Natural killer cell cytotoxicity is enhanced by very low doses of rIL-2 and rIFN-alpha in patients with renal cell carcinoma.

Very low doses of recombinant interleukin-2 (rIL-2) and interferon-alpha (rIFN-alpha) induce, in patients with advanced renal cell carcinoma (RCC) clinical response rate and median survival time comparable to other protocols, other than immunological response in terms of expansion of NK cells and cT lymphocytes. The aim of this pilot study was to verify whether very low dose immunotherapy can enhance NK cell cytotoxicity against tumoral target cells. Eight patients with advanced and 13 patients with localised disease received 4-week cycles of rIL-2 (total dose per week 7 MIU/m(2), s.c.) and rIFN-alpha (total dose per week 3.6 MUI/m(2), i.m.) according to the scheme proposed by Buzio et al. Neutrophils, monocytes, eosinophils, NK cells (CD56+bright, CD56+dimmer, CD3-CD56 +), NK-T cells (CD3+CD56+), Th-lymphocytes, cT-lymphocytes, HLA-DR+ and CD25+ lymphocytes and NK cell cytotoxicity were evaluated before and after cycle. The treatment led to the significant expansion of eosinophils (P < 0.001), NK cells (P < 0.001), CD56+bright (P < 0.001), CD56+dimmer (P < 0.001), Th-lymphocytes (P = 0.001), cT-lymphocytes (P = 0.014), HLA-DR+ (P = 0.007) and CD25+(P = 0.002) cells. Neutrophils significantly decreased (P = 0.001), whereas no significant effect was observed on monocytes (P = 0.22) or NK-T cells (P = 0.20). Patients with localised disease responded significantly better to treatment than metastatic patients in terms of the expansion of CD56+bright (P = 0.038), DR+ (P = 0.021), CD25+ (P = 0.006) and Th-lymphocytes (P = 0.014). The NK cell cytotoxicity was significantly increased by the immunotherapy in the whole population (P = 0.021) and similarly in the two groups of patients (P = 0.860); a reverse relation, even if not significant, was seen between the variation of NK-T cells and NK cells cytotoxicity (r = -0.39; P = 0.074).

Atherosclerotic renovascular disease: medical therapy versus medical therapy plus renal artery stenting in preventing renal failure progression: the rationale and study design of a prospective, multicenter and randomized trial (NITER).

BACKGROUND: Many studies suggest a major prevalence of atherosclerotic renovascular disease (ARVD), caused by mono or bilateral renal artery stenosis (RAS). Unfortunately, there is no definite therapy to cure this disease to date; therefore, ARVD is burdened by important clinical complications with high social and economic costs. The last few years have seen important advancements in both medical therapy and in interventional radiology (for example, percutaneous transluminal renal artery stenting (PTRS)). All of them could affect, in some way, the natural history of ARVD, but to date the optimal strategy has not been established. METHODS: The protocol of a prospective, multicenter, randomized trial "Nephropathy Ischemic Therapy (NITER)" is presented. It enrolls patients with stable renal failure (glomerular filtration rate (GFR) >or=30 ml/min) and hypertension, and hemodynamically significant atherosclerotic ostial RAS (>or=70%) diagnosed by duplex Doppler (DD) ultrasonography and confirmed by magnetic resonance angiography (MRA). This study aims to evaluate whether medical therapy plus interventional PTRS is superior to medical therapy alone according to the following combined primary endpoint: death or dialysis initiation or reduction by >20% in estimated GFR after 0.5, 1, and 2 yrs of follow-up and an extended follow-up until the 4th year. Medical therapy means drugs to control hypertension, improve dyslipidemia and optimize platelet anti-aggregant therapy. The sample size is estimated in 50 patients per group to achieve a statistical significance of 0.05 in case of a reduction by 50% in the combined endpoints.

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.

Influence of protein catabolic rate on nutritional status, morbidity and mortality in elderly uraemic patients on chronic haemodialysis: a prospective 3-year follow-up study.

It has been recently reported that elderly chronic haemodialysis (CHD) patients have a reduced protein catabolic rate (PCRn) in spite of an adequate Kt/V. However until now the long-term consequences of this fact on the nutritional status, morbidity, and mortality were not known. This prospective study evaluates, over a period of 3 years, the effect of the reduced PCRn on some nutritional parameters, morbidity mortality in CHD patients older than 65 years with adequate and stable Kt/V. Over the period 1990-1993 we evaluated 42 CHD patients over 65 years (mean +/- SD 72 +/- 5 years). PCRn, total serum proteins, serum albumin concentration, body weight, body mass index (BMI) and serum transferrin were determined at the start of the study and followed yearly until the end of observation. The incidence of hospitalization/patient-year, the mortality rate and the causes of death were also recorded. All the patients were managed to maintain a Kt/V > 0.9 throughout the study. Twenty-two patients (Group A), mean age 70 +/- 4 years, completed the entire period of observation. Their Kt/V was 1.10 +/- 0.12, PCRn was 0.95 +/- 0.12 g/kg/day, and serum albumin concentration was 40.2 +/- 1.5 g/l, and these did not change significantly. The other parameters also remained stable over time. Twenty patients (Group B) died. Their mean age was 74 +/- 6 years. This group's Kt/V was 1.11 +/- 0.15, PCRn was 0.94 +/- 0.18 g/kg/day, and serum albumin concentration was 39 +/- 3.1 g/l, and there were no significant variations between the start and the end of observation for all the parameters studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Atheromatosis and double media: uncommon vascular lesions of renal allografts.

