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Innate immunity is the first barrier against pathogen infection and has also the important function of activating the adaptive immunity. The receptors of innate immunity, such as toll-like receptors and other receptors, recognize as danger signals the molecular patterns of pathogens as well as those of endogenous molecules released by dying cells. The information is transmitted to adapter proteins that, through a chain of kinases that translate the signal to transcription factors regulating inflammatory genes. In the inflammatory milieu dendritic cells become mature, intercept the antigen and migrate to lymphoid organs where they present the antigen to naïve T cells. Complement also exerts an important role of bridge between innate and adaptive immunity. In donor-deceased kidney transplantation, the innate immunity is triggered in the donor by brain death and is aggravated by the cold ischemia and even more by reperfusion. Once activated, innate immunity produces a local inflammatory environment leading to dendritic cell maturation and complement activation. Dendritic cells present the alloantigen to T cells and induce their differentiation towards effector Th1 and Th17 while inhibiting Th2 and T regulatory cells. A main goal of the current research in transplantation is to obtain an immunological tolerance. Experimental studies showed the possibility of inducing operative tolerance in murine models and even in primates with the infusion of regulatory dendritic cells. However, there are no data with this technique in clinical transplantation.

Connexins are membrane-spanning proteins that allow for the formation of cell-to-cell channels and cell-to-extracellular space hemichannels. Many connexin subtypes are expressed in kidney cells. Some mutations in connexin genes have been linked to various human pathologies, including cardiovascular, neurodegenerative, lung, and skin diseases, but the exact role of connexins in kidney disease remains unclear. Some hypotheses about a connection between genetic mutations, endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) in kidney pathology have been explored. The potential relationship of kidney disease to abnormal production of connexin proteins, mutations in their genes together with ER stress, or the UPR is still a matter of debate. In this scenario, it is tantalizing to speculate about a possible role of connexins in the setting of kidney pathologies that are thought to be caused by a deregulated podocyte protein expression, the so-called podocytopathies. In this article, we give examples of the roles of connexins in kidney (patho)physiology and propose avenues for further research concerning connexins, ER stress, and UPR in podocytopathies that may ultimately help refine drug treatment.

Background: We conducted a pilot trial to compare the effectiveness and safety of 2 different treatments in patients with membranous nephropathy and nephrotic syndrome. Methods: To validate the hypothesis that the 2 treatments were equivalent, patients with biopsy-proven membranous nephropathy and nephrotic syndrome were randomly assigned to methylprednisolone alternated with a cytotoxic drug every other month for 6 months (group A) or to intramuscular synthetic adrenocorticotropic hormone administered twice a week for 1 year (group B). Results: The primary outcome measure is cumulative number of remissions as a first event. Fifteen of 16 patients in group A and 14 of 16 patients in group B entered complete or partial remission as a first event. After a median follow-up of 24 months (interquartile range, 15 to 25 months), there were 4 complete remissions and 8 partial remissions in group A versus 8 complete remissions and 6 partial remissions in group B. Median proteinuria decreased from protein of 5.1 g/d (interquartile range, 4.0 to 7.3 g/d) to 2.1 g/d (interquartile range, 0.4 to 3.8 g/d; P = 0.004) in group A and 6.0 g/d (interquartile range, 4.4 to 8.5 g/d) to 0.3 g/d (interquartile range, 0.2 to 1.9 g/d; P = 0.049) in group B. Two patients from each group interrupted treatment because of side effects or inefficacy. Conclusion: Most nephrotic patients with membranous nephropathy responded to either treatment. Proteinuria was significantly decreased with both methylprednisolone and cytotoxic agents or prolonged administration of synthetic adrenocorticotropic hormone, without significant differences between these 2 therapies.

