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.     

Increased erythropoietin requirements in patients with failed renal transplants returning to a dialysis programme

The response to erythropoietin (Epo) is dose dependent but,for various poorly understood reasons, variable. In a cross-sectionalstudy we determined the Epo requirement of 60 patients in adialysis population to identify those patients requiring a highdose of Epo, and ascertained the reasons for higher requirements,paying particular attention to the effect of previous transplantation.All 289 patients attending a single centre were surveyed. Ofthese, 164 were receiving renal replacement therapy by continuousambulatory peritoneal dialysis (CAPD) and 125 were on haemodia-lysis(HD). Patients on HD needed more Epo than those on CAPD (129.0±14.9U/kg/week versus 86.9±10.7 U/kg/week, P<0.05). However,this difference was accounted for by a subgroup of patientswho had a previously failed transplant. The Epo requirementin those patients on HD with a failed transplant was significantlygreater than those on HD who had never been transplanted (164.0±24.5 U/kg/week versus 96.6 ± 11.9 U/kg/week, P<0.05).The seven patients who retain their transplanted kidney hadthe highest Epo requirement of all (213.4±46.6 U/kg/week).These studies have shown that previous transplantation is asignificant determinant of Epo requirement upon return to dialysis.They also show that it is necessary to ‘correct’for the effect of previous transplantation when investigatinggenerally accepted determinants of Epo need. Interpretationof previously published studies needs to take account of this.     

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.     

Vitamin D3 Metabolites in Chronic Renal Failure and After Renal Transplantation

Circulating vitamin D3 metabolites were measured in 31 adultpatients with chronic renal failure and 31 adults between 3and 30 months after renal transplantation. No subject excretedover 1 g urinary protein daily nor received vitamin D or itsmetabolites. There was a positive correlation between 1,25(OH)₂D3and GFR between 15 and 90 ml/min in both chronic renal failure(r=0.60, P<0.001) and transplant subjects (r=0.49, P<0.01)and between 1.25(OH)₂ and 25(OH)D3 after transplant (r=0.69,P<0.001), but not in chronic renal failure (r=0.22, P=ns).There was a weak inverse correlation between 1,25(OH)₂D3 andserum phosphate in chronic renal failure (r=0.36, P<0.05)but not post transplant (r=0.03, P=ns). Compared with 1,25(OH)₂D3concentrations in 16 normal subjects (mean±SEM: 39.5±1.9 pg/ml), chronic renal failure subjects with mild renal impairment(GFR 45–90 ml/min, mean: 61.5±3.3 ml/min, n=17)had reduced 1,25(OH)₂D3 (28.9±2.7 pg/ml, P<0.01).In transplant subjects with mild impairment (GFR 45–90ml/min, mean: 61.4±3.7), 1,25(OH)₂D3 was positively (r=0.79,P<0.001) and iPTH inversely correlated (r=0.51, P<0.05)with 25(OH)D3. In each of nine such subjects studied, seasonalvariations in 1,25(OH)₂ (P<0.001) and PTH (P<0.05, 1-tailedtest), as well as in 25(OH)D3 and 24,25(OH)₂D3 were observed.We conclude that (1) 1,25(OH)₂D3 may be reduced early in thecourse of chronic renal failure and that (2) because of abnormaldependence of 1 ,25(OH)₂D3 on 25(OH)D3, low 25(OH)D3 may resultin reduced 1,25(OH)₂D3 values post transplant. Increased PTHin such cases suggests the functional significance of theseobservations.     

Long-term graft survival after conversion from cyclosporin to azathioprine 1 year after renal transplantation. A prospective, randomized study from 1 to 6 years after transplantation

