A randomized trial comparing triple-drug and double-drug therapy in renal transplantation.

A controlled trial was carried out in 86 cadaveric and 14 living haploidentical renal transplant recipients to compare the effects of low doses of cyclosporine (CsA), azathioprine (Aza) and steroids with those of higher doses of CsA plus steroids. Patients were followed for 12-26 months after transplantation. The actuarial 2-year patient and graft survival rate was 100% for living-donor transplants. In cadaver renal transplants the 2-year patient survival rate was 100% for patients assigned to the triple regimen and 93% for those allocated to the double regimen. The actuarial 2-year cadaver graft survival rates were 86% and 90.6%, respectively. There were significantly more patients who had severe infections (P less than 0.05), particularly interstitial pneumonia (P less than 0.005), in the double-therapy group. On the other hand, there were more patients who rejected and more patients with severe rejections; more pulses of steroids were also required for patients on the triple regimen, although these differences were not significant. The mean trough blood levels of cyclosporine at the various times were about half as high in patients on triple therapy. There were no differences between the two groups in creatinine clearance at any time. A control renal biopsy, taken from patients with stable renal function after 6-12 months, showed only mild abnormalities. The lesions were semiquantitatively assessed. There was a higher score for interstitial infiltrate in patients on triple therapy (P less than 0.05). On the other hand, the incidence and the mean score of interstitial fibrosis were greater in patients on double therapy, although these differences were not significant. Thus, although similar results were obtained with both regimens, at the doses we used double therapy seems to have more powerful immunosuppressive effects and may prevent rejection, either acute or chronic, better. However, it might expose the patient to a greater risk of infection and of cyclosporine-related nephrotoxicity than triple therapy.

A prospective randomized trial on azathioprine addition to cyclosporine versus cyclosporine monotherapy at steroid withdrawal, 6 months after renal transplantation.

BACKGROUND: Many attempts have been made to withdraw steroid therapy in renal transplant patients in order to avoid its many side effects. Results have been, so far, controversial. In this randomized prospective study, we compare the efficacy of azathioprine adjuncts to cyclosporine at the time of steroid withdrawal, 6 months after transplantation, versus Cyclosporine monotherapy, in preventing acute rejection. METHODS: One hundred and sixteen kidney transplant patients with good and stable renal function (creatininemia <2 mg/dl) received, in the first 6 months, cyclosporine + steroid. They were then randomized into two groups (A and B), and steroid therapy was withdrawn over 2 months. Group A (58 patients) continued on cyclosporine monotherapy, whereas group B (58 patients) added azathioprine (1 mg/kg/day) at the beginning of randomization and continued on cyclosporine + azathioprine. In both groups, patients resumed steroid therapy at the first episode of acute rejection. Follow-up after randomization was 5.3+/-1.6 years. RESULTS: After 5 years, the incidence of steroid resumption was 57% in group A and 29% in group B (P<0.02); of those, 68% and 88% of them were within 6 months from randomization. Anti-rejection therapy was always successful. Five-year patient and graft survival rates were 90% and 88% in group A and 100% and 91% in group B. Creatininemia did not differ, at follow-up. Side effects differed only for mild and reversible leukopenia caused by azathioprine in group B. CONCLUSION: Cyclosporine plus azathioprine is more effective than cyclosporine monotherapy in reducing the incidence of acute rejection after steroid withdrawal. Graft loss as a result of chronic rejection, mild in both groups, did not differ. Steroid withdrawal is feasible and advantageous, and the addition of azathioprine allowed 71% of our selected patients to remain steroid-free.

Diet or dialysis in the elderly? The DODE study: a prospective randomized multicenter trial.

There are no solid data on the real advantage of an early start of dialysis, as suggested by the DOQI guidelines. Uremic patients frequently have a poor nutritional status. However, we cannot distinguish between the detrimental effect on nutrition of too low a residual renal function or too long a period of low protein-diet, per se. However, it appears that a very-low-protein diet (VLPD) supplemented with essential amino acids and keto-analogs of amino acids, and with an adequate quantity of calories, can prevent hypoalbuminemia at the start of dialysis and can slow the progression of chronic renal failure. EDTA and USRDS data suggest that most patients starting dialysis nowadays are elderly, who also have the highest incidence of morbidity and mortality. Moreover, hospitalization rate becomes higher after the start of dialysis compared to the pre-dialysis period. Can an aminoacid-supplemented VLPD, prolonged beyond the GFR limits suggested by DOQI, offer elderly patients better survival and better quality of life than dialysis? The answer can only come from a prospective, randomized trial, in elderly patients, starting at the GFR values suggested by the NKF-DOQI for starting dialysis, comparing outcomes with a vegetarian VLPD supplemented with a mixture of keto-analogs of amino acids and essential amino acids, and with dialysis.

