Renal allograft immunosuppression: I. Early inflammatory and rejection episodes in triple drug treatment compared to double drug combinations or cyclosporin monotherapy

Abstract. We have investigated the impact of triple drug immunosuppression on the occurrence of early inflammatory episodes, as detected by fine needle aspiration biopsy, and of episodes of clinical rejection during the immediate postoperative period. The prospective component of this study includes 128 consecutive first cadaveric renal transplant recipients receiving triple drug treatment consisting of azathioprine (Aza), cyclosporin (CyA) and methylprednisolone (MP). For controls we have used three historical groups: one immunosuppressed with Aza and MP (group A), another with CyA monotherapy (group B), and the third with CyA together with MP (group C) in equivalent drug dosages. On the average, 0. 8 episodes of inflammation per patient were recorded during the immediate postoperative period of 30 days with triple drug treatment. This was significantly less than the 1. 3 episodes in patients receiving Aza and MP (P < 0. 01), the 1. 7 episodes in patients on CyA monotherapy (P < 0. 001), or the 1. 6 episodes in patients receiving CyA together with MP (P < 0. 001). Although the first episode of inflammation commenced concurrently in each group and the peak intensity of inflammation was the same, the mean duration of inflammation was significantly shorter-2. 7 days-under triple drug treatment than the 7. 8–11. 7 days for controls (P < 0. 001). The frequency of rejection episodes under triple treatment was also significantly lower-0. 2 per patient-than the 0. 8 per patient in controls (P < 0. 001). The first rejection episode occurred later in the triple drug treatment group-on the average, on day 15. 2-than in the historical controls (on days 7. 7–11. 7). There was, however, no difference in the duration of rejection. There were no differences in patient survival between the four groups. Graft survival was 97% at 10 weeks for triple drug-treated recipients and 79%, 68%, and 87% for first grafts in groups A, B, and C, respectively. Disregarding a minor demographic bias for the triple drug-treated group with respect to preformed antibodies and preoperative dialysis treatment, the study suggests that the triple drug protocol, in the short run, is superior to any conceivable double drug combination or CyA monotherapy.     

Renal allograft immunosuppression

The long-term effects of different immunosuppressive drugs and regimens on renal allograft histology are virtually unknown. Therefore, in order to investigate the long-term effects of triple drug treatment versus different combinations of two immunosuppressive drugs on allograft histology, a prospective, randomized trial was performed. One group received triple therapy consisting of low-dose cyclosporin (CyA), azathioprine (Aza), and methylprednisolone (MP), and three groups received combinations of two drugs, i.e., Aza plus CyA, Aza plus MP, and CyA plus MP. At 2 years, there were no significant differences with regard to graft (80%) or patient (87%) survival, or to graft function between the four groups. After 2 years, a protocol core biopsy was taken of all 102 patients having a functioning graft. Of these patients, 61 (60%) were still following the original, randomized treatment protocol; in the remaining cases, changes had occurred in the original protocol and so these cases were considered drop-outs in this study. Histological specimens were examined blindly by two independent observers. Most of the 34 histological variables examined showed no changes. Diffuse fibrosis was most frequent in the CyA plus MP group (70%) and significantly more severe than in the triple therapy group. Mesangial matrix increase in glomeruli was significantly less common in the triple therapy group (8%) than in any one of the double drug combination groups (47%). Two other changes in glomeruli--Bowman capsular thickening and global glomerular sclerosis--were also less frequent in the triple therapy group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal allograft immunosuppression

