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Background: Studies have provided conflicting results as to the protective role of calcium channel blockers (CCB) in cyclosporine-treated patients with regard to blood pressure control and preservation of renal graft function. Lacidipine is a dihydropyridine CCB that possesses antioxidative, anti-atherosclerotic, and anti-adhesion properties and was shown to prevent cyclosporine-induced nephrotoxicity in a rat model., Methods: We conducted a multicenter prospective, randomized, placebo-controlled study in 131 de novo recipients of a cadaveric renal allograft on cyclosporine therapy. The aim of this 2-year study was to assess the effects of lacidipine on graft function (plasma iohexol clearance), renal plasma flow, anastomotic arterial blood flow, deterioration of renal function, blood pressure, acute rejection, and hospitalization rate., Results: A total of 118 recipients were available for intention-to-treat analysis on efficacy (lacidipine: n=59; placebo: n=59). Graft function assessed by serum creatinine concentration and glomerular filtration rate measured as plasma iohexol clearance, was persistently better in lacidipine-treated patients from 1 year onwards (respectively, P<0.01 and P<0.05). Renal plasma flow and anastomotic blood flow were not significantly higher in lacidipine-treated patients. Three patients on lacidipine therapy and four on placebo experienced treatment failure defined as an increase in serum creatinine from baseline of more than 60% (log-rank test: P=0.57). Study groups did not differ in acute rejection rate, trough blood cyclosporine concentrations, blood pressure, number of antihypertensive drugs, hospitalization rate, and adverse event rate., Conclusions: The use of calcium channel blockers in cyclosporine-treated renal recipients results in a significantly better allograft function at 2 years and this effect is independent of blood pressure lowering.

We performed 41 kidney transplants in patients >70 years (35 single and 6 dual), with a mean recipient age of 72+/-2 years, from January 1990 to December 2001. Mean age of the donors was 69+/-12 years. Immunosuppression used triple therapy with steroids, mycophenolate mofetil, and cyclosporine or tacrolimus. Cold ischemia time was 23+/-3 hours. The incidence of primary nonfunction was 4.8%, and delayed graft function 58.5%. Acute rejection incidence was 12%. The actuarial patient survival rates at 12, 24, and 36 months were 82.5%, 82.5%, and 75%, respectively. Actuarial survival rates of the grafts censuring for death of the recipient with a functioning graft were 89.5%, 86%, and 68%, respectively. Nine of the 18 graft losses were due to recipient death. Overall, renal transplant recipients >70 years showed good results. The principal cause of graft loss was recipient death.

Cholestatic hepatitis and diffuse liver fibrosis have been described in immunosuppressed patients with hepatitis B virus or hepatitis C virus infection as fibrosing cholestatic hepatitis (FCH). FCH is characterized by cholestasis, with only a modest increase in aminotransferase levels. The pathologic picture typically shows periportal and perisinusoidal fibrosis, scarce mixed infiltrates, hepatocellular ballooning, and histologic cholestasis. We report two patients with diffuse fibrosis and cholestasis quite similar to the histologic picture of FCH, but in whom neither hepatitis B virus nor hepatitis C virus infection could be shown, highlighting the potential contribution of cytomegalovirus infection and azathioprine toxicity in the development of this severe complication of solid-organ transplantation.

Cyclosporin and tacrolimus have improved survival figures in organ transplantation. However, both drugs are potentially nephrotoxic. The immunosuppressive and nephrotoxic effects of both drugs appear to depend on the inhibition of calcineurin. Cyclosporin and tacrolimus cause acute (functional changes) and chronic nephrotoxicity (structural lesions in the kidney). These last important lesions include arteriolar hyalinosis, stripped interstitial fibrosis and tubular atrophy. It is possible that repeated episodes of renal ischaemia contribute to the development of chronic nephrotoxicity and then chronic allograft nephropathy. Cyclosporin and tacrolimus also induce arterial hypertension. Therefore, the beneficial effects of immunosuppression have been limited due to nephrotoxicity and arterial hypertension. Rapamycin, a novel immunosuppressive agent, that does not inhibit calcineurin, provides immunosuppression without nephrotoxicity. In fact, in the trials performed in Europe, sirolimus-treated immunosuppression patients exhibited a much better renal function than cyclosporin-treated patients. However, sirolimus can potentiate the nephrotoxic effect of cyclosporin. Therefore, when cyclosporin and sirolimus are used in combination, a reduction of the cyclosporin dose is desirable.