Study of 45 renal allograft nephrectomy specimens revealed the presence of relatively uncommon arterial vascular lesions: atheromatosis (12 cases) and a double layer of smooth muscle in the intima (Double Media) (4 cases). Histopathologic features of atheromatosis showed the presence of large lipid-laden cells localized in the intimal layer of arteries. Diagnosis of acute vascular rejection (AVR) was made in 19 cases. Diagnosis of chronic vascular rejection (CVR) was found in 4 cases. 22 cases showed lesions of both AVR and CVR. In 12 cases there was infiltration of the intima and media wall by foam cells closely resembling an atheromatous lesion. Four cases of Double Media were found in allografts with survival varying from 51 to 344 days. The presence of either atheromatous or double media does not correlate statistically with immunosuppressive treatment, blood pressure or with the presence of hypertriglyceridemia and/or hypercholesterolemia. Immunohistochemical investigation of atheromatosis revealed total negativity of the foam cells with antisera to: actin, myosin, desmin and myoglobin. Variable reactivity was observed with antisera to vimentin. Myointimal cells of Double Media expressed slight positivity for actin and vimentin. The double media lesion seems to be the result of a reparative vascular process secondary to rejection changes. Atheromatosis seems to be closely correlated to episodes of acute rejection. Vascular lesions in grafts are harbinger of poor prognosis. Double media lesion and atheromatosis do not seem to have a more unfavourable prognostic significance on the evolution of the transplants.

Viral hepatitis in HBsAg-positive renal transplant patients treated with cyclosporin and steroids.

This study reports clinical, serological and immunomorphological observations on viral hepatitis in 14 HBsAg-positive renal transplanted patients treated with cyclosporin and steroids. Eleven patients who were HBsAg positive before transplantation developed signs of hepatitis. This was due to HBV in six cases and progressed into a mild chronic disease. The remaining five subjects lacked signs of HBV reactivation. The hepatitis, attributed to non-A non-B agents, recovered completely. Two more patients became HBsAg positive after transplantation both developed acute hepatitis, respectively drug and HBV related. Transition into chronicity occurred only in the latter case. The results seem to indicate: (1) the possibility of a high incidence of non-B virus hepatitis in HBsAg-positive transplanted patients under cyclosporin treatment; (2) a good prognosis in non-B hepatitis as compared to hepatitis B for the same patient group; and (3) a mild degree of disease activity in cases who develop chronic hepatitis.

Familial IgM mesangial nephropathy: a morphologic and immunogenetic study of three pedigrees.

Eight patients belonging to 3 unrelated families had biopsy-proven IgM mesangial nephropathy. In the first family, the mother and the 2 daughters were affected; in the second, the mother and the son; in the third, 2 sisters and the brother. Two additional sisters of the third family showed a clinical picture consistent with chronic glomerulonephritis. The clinical picture was that of hematuria and/or proteinuria. No patients had nephrotic syndrome. Genealogic investigation enabled us to discover 2 additional affected members in the kindred of the first family (1 with IgA nephropathy, 1 with clinical glomerulonephritis) and 3 other affected members in the pedigree of the third family (1 with IgA nephropathy, 1 with sclerosing glomerulonephritis, 1 with clinical glomerulonephritis). Immunogenetic studies showed the recurrence of an extended haplotype bearing DR beta 11-DQ beta 3B-DQ alpha 2-C4A3-C4B1-BfS in 9 of 10 affected members. Our data suggest that genetic factors may be involved in the mechanism of the disease and support the hypothesis that IgM nephropathy is a distinct disease entity.

Ultrastructural renal findings in allografted kidneys of patients treated with ciclosporin A.

22 renal biopsies of 22 patients with 6-month-old transplants have been examined at the light- and electron-microscopic level to demonstrate the toxic effects induced by ciclosporin A (CS). These patients presented stable renal function and were exempt from acute rejection symptoms or nephrotoxicity. Interstitial fibrosis, tubular atrophy and interstitial lymphocytic infiltration were the lesions most often observed by light microscopy. In a single case an arteriolar lesion suggestive of arteriolopathy due to Cs was seen. Ultrastructural observations of renal tubular cells showed a tendency of rough and smooth endoplasmic reticulum to microdilate and microvacuolize. In 4 out of 22 cases there were mitochondrial alterations with giant mitochondria. In only 1 case, clusters of cilia were seen. Clinical histological correlations show that interstitial fibrosis is directly proportional to CS blood level. CS higher blood levels suggest a higher risk of nephrotoxicity.