A prospective randomized study was conducted to evaluate the impact of four different conversion protocols on graft outcome in long-term follow-up. Between January 1986 and May 1987, 128 patients with first cadaveric kidnery allografts were randomized at the time of transplantation to four treatment groups of 32 patients each, to be assigned 10 weeks post-transplantation. During the first 10 weeks, all patients received triple therapy with low-dose azathioprine (Aza), cyclosporin (CyA), and methylprednisolone (MP). After 10 weeks, one group continued with triple therapy (group A) while the three other groups received different combinations of two drugs, namely, Aza and CyA (group B), Aza and MP (group C), or CyA and MP (group D). Withdrawal of MP (group B) or especially of CyA (group C) was associated with 4/29 (14%) and 10/28 (36%) acute rejection episodes, respectively, for 60 days after conversion. All rejections were mild and reversible. There were no rejections after Aza withdrawal or in the group that continued on triple therapy during the corresponding time period. The most common reason for dropping out after withdrawal, for those patients who could not continue on the originally randomized medication, was azathioprine intolerance (n=12). Five patients were switched back to triple therapy after CyA withdrawal due to rejection. Steroid intolerance was rare and CyA in low doses was very well tolerated. At 1 year there were no statistically significant differences in graft survival between groups A, B, C, and D-81%, 88%, 88%, and 88%, respecively-or in patient survival-88%, 88%, 88%, and 97%, respectively. For those patients continuing with the originally randomized treatment protocol, there were no differences in patient or graft survival either, the means being 91% and 89%, respectively. The most common cause of death after withdrawal was cardiovascular in nature, and there were no more fatal infections under triple drug treatment than with double drug regimens. There were no statistically significant differences in mean serum creatinine values at 1 year. The median serum creatinine values for groups A, B, C, and D were 112, 132, 133, and 133 mol/l, respectively. At 1 year the mean CyA dose in the groups that continued with CyA was 3.5–4.2 mg/kg per day and CyA concentrations were equal.     

Renal allograft immunosuppression III. Triple therapy versus three different combinations of double drug treatment: two year results in kidney transplant patients

A prospective randomized trial was carried out to compare the long-term effects of triple therapy based on low-dose cyclosporin A (CyA), low-dose methylprednisolone (MP) and azathioprine (Aza) with three different double drug immunosuppressive regimens. After initial triple drug immunosuppression for 10 weeks, 128 patients were randomized into four different immunosuppressive groups: one group continued with triple therapy (group A) and the three other groups were treated with different combinations of two drugs: Aza and CyA (group B), Aza and MP (group C) and CyA and MP (group D). This report presents the 2-year results. For groups A, B, C and D, graft survivals were 75%, 78%, 84% and 81%, respectively, and patient survivals were 84%, 84%, 84% and 94%, respectively. After 2 years no patient had returned to dialysis in group C compared with one to three patients in every CyA-using group. However, at the end of the 2nd year, group C included more patients with deteriorating graft function than the other groups. Median serum creatinine was 107, 120, 139 and 129 mol/l for groups A, B, C and D, respectively. For the patients who remained on the original randomized protocol, there were no significant differences in graft function tests between the four groups, the median creatinine being 115, 115, 118 and 113 mol/l for groups A, B, C and D, respectively. Thus, no graft deterioration had occurred during the 2 years for these patients following the original protocol. Our results suggest that after initial triple therapy, patients with a first cadaveric kidney allograft can either continue with triple therapy or be converted to any of the double drug regimens without detriment to graft function, graft survival or patient survival for the next 2 years. This will allow more flexible and individual immunosuppressive treatment.     

Renal allograft immunosuppression

Serum lipid and lipoprotein profiles were performed in order to investigate lipid abnormalities 2 years post-transplantation in first cadaveric renal allograft recipients immunosuppressed with cyclosporin (CyA), azathioprine (Aza), and methylprednisolone (MP), or with any combination of two drugs. CyA was used in low doses. Total serum cholesterol, triglyceride, LDL cholesterol, HDL cholesterol, HDL2 cholesterol, HDL3 cholesterol, apolipoprotein A1, and apolipoprotein B were determined in 88 prospectively randomized patients with functioning grafts. When considering only the patients who remained on the original randomized treatment, there were no significant differences between the four groups in any of the measured variables. Mean total cholesterol was highest in the group receiving Aza and MP (6.8 mmol/l) and lowest in the group receiving triple therapy (5.8 mmol/l; NS). Mean triglyceride level was highest in the group receiving Aza and MP (2.3 mmol/l) versus 1.8–2.2 mmol/l in the groups receiving triple therapy, Aza+CyA, and CyA+MP. For all patients mean triglyceride level was highest in the group receiving Aza and MP (2.7 mmol/l) and lowest in the group receiving triple therapy (1.7 mmol/l; P<0.05). Mean HDL cholesterol ranged from 1.5 to 1.6 mmol/l in all groups. Neither CyA concentration nor CyA or MP dose correlated with cholesterol or triglyceride concentration. However, the average MP dose was twice as high in the group receiving Aza and MP as in the other two groups employing steroids. Serum cholesterol and triglyceride concentrations were related to body mass index (r=0.28, P=0.045 and r=0.30, P=0.029, respectively). Hyperlipidemia was most common in the group receiving Aza and MP. The frequency of hypercholesterolemia (serum cholesterol level >6.5 mmol/l) was 18%, 45%, 60%, and 35% for the patients continuing with the originally randomized treatment in the groups receiving triple therapy, Aza+CyA, Aza+MP, and CyA+MP, respectively. In a normal Finnish reference population, 35% of all males and 31% of all females have a serum cholesterollevel above 6.5 mmol/l. Thus, only patients receiving Aza and MP had a clearly higher frequency of hypercholesterolemia than that found in a normal population. Taken together, this study shows no lipid abnormalities associated with the use of low-dose CyA for 2 years after transplantation. Hyperlipidemia occurring after transplantation is probably multifactorial and more associated with other risk factors than with the immunosuppressive therapy.     