CAPD viability: a long-term comparison with hemodialysis.

OBJECTIVE: To compare the long-term viability of continuous ambulatory peritoneal dialysis (CAPD) to that of hemodialysis (HD). DESIGN: Retrospective study of patients of our institution starting dialysis between January 1, 1981, and December 31, 1993, and surviving for at least 2 months. PATIENTS: Five hundred and seventy-eight new patients (51.3% on CAPD and 48.6% on HD). MAIN OUTCOMES STUDIED: Cox-adjusted assessment of patient and technique survival, and of technique success. Differences in results for two successive periods of time. RESULTS: Patient survival did not differ between CAPD and HD after adjusting for age and comorbidity, and significantly improved in the second part of the follow-up (1987-1993). Technique failure was significantly higher on CAPD, in which it was inversely related to age. The probability of a patient continuing on the first method of dialysis ("technique success") was significantly lower on CAPD than on HD, but the difference decreased progressively with age and disappeared in patients > or = 75 years. CONCLUSION: CAPD is as effective as HD in preserving life in uremic patients in the long-term, and gives better results in the older elderly. In adults, the lower technique success rate may not be a problem for patients with access to a good transplantation program; for others, this drawback must be weighed against the advantages of home treatment.

Experience with cyclosporine.

Six hundred thirty-eight cadaveric kidney transplant patients between 1983 and 2001 were treated with cyclosporine (CsA) for 87 +/- 58 months. Among 571 patients with follow-up greater than 12 months, the 15-year renal function was investigated to assess the probability of a >30% increase in serum creatinine (sCr) above the month-6 value (baseline) and the impact on graft survival. At 15 years, patient and graft survival rates were 82.7% and 56.1%, respectively, with a 19.5-year half-life (censored for deaths). The main causes of graft loss were chronic rejection (33.0%) and patient death (24%). Cardiovascular disease and neoplasms were the main causes of death. Renal function remained stable in 266 patients (46.6%) with excellent sCr values observed even after a 15-year treatment period. An increased sCr was observed in 305 patients (53.4%) with a 15-year probability of 74%. In 178 patients (59.3%) it was self-limited; their grafts are still functioning well. One hundred three patients (32.8%) lost their graft which was more likely when the sCr had increased >45%. Twenty-four patients (7.9%) died with a functioning graft. Multivariate analysis showed the progression of graft deterioration to be related to proteinuria (P<.0001), a late acute rejection episode (P<.002), or the extent of sCr increase (P<.008). In conclusion, the long-term use of CsA has allowed us to achieve excellent long-term patient and transplant survival rates. Our data indicate a high 15-year probability of an increased sCr, but the rate of progression is slow.

Comparison of long-term survival between hemodialysis and peritoneal dialysis.

We have reviewed the literature and our own center's results for patients on long-term continuous ambulatory peritoneal dialysis (CAPD) in comparison to results for patients on hemodialysis (HD). Contrary to recent American data showing one-year survivals to be worse on CAPD, the Canadian Registry and other studies show no significant difference in survivals on the two methods. Results are also conflicting for diabetics. Insufficient adjustments for age and case-mix variations are probably the most important causes for differences. For the general population, personal Cox-adjusted data show no difference between CAPD and HD up to ten-year follow-up, with very close curves for the adults and non-significant differences for the elderly. Old elderly (> 75 years) have better survival on CAPD in the first years of treatment. Dropout, which is higher on CAPD, decreases with age, and the patient retention on CAPD is worse than on HD for all patients, except the old elderly, for whom it is similar. These data were obtained in patients receiving a standard treatment, modified in order to give a more adequate dialysis dose only in recent years. The results of a prospective three-year study on the effect of nutritional [serum albumin and transferrin, normalized protein catabolic rate (PCRN), and subjective global assessment of malnutrition] and adequacy indices [Kt/V, creatinine clearance (Ccr), residual renal function] on patient survival on CAPD and HD are reported. Survival was not different for the two methods. Using the Cox analysis, nutritional indices did not affect survival whereas adequacy indices did. The effect of low serum albumin on survival was referable to the predialysis nutritional state. The similar survivals obtained on CAPD and HD, with Kt/V more or less than 1.0/treatment for HD and 1.7/week for CAPD, support the "peak concentration hypothesis" of Keshaviah et al. Survival in different groups of patients with different Kt/V and Ccr shows that the adequate dose on CAPD is Kt/V between 1.96 and 2.03 and Ccr > or = 70 L/week. A group of 26 patients who remained on CAPD treatment for more than eight years was also studied. Patient age and predialysis comorbidity were the most important factors affecting survival. Patients surviving longest had > 3 g/dL of serum albumin, > 0.8 g/kg/day of PCRN, a Kt/V > 1.6, and a weekly Ccr > 54L/week.