Cyclosporin has improved graft survival after renal transplantation,but cyclosporin nephrotoxicity is a severe clinical problem.Conversion from cyclosporin to azathioprine 1 year after transplantationmight improve long-term graft survival by avoidance of cyclosporinnephrotoxicity. After treatment with cyclosporin and prednisoloneduring the first year after renal transplantation, 106 patientswere consecutively randomized to treatment with either azathiprineand prednisolone or cyclosporin and prednisolone in a prospective,controlled study during the following 5 years, i.e. 6 yearsafter transplantation. Actuarial estimates of graft survivalrates after inclusion in the study were obtained by the product-limitmethod of Kaplan-Meier, and the Mantel-Cox log rank test wasused to compare the two treatment regimens. When the end-pointsin the analyses were cessation of graft function or withdrawalof immunosuppressive treatment due to side-effects, and whenpatients alive with graft function or who had died with a functioninggraft were treated as censored observations, graft survival5 years after inclusion in the study was 57.7±5.2% inthe total material and was the same in both the azathioprinegroup (52.4±7.7%) and the cyclosporin group (63.3±6.7%)(log rank=0.40, P=0.53). When cessation of graft function wasthe only end-point, graft survival 5 years after inclusion inthe study was 73.7±5.2% for the total material with nosignificant differences between the two groups (log rank=0.58,P=0.45). Assuming that cyclosporin and prednisolone were usedduring the first year after renal transplantation, it can beconcluded that conversion to treatment with azathioprine andprednisolone does not deviate from continued treatment withcyclosporin and prednisolone with regard to long-term graftsurvival for the following 5 years.     

Reduced left ventricular hypertrophy in type 1 diabetic patients with end-stage renal failure. A comparison between groups investigated 1977-80 and 1991-93

BACKGROUND.: During the last decade, control of hypertension, oedema, anaemia,uraemia, and blood glucose has improved in patients with diabeticnephropathy. We have investigated whether this has influencedcardiac function at the time of end-stage renal failure. STUDY DESIGN.: Echocardiographic investigations were performed in 26 type 1diabetic patients evaluated for kidney transplantation and theresults compared with those obtained in healthy controls andin a similar group of patients investigated in 1977–1980. RESULTS.: Blood pressure was 153 ± 21/85 ± 12mmHg versus174±17/91±9 (recent group versus early group).The left ventricular (LV) diameter index, ameasure of volaemia,was increased in systole and diastole in the early but not inthe recent group. Both groups had LV hypertrophy, but this wasmuch less pronounced in the recent group; posterior wall thicknesswas 1.1 ± 0.16 cm versus 1.3 ± 0.26 cm (P = 0.0001)and LV mass index 132±43 g/m² versus 166 ± 44g/m² (P = 0.009). Blood pressure correlated significantly withindices of LV hypertrophy in the recent group. Systolic functionwas normal in both groups but diastolic function was disturbedin both and to the same extent, atrial systole contributingby 27±14% to ventricular filling. CONCLUSION.: Better treatment of hypertension, fluid overload, and uraemiahas led to less pronounced LV hypertrophy. The remaining correlationwith blood pressure suggests that more could be gained by intensifiedantihypertensive treatment.     

Recombinant human erythropoietin corrects anaemia during the first weeks after renal transplantation: a randomized prospective study

BACKGROUND.: Studies on the effect of recombinant human erythropoietin (rHuEpo)on haematopoiesis in patients with kidney transplants, havebeen limited to progressive chronic graft failure, late aftertransplantation. In the present prospective randomized study,the efficacy of rHuEpo in the correction of anaemia during thefirst weeks after renal transplantation (RTP) was evaluated. METHODS.: Patients were allocated to either an Epo-(n=14) or a non-Epo-treatedgroup (n=15). Epo (150 U/kg.week s.c.) was started at a haematocrit(Hct) <30% and was increased at weekly intervals by 30 U/kg.week,as long as Hct remained <25%. RESULTS.: In the Epo group, Hct increased from a nadir of 22±4%2 weeks after RTP to 30±4% at week 4 and to 36±4%at week 6 (P<0.001 and P<0.0001 respectively vs week 2).Corresponding values in the non-Epo group were 25±6%,28±6% (P=NS) and 32±6% (P<0.05 vs week 2) (overallevolution Epo vs non-Epo: P=0.038 by variance analysis). Thedifferences in Hct between the Epo and non Epo group were evenmore marked in patients without major complications (varianceanalysis P=0.009). The Epotreated patients required fewer post-surgicalblood transfusions (0.005 vs 0.014/days follow-up, P<0.05),in spite of greater post-surgical blood losses, especially atday 1 (P<0.05) and the presence of more major complications(7 vs 4) and a higher number of ganciclo vir-treated patients(4 vs 0; P<0.05). The maximum Epo dose after RTP was >2xhigher than the one required before RTP (197.1±45.1 vs85.0±76.0 U/kg.week; P<0.05). CONCLUSIONS.: It is concluded that rHuEpo during the first weeks after RTPis of benefit in the correction of the Hct in the early post-surgicalperiod, in spite of relative Epo resistance.     