Increased levels of circulating endothelial cells in chronic periaortitis as a marker of active disease. Background The pathogenesis of chronic periaortitis (CP) has not been clarified. The histologic features and the association with autoimmune diseases suggest an immune-mediated disorder with marked inflammatory vascular and perivascular lesions. To clarify the role of vascular damage we looked for the presence and the surface phenotype of circulating endothelial cells (CECs) in the peripheral blood of patients with chronic periaortitis. Methods Eleven patients with CP were evaluated for the presence of CECs; 9 patients had active and 2 inactive disease. Three patients with active disease were also evaluated 3 months after therapy. Ten atherosclerotic patients, 10 patients with renal insufficiency of variable degree and etiology, and 40 healthy subjects were evaluated as controls. Five-parameter, 3-color flow cytometry was performed with a FACScan. CECs were defined as CD45 negative, CD31, P1H12, and CD36 positive, and activated CECs as CD45 negative and P1H12, CD62 positive. Results The median number of CECs in patients with CP (10 6 cells/mL) was significantly higher than in healthy controls (16 cells/mL, P = 0.0004) and atherosclerotic patients (25 cells/mL, P = 0.0005) Two patients with inactive disease had a CEC count comparable to that of normal subjects. In 2 of the 3 patients reevaluated, 3 months after therapy CEC numbers normalized. Almost all CECs were microvascular in origin and showed an activated phenotype. Conclusion The presence of a high number of CECs in the active phase of chronic periaortitis and their normalization during inactive disease suggest that endothelial damage may play a role in the pathogenesis of the disease.

Over the last 20 years, cyclosporine (CsA) has been the mainstay of immunosuppression in renal transplantation. Initially, CsA was administered at high doses, which enhanced its potential nephrotoxicity. Better handling of the drug was obtained by lowering the dose, monitoring CsA concentration and renal function, and using graft biopsy in difficult cases. In the early 1990s, a new microemulsion showed better pharmacokinetics and efficacy than did the previous formulation. A few years later, evidence showed that checking blood levels 2 hours after administration was a more reliable indicator of CsA exposure than were trough blood levels. The combination with newer immunosuppressive drugs allowed further reduction in the doses of CsA to maintain stable renal allograft function and to improve long-term graft survival. CsA has largely been used in autoimmune diseases. There is concern about its nephrotoxicity, however, as in some studies control renal biopsies showed that CsA-treated patients developed progressive interstitial fibrosis. The risk of nephrotoxicity was related to the initial doses of CsA and to the increase in serum creatinine. Avoiding CsA in patients with creatinine clearance

The aims of the current study were to determine whether therapeutic drug monitoring (TDM) might benefit kidney transplant recipients receiving everolimus, and to establish dosage recommendations when everolimus is used in combination with cyclosporine and corticosteroids. The analysis was based on data from 779 patients enrolled in two 12-month trials. Everolimus trough concentrations >/=3 ng/mL were associated with a reduced incidence in biopsy-proven acute rejection (BPAR) in the first month (p = 0.0001) and the first 6 months (p = 0.0001), and reduced graft loss compared with lower concentrations (4% vs. 20%, respectively). By contrast, cyclosporine in the standard concentration range had no impact on BPAR within the same timeframes. Most patients receiving everolimus 1.5 or 3 mg/d achieved trough concentrations above the therapeutic threshold of 3 ng/mL, regardless of reductions in cyclosporine dose. TDM simulation showed that just two dose adjustments would achieve median everolimus trough values >/=3 ng/mL in 95% of patients during the first 6 months. This investigation indicates that improved efficacy is likely when TDM is considered as an integral component of the immunosuppressive strategy of everolimus.