Renal allograft immunosuppression: II. A randomized trial of withdrawal of one drug in triple drug immunosuppression

Abstract. A prospective randomized study was conducted to evaluate the impact of four different conversion protocols on graft outcome in long-term follow-up. Between January 1986 and May 1987, 128 patients with first cadaveric kidney allografts were randomized at the time of transplantation to four treatment groups of 32 patients each, to be assigned 10 weeks post-transplantation. During the first 10 weeks, all patients received triple therapy with low-dose azathioprine (Aza), cyclosporin (CyA), and methylprednisolone (MP). After 10 weeks, one group continued with triple therapy (group A) while the three other groups received different combinations of two drugs, namely, Aza and CyA (group B), Aza and MP (group C), or CyA and MP (group D). Withdrawal of MP (group B) or especially of CyA (group C) was associated with 4/29 (14%) and 10/28 (36%) acute rejection episodes, respectively, for 60 days after conversion. All rejections were mild and reversible. There were no rejections after Aza withdrawal or in the group that continued on triple therapy during the corresponding time period. The most common reason for dropping out after withdrawal, for those patients who could not continue on the originally randomized medication, was azathioprine intolerance (n= 12). Five patients were switched back to triple therapy after CyA withdrawal due to rejection. Steroid intolerance was rare and CyA in low doses was very well tolerated. At 1 year there were no statistically significant differences in graft survival between groups A, B, C, and D-81 %, 88%, 88%, and 88%, respectively-or in patient survival-88%, 88%, 88%, and 97%, respectively. For those patients continuing with the originally randomized treatment protocol, there were no differences in patient or graft survival either, the means being 91% and 89%, respectively. The most common cause of death after withdrawal was cardiovascular in nature, and there were no more fatal infections under triple drug treatment than with double drug regimens. There were no statistically significant differences in mean serum creatinine values at 1 year. The median serum creatinine values for groups A, B, C, and D were 112, 132, 133, and 133 μmol/l, respectively. At 1 year the mean CyA dose in the groups that continued with CyA was 3. 5–4. 2 mg/kg per day and CyA concentrations were equal.     

Triple therapy immunosuppression in cadaveric renal transplantation

One hundred and ninety-two patients received 200 consecutive cadaver renal transplants (158 first and 42 regrafts) and were treated with triple therapy immunosuppression consisting of low-dose cyclosporin, azathioprine and prednisolone. One-year patient and graft survival rates were 95% and 82%, respectively. Against this low rate of graft loss, the proportion of rejection-free patients in the first 3 months was strongly related to matching for HLA-DR (P<0.01), although HLA-DR matching was not associated with improved graft survival. More grafts were lost to nonimmunological causes than to rejection, and these losses fell into three main categories, namely, losses in elderly and diabetic patients and losses due to renal vascular thrombosis. Thus, triple therapy immunosuppression appears to offer effective immunosuppression, resulting in good graft and patient survival, especially in highly sensitised patients or patients receiving regrafts. There are relatively few serious adverse effects, although elderly and diabetic patients experienced significant morbidity and mortality after transplantation.     