Cyclosporine (CsA) treatment in solid organ transplantation has represented one of the greatest advances in the past 20 years, reducing acute rejection and increasing long-term survival. However, CsA has an important side effect, producing renal vasoconstriction and systemic hypertension. The main histological findings in the kidney are vascular lesions in the endothelium and smooth muscle cells. On proximal tubule cells, severe atrophy, vacuolization and thickening of the basal membrane can be found. The main mechanisms of vasoconstriction are secondary to endothelium disorders, increasing vasoconstrictor substances like endothelin, thromboxane, free radicals, etc., and reducing vasodilator substances like nitric oxide and prostaglandins. CsA acute nephrotoxicity produces haemodynamic changes with minor histological lesions, which will disappear when the medication is discontinued. Long-term CsA nephrotoxicity has been widely discussed in the literature. For some authors, a limited number of patients can develop end-state renal failure but others did not suffer these complications. Nevertheless, it seems clear that high doses of CsA can produce renal lesion and renal insufficiency, being difficult to evaluate in renal transplant patients because of the frequent association with chronic rejection lesions. Several types of drugs have been used to treat CsA nephrotoxicity in renal transplant patients but calcium antagonists and angiotensin converting enzyme-inhibitors are the most frequently used, especially the former due to their effect on the afferent arteriole vasodilatation, their natriuretic properties and their reducing intracellular calcium. The greatest experience has been with nifedipine, but other drugs like verapamil, diltiazem, amlodipine, felodipine, isradipine, etc., have also been used. Lacidipine, a 1,4-dihydropiridine, has demonstrated a beneficial effect during the short term after renal transplantation, and a multicentre, multinational, double-bind, placebo-controlled clinical trial for the long term currently ongoing.

Severe hepatitis C virus (HCV)-related fibrosing cholestatic hepatitis leading to early liver failure has been reported only exceptionally. Of 259 HCV-infected renal transplant (RT) patients in one hospital unit, four (1.5%) are described, representing the first series of this particular post-RT disease. Patient mean age was 55.7 yr. Three were men. All had pretransplant, hepatitis B surface antigen-negative and were anti-HCV antibodies positive. Three of them showed pretransplant mild liver enzyme abnormalities, and all received kidneys from HCV-negative donors. All were on steroids, cyclosporine, and azathioprine (AZA). The clinical pattern appeared early after RT (mean, 11.5 mo). In three patients, hyperbilirubinemia (6.5 to 20 mg/dl) and high alkaline phosphatase levels (428 to 859 IU/L) were observed. Also, in all subjects, high gamma glutamyl transpeptidase levels (639 to 4270 IU/L), mild aspartate aminotransferase and alanine aminotransferase abnormalities, and serum HCV RNA were observed. Liver biopsy revealed diffuse fibrosis, leukocyte infiltrates, and different degrees of cholestasis, with typical signs of HCV hepatitis in only one patient. Two patients developed subfulminant liver failure and died 2 and 3 mo after biopsy, respectively. One patient also suffered hepatic failure, receiving a liver transplant. The fourth is alive on dialysis awaiting a combined kidney and liver transplant. It is concluded that fibrosing cholestatic hepatitis is a new, early, and severe complication after RT in HCV(+) patients, which appears in patients with ongoing HCV infection under AZA therapy, despite a nonaggressive immunosuppressive protocol. Both HCV and AZA could play a concurrent role in the pathogenesis of this severe complication after RT.

Hyperlipidemia is a common feature after organ transplantation. Most studies have evaluated the lipid profile in recipients of a particular graft, usually renal. In the present work, we studied the lipid profiles of 30 long-term stable liver transplant patients (LTP) and compared their pattern with 40 long-term stable renal transplant patients (RTP) matched for gender, age, and time from transplantation. There were no significant differences between both groups in body mass index, serum glucose, serum creatinine, or urinary protein excretion. In contrast, RTP had higher pre-transplant total cholesterol and triglycerides, received higher doses of steroids (both average and cumulative) and had higher cycosplorine blood levels. After a mean time of 60 months after transplantation, RTP exhibited higher levels of total serum cholesterol (226 +/- 26 vs. 180 +/- 39 mg/dl; p = 0.000 002) and low-density lipoprotein (LDL) cholesterol (152 +/- 22 vs. 112 +/- 37 mg/dl; p = 0.00001). In contrast, there were no differences between RTP and LTP in high density lipoprotein (HDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, total triglycerides, VLDL triglycerides, or lipoprotein (a) [Lp(a)]. By univariate analysis in the whole group, renal graft, prednisone daily dose, cyclosporine blood levels, pre-transplant cholesterol, and triglycerides were associated with increased post-transplant cholesterol levels. By multivariate analysis, prednisone daily dose was the only independent variable predicting increased post-transplant serum cholesterol levels. The present data show that hypercholesterolemia is more frequent among RTP than among LTP. In addition, our data suggest that corticosteroid therapy, rather than the transplanted organ, may be the major contributor to this difference.