Compliance and effects of nutritional treatment on progression and metabolic disorders of chronic renal failure

Low-protein, low-phosphorus diets (LPD) are prescribed to patientswith chronic renal failure (CRF) to slow down the rate of progressionof CRF and to control uraemic symptoms. A satisfactory adherenceof patients to the prescribed diet is needed to meet these twogoals. We studied the compliance of CRF patients to a LPD providingdaily (per kg body weight) 0.3 g protein, 3–5 mg phosphorus,35 kcal, and supplemented with essential amino-acids and ketoanalogues.Forty CRF patients were studied for 23.3±10.8 months(range 12–45). Compliance to LPD was evaluated by dietaryinquiry and protein intake estimated from urinary urea excretion.According to compliance to LPD, patients were retrospectivelyassigned to the compliant (n=27) or the non-compliant (n=13)group. GFR measured by the urinary clearance of [⁵¹Cr]-EDTAwas identical in the two groups at the start of the study: compliantpatients 15.7±5.3 ml/mn, non-compliant patients 15.4±5.9ml/mn. The decrease of GFR was – 0.08±0.22 ml/minper month in compliant patients versus –0.31±0.37ml/min per month in non-compliant patients (P<0.02). Theseresults were not demonstrated if the progression of CRF wasassessed by the linear regressions over time of creatinine clearanceor the reciprocal of creatinine. Serum bicarbonate, serum phosphorusand PTH levels were corrected by LPD in compliant patients (P<0.005 for all parameters) but not in non-compliant patients.These results suggest that evaluation of compliance is necessaryto assess the response of CRF patients to LPD, whether the aimis to slow the progression of CRF or to control its metabolicconsequences. A beneficial effect of compliance to LPD was demonstratedupon these two goals.     

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.     

Excellent uricosuric efficacy of benzbromarone in cyclosporin-A-treated renal transplant patients: a prospective study

Patients on cyclosporin A (CsA) often develop hyperuricaemiaand gout. In transplant patients the use of uricosuric drugsfor treating hyperuricaemia may be preferable to allopurinolbecause of the known interaction of the latter with azathioprine.We therefore prospectively studied the uricosuric efficacy of100 mg benzbromarone (Bbr;Desuric®) daily in 25 CsA-treatedrenal transplant patients with stable graft function and hyperuricaemia(>359 µmol/l for females, >491 µmol/l formales). Benzbromarone decreased plasma uric acid from 579±18µmol/l to 313±24 µmol/l (mean±SEM;P<0.001) and thereby normalized plasma uric acid in 21 of25 patients. The remaining four patients had creatininc clearancesbetween 21 and 25 ml/min, the lowest of the entire study group.Mean fractional clearance of uric acid increased from 5.4±0.4%to 17.2±1.0% (P<0.001). The relative decrease of plasmauric acid closely correlated with baseline creatinine clearance(r=0.67; P<0.001). CsA trough values were not influenced.None of the patients experienced any significant side-effects.As an unexpected find-ing, urinary uric acid excretion increasedfrom 2082 ± 175 µmol7sol;24 h to 3233 ±232µmol/24 h after 4 weeks' treatment with benzbromarone. In conclusion, benzbromarone normalized plasma uric acid inall CsA-treated renal transplant recipients with a creatinineclearance >25 ml/min. Due to its excellent efficacy and lackof significant side-effects, benzbromarone appears to be preferableto allopurinol in CsA-treated renal transplant recipients witha creati nine clearance over 25 ml/min.     