Renal allograft immunosuppression: VI. Triple drug therapy versus immunosuppressive double drug combinations: histopathological findings in renal allografts

Abstract. The long-term effects of different immunosuppressive drugs and regimens on renal allograft histology are virtually unknown. Therefore, in order to investigate the long-term effects of triple drug treatment versus different combinations of two immunosuppressive drugs on allograft histology, a prospective, randomized trial was performed. One group received triple therapy consisting of low-dose cyclosporin (CyA), azathioprine (Aza), and methylprednisolone (MP), and three groups received combinations of two drugs, i.e., Aza plus CyA, Aza plus MP, and CyA plus MP. At 2 years, there were no significant differences with regard to graft (80%) or patient (87%) survival, or to graft function between the four groups. After 2 years, a protocol core biopsy was taken of all 102 patients having a functioning graft. Of these patients, 61 (60%) were still following the original, randomized treatment protocol; in the remaining cases, changes had occurred in the original protocol and so these cases were considered drop-outs in this study. Histological specimens were examined blindly by two independent observers. Most of the 34 histological variables examined showed no changes. Diffuse fibrosis was most frequent in the CyA plus MP group (70%) and significantly more severe than in the triple therapy group. Mesangial matrix increase in glomeruli was significantly less common in the triple therapy group (8%) than in any one of the double drug combination groups (47%). Two other changes in glomeruli - Bowman capsular thickening and global glomerular sclerosis - were also less frequent in the triple therapy group. Vascular changes other than intimal proliferation (39%) and arteriosclerosis (24%) were uncommon in all groups and least frequent in the triple therapy group. Isometric vacuolation in proximal tubules was found in every group using CyA. It was least prominent in the triple therapy group and most prominent in the CyA plus MP group; it was not seen in the Aza plus MP group. Other specific findings for the groups treated with CyA could not be identified. To summarize, the changes shown were mild and rather similarly distributed in the four treatment groups. Histopathological alterations comparable with chronic rejection, i.e., persistent interstitial inflammation with pyroninophilic cells, vascular intimal proliferation, and arteriosclerosis, were seen in all groups, but these changes were least prominent in the group receiving triple therapy.     

Effect of reduced cyclosporin dosage on long-term renal allograft histology

The effect of different doses of cyclosporin (CyA) on the occurrence of histological lesions in renal allograft biopsies was investigated 2 years after transplantation. Biopsy findings were compared in three different groups of patients. In group 1, patients were immunosuppressed with CyA and prednisolone according to an early, high-dosage schedule (initial CyA dose 15–17.5 g/kg body weight); in group 2, they were treated with a medium CyA dose (initial dose 12 mg/kg), together with prednisolone; and in group 3, patients were given triple drug therapy consisting of low doses of CyA (initial dose 8 mg/kg), together with both azathioprine and prednisolone. Interstitial fibrosis and tubular atrophy were common findings in all groups, and on the basis of all biopsies, no difference could be found between the groups with respect to the relative volume of the renal cortical interstitium, which was used as a quantitative parameter for interstitial fibrosis. Likewise, no difference was found with respect to serum creatinine levels. When grafts, that showed signs of rejection (usually vascular rejection) in the biopsy were excluded (two in group 1, six in group 2, and ten in group 3), the mean interstitial volume was significantly lower in group 3 (triple drug therapy) than in the other groups. The serum creatinine levels were also significantly lower in group 3 than in group 1. Thus, chronic renal lesions could be ameliorated when CyA doses were lowered, but this appeared to entail an increased risk of acute or chronic vascular rejection.     