During the past 12 months additional evidence has emerged from several studies, indicating that hepatitis C virus infection is the most important liver disease after renal transplantation. A new, severe and rare entity called fibrosing cholestatic hepatitis can lead to early liver failure, although the most important complications appeared in the long-run. Encouraging results with ribavirin have been described. Although glomerular lesions and more severe infections can appear in hepatitis C virus patients, graft and patient survival rates in most series are similar to those in hepatitis-C-negative patients. Survival is also better among hepatitis-C-positive patients after renal transplantation than in hepatitis-C-positive patients on dialysis on the waiting list for transplantation. Finally, the use of kidneys from hepatitis-C-positive donors is suggested for transplant into hepatitis C RNA positive patients matching the hepatitis C genotype.

Currently, it is well known that hepatitis c virus (HCV) represents the major cause of chronic liver disease in renal transplant patients. On the other hand, HCV has been described in association with different types of glomerular diseases, usually type I membranoproliferative glomerulonephritis (MGPN) and less frequently membranous glomerulonephritis (MGN). After renal transplantation two glomerular entities have described in HCV positive patients: MPGN, associated or not with cryoglobulinemia, hypocomplememtemia and rheumatoid factor and another lesion was MGN. All patients had chronic HCV infection and with detectable HCV RNA in the serum, developed proteinuria, nephrotic syndrome and microhematuria. Characteristically MGN occurs without cryoglobulinemia, hypocomplememtemia and rheumatoid factor. The clinical pictures and outcomes of these pathological pictures seem to be similar to those of the novo MPGN or MGN in renal transplant patients. These entities seem to be more frequent in HCV-positive than in HCV-negative patients. Also, a possible relationship between HCV infection and transplant glomerulopathy has been described. Therefore, in renal transplant patients with proteinuria, serology for HCV infection, HCV RNA and immunological tests should be performed as part of the differential diagnosis.

Background: Cyclosporin has been shown to facilitate renal vasoconstriction and to have an antinatriuretic effect. The existence of an interference of cyclosporin with the vasodilating properties of endothelium mediated by nitric oxide production could mediate these effects. On the other hand, the infusion of the nitric oxide precursor L-arginine has been shown to induce renal vasodilatation and to facilitate natriuresis in normal volunteers. We have investigated the renal effects of the administration of an infusion of L-arginine in renal transplant patients chronically treated with cyclosporin. To facilitate the analysis of the data the effects of the administration of a similar dose of cyclosporin on renal function during the infusion of a vehicle were also investigated during the administration of a vehicle of L-arginine., Design: Ten male renal transplant patients, chronically treated with cyclosporin and with a stable renal function were studied during 2 consecutive days after the administration of the usual morning dose of cyclosporin. The first day they received an intravenous infusion of vehicle and the second the infusion of graded doses of L-arginine (50, 100, 150 mg/kg/h) during 3 consecutive h., Results: The first day, after cyclosporin administration a significant fall (P < 0.01) was observed in natriuresis and kaliuresis in the absence of changes in renal plasma flow and glomerular filtration rate. After the administration of L-arginine significant (P < 0.01) increases of renal plasma flow, glomerular filtration rate, and natriuresis were seen. The increase in blood levels of cyclosporin after its administration did not differ between days 1 and 2., Conclusion: These results indicate that L-arginine facilitates renal vasodilatation and natriuresis in renal transplant patients. Furthermore, the observed increase in sodium excretion could indicate that L-arginine counteracts the antinatriuretic effect of cyclosporin.

Background: Hepatitis C virus (HCV) infection has been described in association with various types of glomerular diseases, usually type I membranoproliferative glomerulonephritis and rarely membranous glomerulonephritis (MGN). In this article, we describe the first series of MGN exhibited in renal transplant patients and associated with HCV infection., Methods: From January 1980 to December 1994, 2045 kidney transplantations were performed in our renal transplant units. A retrospective analysis demonstrated an overall 20% prevalence of HCV virus-positive patients; 409 transplanted patients were HCV positive (ELISA and RIBA)., Results: Fifteen patients developed an allograft MGN (3.66%) 24 months after renal transplantation. MGN appeared in the form of significant proteinuria (>1.5 g/24 h) with stable renal function. In all cases, graft biopsy demonstrated a thickening of the capillary wall, subepithelial electron-dense deposits, and IgG and C3 diffuse granular deposits along the basal membrane. Ten cases were considered de novo, two cases were considered recurrent MGN, and three cases were considered undetermined because the primary renal disease was chronic glomerulonephritis. All patients showed negative antinuclear antibodies and cryoglobulins, normal complement, and negative rheumatoid factors. During follow-up (an average of 2 years), 12 patients developed a progressive worsening of renal function, with increased serum creatinine and persistent proteinuria; 8 of the 12 patients returned to dialysis. Of the remaining three cases, two patients showed partial remission of nephrotic syndrome after high doses of steroids, and one patient persisted with stable renal function and proteinuria (<2 g/24 h.)., Conclusions: In summary, HCV is preferentially associated with MGN in renal transplant patients, rather than with membranoproliferative glomerulonephritis as in the normal adult population. MGN associated with HCV infection has a similar clinical picture and outcome to posttransplant idiopathic de novo MGN, with persistent massive proteinuria and progressive deterioration of renal function.