Bilateral nephrectomy simultaneously with renal allografting does not alleviate hypertension 3 months following living-donor transplantation

Severe hypertension prior to renal transplantation has traditionallybeen an indication for bilateral nephrectomy. The reasons forhypertension after successful renal transplantation are howevermany, and the impact of simultaneous bilateral nephrectomy (BN)in this setting has not been well documented. We retrospectivelyevaluated 158 living-donor renal graft recipients. BN had beenperformed in 76 patients at the time of the transplantationand 82 were not nephrectomized (controls). All received a tripleimmunosuppressive drug regimen. Before transplantation, patientsin the BN group used 1.8±0.9 (mean±SD) antihypertensivedrugs/day, significantly more than in the control group (1.3±0.8;P<0.05). Three months after renal transplantation no differencewas found (0.9±1.0 drugs/day in the BN group vs 1.0±0.8drugs/day in the control group). No difference was found withrespect to serum creatinine, whole blood cyclosporin A (CsA)concentration or blood pressure between the groups. The numberof blood transfusions during the first week after transplantationwas significantly increased in the BN group (66 SAG units vs4 SAG units). The median hospitalization length was also longerin the BN group (21 days vs 16 days). In order to circumscribethe pre-transplant difference in use of antihypertensive medicationwe studied a subgroup of 62 hypertensive recipients (BN/control= 31/31) matched for number of antihypertensive drugs at thetime of transplantation (2.3±0.5 drugs/day in the BNgroup, 2.1±0.3 drugs/day in the control group). Threemonths after transplantation the use of antihypertensive drugsremained the same in the two groups (1.3±1.0 drugs/dayin the BN group vs 1.3±0.9 drugs/day in the control group).At 3 months no difference was found between the two hypertensivesubgroups regarding serum creatinine, whole blood CsA and haemoglobinconcentration or systolic blood pressure. However, the BN patientswere younger than the control group (38±10 years vs 49±11years, P<0.05) and this may explain the marginally lowerdiastolic blood pressure observed in the BN group (82±10mmHg vs 87±7 mmHg, P<0.05). It is concluded that,in recipients of living-donor grafts, bilateral nephrectomyperformed at the time of transplantation did not influence thenumber of antihypertensive drugs used 3 months after a successfultransplantation. Bilateral nephrectomy did however increasethe need of blood transfusions during the first week after transplantationand also the hospitalization length.     

The effect of rhubarb extract on experimental renal fibrosis

In order to explore the therapeutic potential of traditionalChinese medicinal herbs on the progression of experimental chronicrenal failure (CRF), we have studied the effect of orally administeredrhubarb extract on the course of CRF in rats submitted to subtotalnephrectomy (SNx). Adult male Wistar rats were submitted toeither a SNx (n=18) or a sham operation (n= 10). Thirty daysafter SNx, nine SNx and five sham operated rats were given aqueousrhubarb roots extract (150 mg/day) in drinking water. The ratswere followed up for 120 days. Rhubarb treatment had no effecton the systemic hypertension observed in SNx rats. Rhubarb-treatedSNx rats had significantly less proteinuria 90 days (172±63mg/24 h) and 120 days (228±92 mg/24 h) after SNx whencompared to untreated SNx controls (day 90, 246 ± 80mg/24 h; day 120, 335±113mg/24 h, P<0.05). Renal functionwas comparable in rhubarb-treated and untreated SNx rats. However,at sacrifice the severity of glomerulosclerosis was significantlyreduced in SNx rats treated with rhubarb (2.03±0.44;SNx controls, 2.58±0.53, P<0.05). The difference intubulointerstitial scarring between the two groups did not reachsignificance. Our results suggest that rhubarb extract reducesproteinuria and the severity of glomeruloscierosis in rats withremnant kidneys.     

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.     

A double-blind, randomized, placebo-controlled study of nifedipine on early renal allograft function