Long-term renal allograft function under maintenance immunosuppression with cyclosporin A or azathioprine

In order to evaluate long-term renal graft function, 149 cyclosporin A and prednisolone (CyA/P)-treated renal transplant recipients were compared with 119 azathioprine and prednisolone (Aza/P)-treated patients. Only patients who had a functioning graft for at least 1 year and who were maintained on their initial immunosuppressive protocol were included. The minimum follow-up period was 4 years. Renal graft function was estimated by yearly determinations of serum creatinine and creatinine clearance. The CyA/P-treated patients had a significantly higher serum creatinine and a significantly lower creatinine clearance at every point in time posttransplantation than Aza/P-treated patients (P<0.001). The evolution of renal graft function, as reflected in the line of regression for serum creatinine and creatinine clearance versus time, was estimated for each individual patient. There was an almost stable renal function, as assessed by the median of the slopes of the regression line for serum creatinine versus time in both groups. The median increase in serum creatinine was only 1.4 mol/l per year for Aza/P-treated patients and 2.4 mol/l per year for CyA/P-treated patients (difference NS). The median decline in creatinine clearance was 2.18 ml/min per 1.73 m²/year in the Aza/P group and 1.07 ml/min per 1.73 m²/year in the CyA/P group (P=0.05). In patients with a functioning graft for at least 5 years, creatinine clearance remained unchanged in both groups during the study period. In conclusion, renal graft function, as assessed by measurements of serum creatinine and creatinine clearance, remained essentially unchanged for at least 5 years after transplantation, regardless of the immunosuppressive protocol used. Thus, these data do not indicate a progression with time of the nephrotoxicity observed in CyA-treated patients.     

Renal allograft immunosuppression: IV. Comparison of Iipid and lipoprotein profiles in blood using double and triple immunosuppressive drug combinations

Abstract. Serum lipid and lipoprotein profiles were performed in order to investigate lipid abnormalities 2 years post-transplantation in first cadaveric renal allograft recipients immunosuppressed with cyclosporin (CyA), azathioprine (Aza), and methylprednisolone (MP), or with any combination of two drugs. CyA was used in low doses. Total serum cholesterol, triglyceride, LDL cholesterol, HDL cholesterol, HDL2 cholesterol, HDL3 cholesterol, apolipoprotein A1, and apolipoprotein B were determined in 88 prospectively randomized patients with functioning grafts. When considering only the patients who remained on the original randomized treatment, there were no significant differences between the four groups in any of the measured variables. Mean total cholesterol was highest in the group receiving Aza and MP (6.8 mmol/l) and lowest in the group receiving triple therapy (5.8 mmol/l; NS). Mean triglyceride level was highest in the group receiving Aza and MP (2.3 mmol/1) versus 1.8–2.2 mmol/l in the groups receiving triple therapy, Aza + CyA, and CyA + MP. For all patients mean triglyceride level was highest in the group receiving Aza and MP (2.7 mmol/1) and lowest in the group receiving triple therapy (1.7 mmol/l; P<0.05). Mean HDL cholesterol ranged from 1.5 to 1.6 mmol/l in all groups. Neither CyA concentration nor CyA or MP dose correlated with cholesterol or triglyceride concentration. However, the average MP dose was twice as high in the group receiving Aza and MP as in the other two groups employing steroids. Serum cholesterol and triglyceride concentrations were related to body mass index (r= 0.28, P= 0.045 and r= 0.30, P= 0.029, respectively). Hyperlipidemia was most common in the group receiving Aza and MP, The frequency of hypercholesterolemia (serum cholesterol level > 6.5 mmol/1) was 18%, 45%, 60%, and 35% for the patients continuing with the originally randomized treatment in the groups receiving triple therapy, Aza + CyA, Aza + MP, and CyA + MP, respectively. In a normal Finnish reference population, 35% of all males and 31% of allfemaleshaveaserumcholesterollevel above 6.5 mmol/l. Thus, only patients receiving Aza and MP had a clearly higher frequency of hypercholesterolemia than that found in a normal population. Taken together, this study shows no lipid abnormalities associated with the use of low-dose CyA for 2 years after transplantation. Hyperlipidemia occurring after transplantation is probably multifactorial and more associated with other risk factors than with the immunosuppressive therapy.     

Older donors and kidney transplantation

Reluctance to use kidneys from older donors (>50 years of age) is based on reports of inferior results. We reviewed our experience with 45 kidneys transplanted from older donors. Primary nonfunction, immediate graft function, and 1-, 2- and 3-year graft survival rates were similar to those obtained with kidneys transplanted from donors aged between 20 and 40 years. Renal function at 1 year (as measured by serum creatinine) was poorer in kidneys from older donors. No beneficial effect with respect to graft survival was noted with cyclosporin therapy compared to conventional immunosuppression; however, the numbers are small. We conclude that kidneys from older donors are a valuable source for transplantation.     

