) when compared with initialvalues. These studies suggest that verapamil and ANF can prevent CsA-inducedrenal toxicity. Further studies should evaluate their usefulnessin clinical practice.     

Effect of L-carnitine administration on erythropoietin use in thalassemic minor haemodialysis patients.

Sir, We read with great interest the recent letter by Arduini etal. [1], on the effect of L-carnitine (LC) on erythrocyte survivalin haemodialysis patients. In the same issue, there is a paperby Hothi et al. [2] showing that plasma free-carnitine (FC)levels fell from 26.54 ± 2.99 to 15.6 ± 2.34 µmol/l(P < 000.1) in nocturnal haemodialysis (NHD). A similar reductionin plasma acyl-carnitine (AC) levels was observed (from 13.22± 1.34 to 6.24 ± 1.20 µmol/l (P < 0.001)).The AC : FC ratio improved from 0.51     

Low-dose simvastatin is safe in hyperlipidaemic renal transplant patients

Hyperlipidaemia is common after renal transplantation, and becauseof its association with atherosclerosis, interest has increasedin the use of lipid-lowering drugs in transplant patients. Dietaryapproaches have not been consistently successful, and multiplepharmacotherapy and drug interactions have led to difficultiesin establishing lipid-lowering drug regimes. The statins reduceplasma cholesterol by inhibiting the rate-limiting step in cholesterolsynthesis, and although some side-effects have been reportedin their use after transplantation, the efficacy and safetyof low doses has not been formally established. A randomized single-blind placebo crossover study designed todetermine the safety and effectiveness of simvastatin in a singledaily 5-mg evening dose was therefore conducted in 26 stablerenal transplant patients, 14 of whom were receiving cyclosporinA. The results demonstrated no difference between total cholesterollevels in the baseline simvastatin and placebo periods: 7.97± 1.2 and 7.59±1.5 mmol/l respectively. After8 weeks of simvastatin, the total cholesterol declined significantlyto 6.72±0.87 mmol/l (P<0.001). A significant differencewas found when the placebo and simvastatin cholesterol levelswere compared at 4 and 8 weeks (P<0.01). LDL cholesterol decreased from 4.74 ± 0.87 to 3.78 ±0.78 mmol/l after 8 weeks on simvastatin (P<0.001), and apoB fell from 142 ± 31 to 112 ± 22 mg/dl (P<0.001).The difference in LDL cholesterol and apo B after 8 weeks ofsimvastatin when compared with the corresponding values on placebowas also significant (P<0.01). A slight but not significantincrement in HDL cholesterol from 1.10 ± 0.47 to 1.13± 55 mmol/l (NS) was seen after 8 weeks on simvastatin. Triglycerides and serum creatinine did not change during thestudy in any of the groups. Creatine kinase (CK.) remained inthe normal range (0–200 U/l), except for one patient nottaking cyclosporin who had a CK value slightly above the upperlimit of normal during the simvastatin period, without abnormalclinical signs. Repeated cyclosporin measurements remained withinthe therapeutic range (50–150 ng/ml). These results suggestthat low-dose simvastatin is effective and safe in reducingtotal cholesterol and LDL cholesterol in renal transplant patients.     

Long-term Cyclosporin Nephrotoxicity in the Rat: Effects on Renal Function and Morphology

This long-term study elucidates the development and reversibilityof functional and morphological cyclosporin (CsA) nephropathy. Sprague–Dawley rats were given CsA (12.5 or 25 mg/kg perday) for 4, 8 or 16 weeks, or CsA during the first half of the8- or 16-week period, and vehicle during the second half. Controlswere given CsA vehicle throughout the study. Renal functionwas investigated with clearance methods (inulin, lithium, sodiumand potassium). CsA-treated rats developed a focal renal interstitial fibrosis,the severity of which correlated to the accumulated CsA dosegiven (Kendall's tau=0.56, P<0.000l). This renal lesion wasnot reversible. CsA reduced GFR and lithium clearance, and increased proximalfractional reabsorption. There was significant correlation (P<0.000l)between accumulated CsA dose and severity of functional impairment.Renal function improved following drug withdrawal, but in thecompiled material, low-grade nephrotoxicity was evident 4 to8 weeks after CsA withdrawal: GFR was decreased to 84% (P<0.02)of control levels. This indicates that CsA-induced renal focal interstitial fibrosisis progressive during treatment, and is not reversible, whilefunctional CsA nephropathy is progressive but partly reversibleif CsA is withdrawn.     