A double-blind, randomized, placebocontrolled study was conductedto determine the effect of nifedipine on early renal allograftfunction when added to a triple therapy immunosuppression regimecomprising low-dose cyclosporin (CsA), prednisolone and azathioprine.Fifty adult cadaveric renal allograft recipients were randomizedto placebo (group P n=17), nifedipine 10 mg preoperatively and20 mg b.d. postoperatively for 48 h, followed by matching placebofor 3 months (group NS n=16) or nifedipine 10 mg preoperativelyand 20 mg b.d. postoperatively for 3 months (group NL n=17).Donor and recipient exclusion criteria included recent calciumantagonist treatment. At 3 months after transplantation meanGFR adjusted for graft loss was significantly higher in groupNL than in NS (mean ± SD 61±28 versus 34 ±25 ml/min/1.73 m²; P<0.05), group P being intermediate (45± 34ml/min/1.73 m²). Similarly, effective renal bloodflow (ERBF) at 3 months was higher ingroup NL than in groupsP and NS (mean ± SD 351 ± 175 versus 216±166and 220±162 ml/min/ 1.73 m²; P<0.05). The differenceswere not significant by 6 months post-transplantation. Thisstudy suggests that oral nifedipine commenced preoperativelyand continued for 3 months following transplantation has beneficialeffects on early renal allograft function whenincorporated aspart of an immunotherapy regimen based on cyclosporin.     

Urinary prostaglandins (PGE2 and PGI2) in hyporeninaemic hypoaldosteronism in diabetic patients with chronic renal failure

The present work studies the urinary excretion of PGE₂ and PGI₂(6-keto PGF 1) in 11 insulin-dependent diabetic patients withchronic renal failure with a glomerular filtration rate of 33.9±9.03 ml/min who had hyporeninaemic hypoaldosteronismto evaluate the influence of these prostaglandins on the appearanceof this latter process. The results obtained in this group ofpatients were compared with those of a control group of healthyindividuals, another group of nine non-diabetic patients withCRF, and a last group of eight insulin-dependent diabetic patientswith normal renal functión to evaluate to what extentthe possible variations in prostaglandin excretion could berelated to the diabetes, CRF, or a conjunction of both processes. The results of the groups of diabetic patients with CRF wereC_cr 33.9 ±9.03 ml/min, decreased (P< 0.0001) withrespect to the control group and with no difference with theCRF group without diabetes; plasma potassium (4.7 ±0.4mEq/l), increased P<0.005) with respect to the values foundin the control group; plasma bicarbonate (17.8 ± 1.8mEq/l), decreased (P< 0.005) with respect to the controlgroup and also, though not significantly, with respect to thegroup of non-diabetic patients with CRF. Plasma aldosterone(pg/ml): resting 44.3±14.9; standing 65.7 ±63.5and post-frusemide 65.5 ±58.6, decreased (P<0.01)with respect to the other three groups. Plasma renin activity(PRA) (ng/ml/h): resting 0.34±0.3; standing 0.6 ±0.4, post-fmsemide 0.9 ±0.5, decreased significantlywith respect to the other three groups. PGE₂ (pg/mg Cr): basal1720±397; post-frusemide 2636±462, increased (P<0.05)with respect to the control group and that of the diabetic patientswithout CRF, but with no differences compared with the non-diabeticpatients with CRF. PGI₂ (pg/mg cr): basal 369 ±45 andpost-frusemide 699 ± 103, increased (P<0.01) withrespect to the controls and diabetic patients with normal renalfunction and with no differences compared with the non-diabeticpatients with CRF. Our findings indicate that patients with diabetes mellitus andCRF showing hyporeninaemic hypoaldosteronism have high urinaryexcretion of PGE₂ and PGI₂. The increase in the urinary prostaglandinsis related to CRF. The data rule out the hypothesis that thehyporeninaemic hypoaldosteronism of these patients is due toa deficit of prostaglandins.     

Effect of having a functioning cadaveric renal transplant on cardiovascular mortality risk in patients on renal replacement therapy

Our aim was to estimate the effect of having a functioning cadavericrenal transplant on the risk of cardiovascular and total mortalityin patients on renal replacement therapy (RRT). We retrospectivelystudied (by the Cox proportional hazards regression model) 195subjects who began RRT with maintenance dialysis in our centrefrom 1 January 1978 to 31 December 1991. Out of this number,76 patients received a cadaveric kidney transplant. Cardiovascular abnormalities at the onset of RRT were the principalindependent determinant of both total and cardiovascular mortalityrisk. As compared to patients on dialysis with the same durationof RRT, patients with a functioning renal transplant for morethan 1 year had a significantly lower total mortality risk (meanrelative risk (RR): 0.48 (0.25–0.91) (95% confidence limitsin parentheses), P=0.03), an effect whose significance disappearedafter adjustment for pretreatment conditions (RR=0.62 (0.30–1.30),P>0.3). However, the beneficial effect of a functioning renaltransplant for more than 1 year on cardiovascular mortalityrisk was significant, both before (RR=0.21 (0.06–0.74),P=0.02) and after the adjustment for pretreatment conditions(RR=0.32 (0.11–0.90), P=0.035). During the first yearafter a successful transplantation the beneficial effect ofhaving a functioning transplant on cardiovascular mortalityrisk was only weakly attenuated. During RRT a functioning cadaveric renal transplant decreasescardiovascular mortality risk partially independently of thebetter pretreatment status of the patients selected for transplantation.     