Risk factors for cytomegalovirus infection and disease in renal transplant recipients: HLA-DR7 and triple therapy

In a prospective study, an analysis of risk factors for the development of cytomegalovirus (CMV) infection and disease was performed on 77 renal allograft recipients. Twenty-five out of the 77 recipients (32%) had a CMV infection. Twenty-two of the recipients received triple immunosuppressive therapy (cyclosporin A, prednisolone, and azathioprine) while the remaining 55 received standard therapy (cyclosporin A and prednisolone). In 23 recipients (30%) acute rejection was diagnosed and the first positive parameter of infection occurred 22 days after rejection therapy. Infection occurred in 10 out of 18 HLA-DR7-positive recipients (56%) and in 15 out of 59 HLA-DR7-negative recipients (25%; P< 0.02). In multiple regression analysis, HLA-DR7 was found to be a significant predictor of CMV infection (P< 0.005). CMV disease was diagnosed in only 9 out of 25 recipients with an acute infection. Six recipients (67%) with CMV disease received triple therapy for maintenance immuuosuppression; this was significantly correlated to CMV disease (P< 0.05) as compared to three recipients (33%) with CMV disease maintained with standard therapy. Our data suggest that HLA-DR7-positive recipients are more susceptible to CMV infection and that CMV disease is associated with triple immunosuppressive therapy.     

Renal fibrosis in cyclosporin A-treated renal allograft recipients: morphological findings in relation to renal hemodynamics

Nineteen nondiabetic kidney graft patients treated with cyclosporin A for 2 years underwent percutaneous renal allograft biopsy as well as renal hemodynamic examination. Renal allograft fibrosis was quantitatively evaluated as the relative volume of the renal cortical interstitium (V_v%) and as the intersttium/tubuli ratio (I/T ratio). The histological changes were then classified into four groups, depending on the degree of interstitial fibrosis. The glomerular filtration rate (GFR), renal plasma flow (RPF), renal blood flow (RBF), filtration fraction (FF), and fractional clearance of sodium, potassium, phosphate, chloride, osmoles, and free water clearance were determined in all patients and in 13 healthy controls. Kidney graft recipients had significantly lower GFR, lower RPF, and lower RBF than the healthy controls (P<0.001 for all comparisons) while FF was similar in patients and controls. Transplant recipients had a significantly higher fractional excretion of sodium, potassium, chloride, and phosphate than controls. All except one patients had clearly increased V_v values, indicating increased interstitial fibrosis. The mean V_v in renal allograft patients was 35%±10% (normal <16%±5%) and the I/T ratio was 1.07±0.60 (normal <0.24±0.08). No correlation was found between the quantitative or semiquantitative biopsy analysis and any renal hemodynamic parameter measured. We conclude that renal function is significantly decreased in kidney graft recipients, but that adaptive tubular changes occur in the graft. Interstitial renal fibrosis was common but did not correlate to any renal functional parameter.     

The influence of primary non-function on the accuracy of ultrasound measurements in the diagnosis of renal allograft rejection

Daily ultrasonographic measurements of transplant cross-sectional area were used to quantify allograft swelling as a diagnostic test for acute rejection in a series of 120 renal transplants. Initial graft function (IF) occurred in 86 patients (72%) and primary non-function (PNF) occurred in the remaining 34 (28%). An increase in allograft cross-sectional area greater than or equal to 10% was defined as a positive ultrasound scan suggesting an acute rejection episode and was investigated by needle core biopsy. During periods of PNF, allografts with consistently negative ultrasound scans were submitted to needle core biopsy on a weekly basis. The diagnosis of rejection was based exclusively on the histological findings. In the IF group, agreement between ultrasound and histological diagnosis was good (k=0.63, sensitivity 81%, specificity 83%, positive predictive value 76%, negative predictive value 86% and overall accuracy 82%). In the PNF group, agreement between ultrasound and histology was only fair (k=0.46, sensitivity 77%, specificity 70%, positive predictive value 69%, negative predictive value 78% and overall accuracy 73%). It it concluded that a degree of allograft swelling is sometimes associated with acute tubular necrosis, and this makes ultrasound measurements of transplant size a less useful technique of monitoring kidneys with PNF.     