Simultaneous catheter replacement-removal during infectious complications in peritoneal dialysis.

The aim of this study was to verify whether the replacement of the peritoneal catheter in a single operation and during infectious complications of peritoneal dialysis is effective and safe. Sixty-eight infectious complications refractory to appropriate antibiotic therapy were treated by this technique: 26 tunnel infections, 22 peritonitis-complicating tunnel infections, 12 refractory peritonitis, and 8 recurrent peritonitis. Operations were successful in all cases of tunnel infection and recurring peritonitis, and in all cases but one of peritonitis-complicating tunnel infection. Ten failures occurred among the 12 catheters removed for refractory peritonitis. Microorganisms cultured in these 10 failures were: Fungi (3 cases), Mycobacterium (2 cases), Pseudomonas (2 cases), Acinetobacter (1 case), Acinetobacter+Pseudomonas (1 case), and Enterococcus (1 case). Complications were 3 one-way obstructions and 2 external dialysate leaks. This study supports the simultaneous catheter replacement-removal procedure during infectious complications of peritoneal dialysis (PD) with the exception of refractory peritonitis; this technique spares the patient the temporary vascular access, the shift to hemodialysis, and a second operation to insert a new catheter. There are few complications.

[Still's disease in adults: diagnostic problems]. / Malattia di Still dell'adulto: problemi diagnostici.

Still's disease is a seronegative arthritis of children which, in a limited number of cases, can affect adults. The diagnosis of adult-onset Still's disease is characterized by high fever, arthritis and negative serologic tests for rheumatoid factor and antinuclear antibodies and by at least two minor symptoms (leukocytosis, evanescent rash, serositis, hepato- or splenomegaly, and lympho-adenopathy). Since many diseases present analogous manifestations and the adult-onset Still's disease is generally diagnosed by exclusion, we report two patients, aged 26 and 39, with Still's disease, the former with a classic clinical feature, the latter with a clinical feature characterized by severe hepatic abnormalities. The determination of histocompatibility antigens can be useful because some of them (HLA-DR4 in case 1 and HLA-DRw6 in case 2) are frequently associated with the adult-onset Still's disease. The role of anti-inflammatory therapy (acetylsalicylic acid, indomethacin, steroids) must be emphasized, whose efficacy can constitute the pathognomonic element on which the diagnosis of adult-onset Still's disease can be based in a proper clinical pattern.

[Naloxone and naltrexone in the therapy of advanced COPD]. / Naloxone e naltrexone nella terapia della BPCO in fase avanzata.

We report a patient with COPD and bullous emphysema treated with narcotic antagonists (naloxone and naltrexone) for severe respiratory failure, with hypoxemia and hypercapnia, non responding to traditional medical therapy. According to previous reports, this treatment was started while waiting for lung transplantation, and it improved clinical pattern and arterial blood gas levels. Though the patient died for left ventricular failure fifteen days after the beginning of therapy, we think that narcotic antagonists can be successfully administered in some patients with advanced stage COPD.

[EDTA-induced pseudothrombocytopenia]. / Pseudotrombocitopenia da EDTA.

EDTA-induced pseudothrombocytopenia is a laboratory artifact caused in vitro by platelet aggregation, due to IgG or IgM class antibodies reacting with antigenic binding site of the GP IIb glycoprotein. Pseudothrombocytopenia is rarely found (about 1% of platelets counts), but must be considered in the differential diagnosis of thrombocytopenia, since it could lead to useless investigations and therapies. We report three patients with pseudothrombocytopenia, one of whom underwent bone marrow biopsy and danazol treatment, before establishing the correct diagnosis. The absence of hemorrhagic manifestations with persisting low platelets counts led to a re-examination of peripheral blood smear and to the diagnosis of pseudothrombocytopenia. Therefore a morphological platelets evaluation and their count on citrate-anticoagulated blood must be performed in every patient under assessment for thrombocytopenia.

Which vascular access for chronic hemodialysis in uremic elderly patients?

The type of hemodialysis vascular access (fistula, graft, catheter) employed plays an important role in the results of dialysis treatment. Moreover, different complications can affect the vascular access and interfere with the morbidity and mortality of patients. The ideal vascular access is the Cimino Brescia fistula. Graft and catheter methods should be considered as 'second choice' because they present a higher incidence of complications, mainly due to thrombosis and infections. Finally, in elderly patients the vascular bed is frequently damaged and this may make it difficult to create a Cimino Brescia fistula. In a 5-year period, 140 elderly patients (>65 years) and 63 'young' patients (< 65 years) started dialysis treatment in our facility. In the elderly group, a native fistula was created in 88% of cases, whereas in the younger patients the percentage was 94% (p: NS). The grafts were, respectively, 11% in elderly and 6% in young patients. Only in one case, in one elderly patient, was a permanent catheter the first vascular access. We also report survival rate of the first vascular access, the incidence of thrombosis, and the need for creating another type of access. We suggest that a native fistula can be easily created in elderly patients and a 'second choice' access should be limited to a small proportion of patients.