Misoprostol in renal transplant recipients: a prospective, randomized, controlled study on the prevention of acute rejection episodes and cyclosporin A nephrotoxicity

The aim of this prospective and randomized study was to determinewhether misoprostol, an analogue of PGE1, could decrease theincidence and the number of rejection episodes and could improvethe renal function over a 12-month follow-up, when given at400 µg/day for 12 months in renal transplant patients.Given the known side-effects and the additive cost of misoprostol,a benefit of the therapy should be a decrease of at least 50%in the incidence of rejection episodes in the treated group.Therefore, 60 consecutive renal transplant patients were randomizedto receive misoprostol or to receive aluminium and magnesiumhydroxide. Patients received steroids, azathioprine, antithymocyteglobulins, and cyclosporin A (CsA). CsA was randomly startedon day 0 or on day 8. At 12 months, no difference in the incidenceof rejection episodes was observed: 63.3% in the 30 patientsof the misoprostol + group versus 70.0% in the misoprostol-group(P=0.558 Mantel-Cox). The renal function, assessed by plasmacreatinine, inulin, and para-aminohippuric acid clearances,was not significantly different between misoprostol + and misoprostol-groups.No episode of CsA nephrotoxicity was observed in any patientof group one or group two. At 12 months, the mean dosage ofCsA was 4.9±0.28 mg/kg/day in the misoprostol+group versus4.52 ± 0.23 mg/kg/day in the misoprostol - group andthe trough level was not significantly different between thetwo groups. The graft survival rate at 12 months was 86.7% inthe Misoprostol+ group and 83.33% in the misoprostol- group.The trial failed to demonstrate a significant beneficial effectof misoprostol on the decrease of acute rejection episodes,on the prevention of CsA nephrotoxicity, or on the improvementof renal function over a 12-month period.     

Bone loss after kidney transplantation: a longitudinal study in 115 graft recipients

BACKGROUND.: Bone loss is an important problem in renal transplant recipientsimmediately after surgery. No data are available about the boneloss beyond the first post-transplantation year. METHODS.: In a longitudinal, uncontrolled observational study bone mineraldensity (BMD) was measured by dual X-ray absorptiometry in 115renal graft recipients starting at different times after transplantation(0–20 years after transplantation) with a follow-up timeof 12 months. RESULTS.: A total of 56 patients showed a reduction of BMD during theobservation period. Bone loss depended on the time after transplantation.Mean reduction of BMD at lumbar spine was 7±10%, 1±9%during the first and second postoperative year. Beyond the thirdyear bone mineral density did not change or even increased slightly(0±4% during 3–5th year, 1±6% during 6–10thyear and 2±4% during 11–20th year after transplantation).Decrease of BMD correlated with a higher mean daily prednisonedosage (P<0.001), a higher cumulative prednisone dose (P<0.01),a more frequent and more steroid-resistant rejection (P<0.001)and a higher initial parathyroid hormone level (P<0.001).Patients with 25-OH-cholecalciferol therapy (P<0.05) or morephysical activity (P<0.05) had a smaller bone loss. CONCLUSIONS.: Reduction of BMD after transplantation is highest within thefirst post-transplant year. The effects of acute graft rejection,prednisone dosage and initial parathyroid hormone level arepredominant among the multiple factors associated with pronouncedbone loss.     