Cyclosporin does not inhibit the tubular secretion of creatinine

BACKGROUND: The immunosuppressive drug cyclosporin is known to impair renalfunction. The degree of renal dysfunction is usually estimatedfrom the clearance of creatinine (C_Cr). Theoretically however,a fall in C_Cr can be caused by a decrease of GFR, an inhibitionof the tubular secretion of creatinine, or the combination ofboth. CsA has convincingly been shown to decrease GFR, but detailedinformation on the effects of CsA on tubular secretion of creatinineis lacking. METHODS: We performed two studies to investigate the influence of CsAon tubular creatinine secretion. In study A we simultaneouslymeasured C_Cr and GFR (using inulin) immediately before and 4weeks after cessation of CsA therapy in 17 renal transplantpatients. In study B, the rise in serum creatinine after administrationof cimetidine, which blocks the tubular secretion of creatinine,was compared in renal transplant patients treated with eitherCsA (in whom secretion might already be inhibited) or azathioprine. RESULTS: Study A: After cessation of CsA there was an increase of GFR(54±15 vs 63± 16 ml/min/1.73 m²; P>0.01) andof C_Cr (71±21 vs 82±23 ml/min/1.73 m²; P>0.01),but the ratio between C_Cr and GFR (a measure of the relativecontribution of tubular secretion to the clearance of creatinine)did not change significantly (1.33±0.21 vs 1.32±0.30).Study B: In nine couples of patients matched for GFR the relativerises in serum creatinine after administration of cimetidinewere 26±21% and 22±7% for the CsA and azathioprinetreated patients respectively (NS). CONCLUSIONS: CsA does not substantially inhibit the tubular secretion ofcreatinine. A rise in serum creatinine after administrationof CsA can thus be attributed completely to a fall in GFR.     

Bidirectional peritoneal transport of albumin in continuous ambulatory peritoneal dialysis

The present study was undertaken in order to assess bidirectionalperitoneal kinetics of albumin after simultaneous i.v. and i.p.injection of radioiodinated albumin tracers (¹²⁵I-RISA and ¹³¹I-RISA)in eight clinically stable uraemic patients undergoing continuousambulatory peritoneal dialysis (CAPD). The plasma volume, intravascularalbumin mass (IVM), and overall extravasation rate of albuminwere not significantly different from that found in healthycontrols. Albumin flux from the plasma into the peritoneal cavitywas 3.71 ± 0.82 (SD) µmol/h, which was only 3%of the overall extravasation rate (137 ± 52 µmol/h).Albumin flux from the peritoneal cavity into the plasma wassubstantially lower (0.22 ± 0.07 µmol/h, P<0.01).The net peritoneal accumulation of the albumin from plasma over4 h was 14 ± 3.2 µmol, which was significantlylower than the intraperitoneal albumin mass at the end of thedialysis (54 ± 19 µmol, P<0.01). This indicatesthat only about 25% of the albumin loss during CAPD occurs directlyfrom the plasma. The initial osmotic net filtration was 508± 302 ml. The volume flow equivalent to the albumin fluxwas 6.3 ± 1.5ml/h into the peritoneal cavity and 7.8± 1.9ml/h back into the plasma. Although minor, as comparedto the osmotic net filtration (508 ml), the albumin flux equivalentvolume (31.2 ml) exceeded the steady state filtration (25.2ml) significantly (P<0.01) during the 4 h investigation. In conclusion, albumin flux into the peritoneal cavity is smallcompared to the overall extravasation rate, but our resultssuggest that CAPD loss of albumin predominantly occurs fromthe subperitoneal interstitial space and only to a minor degreedirectly from the plasma. Albumin flux equivalent volume flowis relatively small and most probably represents peritoneallymph drainage.     

Adequacy of dialysis and nutritional status in CAPD

Urea kinetic modelling (UKM) was used to assess adequacy ofdialysis in 50 CAPD patients. Nutritional status was assessedfrom the measurement of visceral protein status (total protein,albumin, transferrin, immunoglobulins, complement), somaticprotein status (anthropometry), and dietary intake (1 week weigheddietary inventory and normalized protein catabolic rate (NPCR)from UKM). Morbidity was assessed from the peritonitis and admissionhistory. Mean Kt/V (corrected to x3 weekly dialysis) was 0.66 ±0.02. Dietary protein intake estimated from the NPCR (1.08±0.03g kg^–1 day^–1) correlated well (r=0.72, P<0.001)with that estimated from the dietary inventory (1.10±0.04g kg^–1 day^–1). There was a strong correlation betweenKt/V and NPCR corrected for actual weight (r=0.65, P<0.001),but when NPCR was corrected for IBW this correlation was weaker(r=0.35, P<0.05). Patients were divided by Kt/V into twogroups (>0.65, n=22 and <0.65, n=28). There were no significantdifferences in the indices of visceral protein status betweenthe two groups. Weight, height, BMI, fat free mass and arm musclearea were significantly greater in the group Kt/V<0.65. Residualrenal function (creatinine clearance) was higher in the groupKt/V>0.65 (3.8±0.7 versus 1.9±0.5 1/24 h, P<0.05)and plasma creatinine less (913±51 versus 1265±51µmol/l, P<0.001). Hb, potassium, bicarbonate, phosphate,alkaline phosphatase, PTH, and blood pressure were not different.Neither was there any difference between the two groups in anyof the indices of morbidity.     