Chronic rejection - also called chronic renal allograft dysfunction (CRAD) - is the main cause of long-term loss of the transplanted kidney, but its pathogenesis is not well known. The aim of this study was to know if lipoproteins, fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and platelet aggregation show more abnormalities in renal transplant patients with CRAD than in those with stable renal function. Sixty patients with renal allograft have been studied; 20 patients with CRAD and 40 controls matched for age, gender and time after transplantation. In a univariate analysis patients with CRAD had higher total serum triglycerides (214+/-153 vs. 133+/-39 mg/dl; p = 0.04) and very-low-density lipoprotein (VLDL) triglycerides (128+/-116 vs. 59+/-29 mg/dl; p = 0.04). Apolipoprotein B levels were also increased in patients with CRAD although this difference was only borderline significant (131+/-58 vs. 98+/-16 mg/dl; p = 0.05). Similarly, there was a trend toward increased total, VLDL, and low-density lipoprotein (LDL) cholesterol and reduced high-density lipoprotein (HDL) cholesterol in CRAD patients, but these differences did not reach statistical significance. Apolipoprotein A-1 and lipoprotein(a) levels were similar in both groups. Neither platelet aggregation nor PAI-1 levels differed between both groups. In contrast, fibrinogen was increased in patients with CRAD (373+/-81 vs. 322+/-62 mg/dl; p = 0.01). In a multivariate analysis triglycerides and fibrinogen were positively correlated to CRAD. These findings add further support to the hypothesis that lipid abnormalities may be involved in the pathophysiology of CRAD. In addition, this is the first report showing that fibrinogen levels are increased in patients with CRAD. Further studies are needed to evaluate a potential role of fibrinogen in the development of CRAD.

The urinary enzymes alanine aminopeptidase (AAP; EC 3.4.11.2) and N-acetyl-B-D-glucosaminidase (NAG; EC 3.2.1.30) were measured daily in 35 renal transplant recipients during the early postoperative period. Each peak value of fractional excretion was corrected for its baseline value (CFE). CFE values above normal for both NAG and AAP were more frequently found in episodes of acute rejection than in cyclosporine acute nephrotoxicity episodes (76 vs. 0%; p < 0.001). Consequently, a rise in CFE levels for both NAG and AAP is strongly suggestive of acute rejection crisis.

Aim: To review the renal benefits of calcium antagonists., Methods: Review of published studies., Results: Both experimental and clinical studies have indicated that, apart from being highly potent antihypertensive agents, calcium antagonists may also provide tissue protection and preservation. In three well defined clinical situations, the use of calcium antagonists has proved to be of value. First, in acute renal failure we and others have shown that the administration of dihydropyridine or diltiazem can, by preventing an intracellular calcium overload, avoid the renal damage induced by the use of a radiographic contrast agent. Second, in chronic renal failure, the administration of a calcium antagonist has been shown to be safe and at least similar in efficacy to other commonly used antihypertensive drug classes. Third, in renal transplant patients, calcium antagonists have been shown to prevent both acute and chronic cyclosporin nephrotoxicity. Calcium antagonists have a clear advantage in the case of acute toxicity because they allow faster renal function recovery and a shorter hospitalization time. The mechanisms by which this class reduces cyclosporin toxicity may be related to a reduction in the calcium influx into cells during ischaemic and reperfusion periods, which would reduce the generation of oxygen-free radicals and perhaps reduce thromboxane production., Conclusions: Calcium antagonists have potential renal protective effects that favour their use in many clinical situations where renal function is impaired.

We report a case of prolonged oliguric acute renal failure after renal transplantation under steroids and ciclosporin (Cs) immunosuppression. In the 2nd week when low fractional excretion of sodium values in the presence of oliguria (as expression of Cs nephrotoxicity) and high Cs blood levels were seen, a calcium antagonist drug was administered. Also, a Cs dose adjustment was made. Then, the diuresis and fractional excretion of sodium increased together with a progressive renal function. Although this evolution could be explained as a spontaneous resolution of postischemic renal failure, we speculated that in this case of established early Cs nephrotoxicity the effect of a calcium antagonist drug, such as nifedipine, could be beneficial.