Atrial natriuretic peptide, sodium retention, and proteinuria in nephrotic syndrome

BACKGROUND.: Oedema formation in the nephrotic syndrome is primarily dueto tubular sodium retention. The pathogenetic role of alphaatrial natriuretic peptide (ANP), a hormonal promoter of natriuresisis unknown. METHODS.: In 31 patients (aged 35±11 years) with nephrotic syndromeand histopathological evidence of primary glomerulonephritis,we investigated plasma ANP concentration and its influence onrenal haemodynamics, natriuresis, and proteinuria (total protein,albumin, IgG excretion). Patients with a compensated treatedform of nephrotic syndrome due to primary glomerulonephritiswere included in the study. Serum creatinine levels were 1.4mg/dl. Diuretic medication was discontinued at least 24 h beforethe investigation was started. Patients were randomly assignedto ANP infusion (0.005 µg/kg*min; group II, n=15) or receivedplacebo (group III, n=16). Ten healthy subjects (group I) servedas normal controls. RESULTS.: In normal subjects (group I), ANP caused an increase in natriuresisfrom 14.5±4.2mmol/h to 26.4±11.1 mmol/h (P<0.01).In patients with nephrotic syndrome (group II), baseline sodiumexcretion of 10.5±6.0 mmol/h was increased to 19.6±14.8mmol/h with ANP infusion (P<0.01). No changes were seen inthe placebo group III. The absolute increase in ANP inducednatriuresis was not significantly different between group Iand II. However, plasma ANP levels were significantly higherin patients with nephrotic syndrome (166±87 pg/ml vs.74±21 pg/ml, P<0.05) and also reached higher levelsafter ANP infusion (P<0.01). Therefore, natriuresis was significantlyreduced when circulating ANP levels were taken into account(P<0.05). ANP administration resulted in an increase of totalprotein excretion in patients with the nephrotic syndrome (groupII, from 219±277 mg/h to 264±268 mg/h). Albuminelimination rose from 128±151 mg/h to 167±170mg/h (P<0.05) and IgG excretion from 4.91±6.67mg/hto 9.27±10.78mg/h (P<0.05). Healthy subjects alsoshowed a small but significant increase in albuminuria (48±38%,P<0.05). Low-dose ANP infusion did not, however, induce anysignificant alteration in GFR, ERPF and blood pressure. CONCLUSION.: ANP plasma concentrations in the steady state are elevated inpatients with the nephrotic syndrome. The natriuretic effectof ANP is reduced when referring to circulating ANP plasma levels.Elevated ANP levels enhance urinary protein excretion in thenephrotic syndrome. This is not due to modulation of GFR orFF, but is most probably attributable to increased glomerularpermeability.     

Effect of prophylactic ganciclovir on cytomegalovirus infection in renal transplant recipients

Cytomegalovirus (CMV) infection is the most frequent infectiouscomplication observed in renal transplant recipients and inducesa significant morbidity in these patients due to CMV diseaseitself and to associated renal dysfunction or opportunisticsuperinfection. In order to evaluate the effect of ganciclovirprophylaxis we conducted an open-label prospective randomizedstudy of ganciclovir administration in CMV seronegative recipientsof a renal allograft from CMV seropositive donors. Ganciclovir(5 mg/kg b.i.d./day for 14 days) was started on day 14 aftertransplantation. Thirty-two patients were included in this study(15 in the control group, 17 in the ganciclovir group). Therewas no significant difference between the two groups for age,immunosuppressive regimen, number of rejection, steroid pulses,and OKT3 treatments. Renal and patient outcomes were similarin both groups. The rate of CMV infection and CMV disease weresimilar in both groups (80% and 73.3% in the control group versus70.6% and 47.1% in the ganciclovir group; P=NS). Less severeCMV disease was observed in the ganciclovir group compared tocontrols. The delay between transplantation and CMV infectionwas significantly longer in the ganciclovir group compared tocontrol group (68.1±5.1 versus 44.0±5.2 days,P<0.005). Twelve control patients (80%) versus nine (53%)of the ganciclovir group required curative treatment with ganciclovirafter the diagnosis of CMV infection (NS). All the patientsrecovered from CMV disease and no significant side-effect wasobserved during ganciclovir administration. We conclude that prophylactic ganciclovir administration fromday 14 to day 28 after transplantation does not prevent CMVinfection in seronegative recipients of renal allograft fromseropositive donors but prolongs the incubation period. Longerprophylaxis by ganciclovir in these patients should be tested.