Hyperhomocysteinaemia: a significant risk factor for cardiovascular disease in renal transplant recipients

Moderate hyperhomocysteinaemia has been shown to constitutean independent risk factor for cardiovascular disease (CVD),a frequent cause of morbidity and mortality in renal transplantrecipients (RTR). In these patients few data regarding bothtotal homocysteine levels and their influence on cardiovas cularrisk have been reported. We therefore studied serum homocysteinelevels in deep-frozen sera from 42 kidney transplant recipientswith a follow-up of 11±4.5 years (mean±SD) aftertransplantation. Eighteen patients had one or more ischaemicevents (CVD(+)) and 24 patients had none (CVD(–)). Serumsamples had been drawn 1–6 months prior to the first vascularevent in CVD(+) patients and serum storage time was comparablein both CVD(–) and CVD(+) patients. Serum homocysteinelevels were measured using a radioenzymatic method. Mean homocysteinelevel was significantly higher in 42 RTR males and females (15.5±6.3,13.5±5.5 µM respectively) compared with 35 controlsubjects matched for age and sex (8.7± 1.9, 7.5±l.9µP<0.001). The difference in serum homocysteine levelsbetween CVD(+) and CVD(–) RTR nearly reached statisticalsignificance in male patients (18.6±7.8 versus 13.1 ±3.4µM, P<0.06) but not in female patients (P=NS). In theCVD(+) group 11/18 patients had homocysteine levels > 14µM (the upper limit in healthy controls) versus 7/24 inthe CVD(–) group (P=0.04). In these patients we simultaneouslymeasured in the same serum samples, serum triglycerides, andtotal and HDL cholesterol, and calculated LDL cholesterol. Bystepwise discriminant analysis and by logistic regression analysisin this relatively small patient population, only serum triglyceridesand homocysteine were selected as risk factors associated withCVD. We conclude that signi ficant hyperhomocysteinaemia ispresent in renal transplant recipients and represents a potentialrisk factor for cadiovascular disease in these patients.     

Plasma Oxalate Concentration, Oxalate Clearance and Cardiac Function in Patients Receiving Haemodialysis

Pre-dialysis plasma oxalate concentration was measured in across-sectional study of 75 patients receiving maintenance haemodialysis.The aims of this study were to enable formulation of hypothesesregarding the determinants of plasma oxalate concentration andto allow preliminary examination of the possibility that hyperoxalaemiaconfers an increased risk of cardiac and vascular disease evenin the absence of primary hyperoxaluria. Plasma oxalate concentrationranged between 7 and 76 µmol/l, mean (SD) 34.6 (18.1)µmol/l(normal range < 0.8–2.0 µmol/l). Significantcorrelations were found between plasma oxalate concentrationand plasma creatinine, duration of dialysis, current dose ofascorbic acid, and serum phosphate, and each of these variablesretained significance on multiple linear regression. Oxalate clearance across a 1 m² hollow-fibre Cuprophan dialyser,at 500 ml/min dialysate flow and blood flow between 175 and225 ml/min, was measured 1 h after commencement of dialysis(n=19). Mean (SD) clearance was 96.5 (27.0) ml/min. No significant association was found between self-reported maximumwalking distance or the occurrence of symptons of cardiac failureand plasma oxalate concentration. No relationship was foundbetween plasma oxalate concentration and electrocardiographicconduction disturbances (n=8) ‘major’ ST/T wavechanges (n=22), ‘minor’ ST/T wave changes (n=49).Plasma oxalate was significantly greater in patients with radiologicallydetectable calcification of medium-sized arteries than in thosewithout calcification, but duration of dialysis was also significantlylonger in these patients. Routine haemodialysis results in marked hyperoxalaemia, whichmay be exacerbated by ascorbate supplementation. Oxalate clearanceis similar to that of other small molecules such as creatinineand phosphate. No relationship was demonstrated between hyperoxalaemiaand symptoms of cardiac disease. The question of whether hyperoxalaemiaconfers an increased risk of vascular calcification will onlybe answered definitively by prospective studies.