Chylous pleural effusion in tuberous sclerosis.

We report on a male patient with tuberous sclerosis (adenoma sebaceum and digital fibromas, renal angiomyolipomas and subependymal brain calcifications), who presented with chylothorax. Chest CT scan did not show pulmonary parenchymal alterations, but only a moderate enlargement of the paracaval mediastinal lymph nodes. Tuberous sclerosis with lung involvement presents clinical, radiologic and pathologic manifestations similar to those of lymphangioleiomyomatosis. The pulmonary manifestations of tuberous sclerosis and lymphangioleiomyomatosis have been observed almost exclusively in women, and it has been suggested that they represent opposite ends of a spectrum of presentations of the same entity. Based on these considerations the formation of a chylothorax in a male with tuberous sclerosis constitutes an extremely rare finding.

Antithyroid antibodies during amiodarone treatment.

In 44 euthyroid and goitre-free patients, 23 treated with amiodarone (group A) and 21 treated with other antiarrhythmic drugs (group B), antimicrosomal antibodies and antithyroglobulin antibodies were determined before the beginning of treatment and after 7, 15, 30, 60, and 180 days. In group A, none of the patients had antithyroid antibodies before treatment. 1 of 15 patients (6.7%) had antimicrosomal antibodies (titre 1:100) on day 7 only, and 1 of 18 (5.5%) had antithyroglobulin antibodies (titre 1:80) on day 180. In group B. 1 of 21 patients (4.8%) had antimicrosomal antibodies (IgG class) at titre 1:400 before the beginning of treatment, which was negative on day 180, and 2 of 17 (11.8%) had antimicrosomal antibodies (titre 1:100) on day 60 only. None of these patients showed clinical and/or laboratory signs of hyper- or hypothyroidism. These data indicated that antithyroid antibodies rarely appear in amiodarone-treated patients and do not differ significantly from patients treated with other antiarrhythmic drugs. The role of autoimmunity and the meaning of antithyroid antibodies in the pathogenesis of amiodarone-induced thyroid dysfunction (mainly of hypothyroidism) in patients without pre-existent thyroid diseases is still unclear.

Differing dialysis treatment strategies and outcome.

The choice of a dialysis treatment depends on many factors, both medical and non-medical. A full and rational treatment requires easy access to a transplantation programme and to all dialysis modalities, extracorporeal or peritoneal. Presently, haemodialysis (HD) is used almost exclusively for in-centre or limited care treatment, peritoneal dialysis (PD) being preferred for home treatment. On HD, bicarbonate buffer is used in preference to acetate. Mixed convective-diffusive HD techniques have a very limited utilization world-wide because of their cost. Use of PD and automated PD continues to grow, although slowly. In our single-centre experience on a large number of patients, 10-year patient survival is not different on CAPD and HD, and there is initial lower risk of death on CAPD for patients > or = 75 years of age. Drop-out from CAPD has increased in recent years, mainly due to the patient/partner 'burn-out'. Drop-out is less for the elderly, and the difference in modality change between CAPD and HD decreases with increasing patient age, suggesting a clear indication for CAPD in the elderly, or in adults waiting for a transplant. The clinical background, e.g. the presence of diabetes mellitus, cardiovascular disease, dyslipidaemia or obesity, is also important in the choice of method.

Which treatment for which patient in the future? Possible modifications in CAPD.

On 578 unselected new patients followed from 1981 through 1993, 51% on CAPD and 49% on HD, long-term patient and method survivals, cause of death, and drop-out in the two methods were compared. Survival, adjusted for patient selection biases, was not different on CAPD and HD up to 10 years. 50% of the patients were still in their first treatment after 3.5 years on CAPD and after 7 years on HD, and 5 and 28% respectively, after 10 years. Patient survival on CAPD was not falsely improved by drop-outs. Drop-out is increasing for CAPD, mainly due to patient/partner burn-out, which should be relieved by a more liberal application of automated PD. Malnutrition is more frequent on CAPD than on HD but not for the elderly. In a 3 year prospective study on 60 CAPD and 34 HD patients serum albumin, nPCR and nutritional status, as assessed by SGA did not influence survival in each modality. Survival was similar with K(p,r)t/V > or = 1.7/week on CAPD and Kt/V > or = 1/treatment on HD, and worse below these values. On CAPD, a Kp,rt/V > or = 1.96 gave better survivals.