Late conversion from steroids to azathioprine in cyclosporin-treated renal graft recipients

In renal graft recipients primarily treated with cyclosporin and low-dose methylprednisolone, withdrawal of the long-term steroid medication increases the likelihood of developing rejection episodes. In order to determine the predictive value of clinical parameters and routine prewithdrawal graft biopsies for the risk of rejection, the authors studied 141 kidney recipients from whom steroids were with-drawn 7–9 months after transplantation in a clinically stable situation. Both the quality of the HLA-match and the results of prospective graft biopsies were found to correlate significantly to the occurrence of acute rejection. In order to investigate the influence of additional azathioprine medication on the incidence of acute rejections in recipients not receiving steroids, immunosuppression was continued with cyclosporin monotherapy in 88 patients and with cyclosporin plus azathioprine in 53 patients. The risk of developing rejection episodes was significantly reduced from 48% after 1 year on monotherapy to 28% after the addition of azathioprine medication.     

Serum hippuric acid concentration in renal allograft rejection,ureter obstruction,and tubular necrosis

Plasma from 35 renal allograft recipients (21 males and 14 females) was sampled daily and analyzed for hippuric acid (HA) by highperformance liquid chromatography (HPLC) and serum creatinine. Twelve of these patients experienced an acute renal allograft rejection or a ureter obstruction as proven by clinical signs and biopsy, as well as by radiography or ultrasound, respectively. Two patients suffered from tubular necrosis followed by rejection during the postoperative period. Mean serum HA increased by 39.9 mol/l from baseline (range 20.4–115.5 mol/l) in patients with acute rejection 3 days after an initial increase that was observed 24 h before the mean serum creatinine increased by 107.1 mol/l (range 21–193 mol/l). In cases of ureter obstruction, HA rose by 1.6 mol/l (range 1–8.2 mol/l), significantly less than elevations due to rejection. The increase in creatinine, however, amounted to 65.3 mol/l (range 22–140 mol/l) and was not different from the change in rejecting patients. Successful antirejection treatment coincided with a decrease in serum HA starting 24 h earlier than the decrease in the serum creatinine concentration. Of special interest was the observation of a parallel decrease in HA with creatinine concentration in patients with tubular necrosis after allotransplantation; HA increased in cases of an additional rejection. Our data suggest that HA, which is excreted by tubular secretion and glomerular filtration, could be a sensitive and early marker of acute allograft rejection. Furthermore, it seems to discriminate between acute renal allograft rejection and ureter obstruction. It might, therefore, be of value in the diagnosis of rejection complicating tubular necrosis after transplantation.     

Cytomegalovirus infection after organ transplantation: an update with special emphasis on renal transplantation

Cytomegalovirus infections are still the most important infectious complications after organ transplantation. Besides historical notes this review will deal with new aspects concerning the epidemiology of the CMV, diagnostic modalities of CMV infection, the delicate counterbalance between the immune system and the CMV, as well as the symptomatology of this infection. Furthermore, aspects like prophylaxis and new, promising therapeutic regimes for treatment of infection will be dealt with. Although this update is applicable for all types of solid organ transplantation, emphasis will be on renal transplantation.     

Tubulointerstitial nephritis caused by the antiviral agent foscarnet

The antiviral agent foscarnet has long been used in our unit to treat cytomegalovirus (CMV) infections in renal transplant patients. The clinical effect has been convincing and, apart from changes in serum calcium levels, very few side effects have been noted. We have, however, observed a nephrotoxic reaction in a series of patients with initially good renal function who therefore received high doses of foscarnet. Transplant biopsies performed in five of those patients revealed degenerative changes in the tubular epithelial cells as well as tubular calcium deposits and an infiltration of the interstitium by mixed mononuclear and polymorphonuclear leucocytes. Renal insufficiency was accompanied by high fever. After withdrawal of the drug, the temperature rapidly normalized, whereas serum creatinine continued to rise for about 3 days and then fell back towards previous levels. We conclude that transplant biopsies are of great value in distinguishing between a foscarnet nephrotoxic effect and CMV nephritis, various forms of rejection, and other causes of impaired renal function.