In spite of considerable progress in immunosuppressive and supportive treatment, numerous problems persist which interfere with the success of renal transplantation. Before transplantation has been performed, factors impacting on outcome include the donor (living vs cadaver, age and HLA system) as well as the recipient (age, immunological reactivity, potential sensitization and duration of dialysis). These are the main factors that affect the outcome of the transplant, particularly in the long-term. After transplantation a number of events may put graft function at risk: potential recurrence of the primary renal disease in the allograft; 'de novo' renal disease triggered by infections, drugs or autoimmunity; and non-specific progression promoters, such as diabetes, hypertension, proteinuria, nephrotoxic agents and/or viral infections. The two most frequent causes of chronic allograft dysfunction are (i) chronic rejection (often triggered by preceding acute rejection, delayed graft function or poor compliance) and (ii) calcineurin-inhibitor nephrotoxicity (more likely to develop in kidneys of older donors or in marginal kidneys). The differential diagnosis between these two entities is generally difficult, but some histological clues (reduplication of glomerular basement membrane, obliterating vasculopathy and C4d deposits) as well as the demonstration of humoral antibodies are pointers suggesting rejection. Treatment of chronic graft dysfunction is difficult, whatever the cause, particularly in cases with advanced renal lesions. Therefore, early diagnosis is of paramount importance. In this regard, graft biopsy can be of great help. In spite of many problems and complications, not only short-term but also long-term results of renal transplantation are improving progressively, as documented by CTS data showing that in Europe for transplants performed between 1982 and 1984 the mean graft half-life was 7 years, while for transplants performed between 1997 and 1999 it was 20 years.

Only a few cases of acute post-infectious glomerulonephritis have been described in renal transplant patients. We report here three cases of acute post-bacterial glomerulonephritis in renal transplants. In contrast to the classic cases of post-streptococcal glomerulonephritis the type of infection was heterogeneous: respectively, Escherichia coli bacteremia, a skin abscess, and cholangitis. The clinical presentation was characterized by a deterioration of graft function in two of our three patients. Acute renal dysfunction recovered in both patients, but in the long term the outcome was severe; two of the three patients lost their graft function. It is difficult to ascertain whether progression was due to chronic allograft nephropathy, to glomerulonephritis, or both. It may be concluded that acute post-infectious glomerulonephritis is a possible, although rare, complication in renal transplant recipients. It has an unusual presentation and may have a poor outcome in the long term. The role of therapy, if any, is still undefined.

Background Little information is available about the role of oxidative stress in renal transplant patients. To evaluate the prevalence and severity of oxidative stress in renal transplantation, the authors conducted a cross-sectional study. Methods In 112 cadaver or living-donor kidney transplant recipients with a follow-up of at least 6 months and with plasma creatinine less than or equal to 2.5 mg/dL, complete blood count, serum vitamin B12, serum folate (s-F), reactive oxygen species (ROS), thiol groups (-SH), total antioxidant activity (TAOC), serum homocysteine (Hcy), and intraerythrocyte folate (ery-F) were measured. Results The mean levels of Hcy (21.1 microM vs. 350 micromol/HclO/mL), were higher than the reference interval, whereas -SH groups, vitamin B12, s-F, and ery-F were within the normal range. In the multivariate model, plasma creatinine (P=0.0062), vitamin B12 (P=0.0121), and TAOC (P=0.0007) were independently associated with oxidative stress. At multiple regression analysis, -SH groups and ROS were directly and inversely related to hematocrit (P=0.0007 and P=0.0073). There was also a negative correlation between -SH groups and blood pressure levels (P=0.0095). Conclusions Renal transplant patients have a pattern of increased oxidant stress that is counterbalanced by an enhancement of the antioxidant mechanisms. Besides the well-known risk factors, the authors found that anemia is an independent risk factor for an increase of ROS. Further studies are needed to evaluate whether the correction of anemia might prevent or reduce the oxidative stress in renal transplant patients.

It has been hypothesized that hemodialysis (HD) treatment per se can preserve patients from an aggressive course of hepatitis C virus (HCV) infection by reduction of viral load. The aim of the present study in HCV-positive (HCV+) HD patients is to determine whether HD induces the production of interferon-alpha (IFN-alpha) and if such production can contribute to viremia reduction.To address this issue, HCV RNA and IFN-alpha levels were determined in 11 HCV+ patients immediately before and at the end of a 4-hour dialysis session using cellulosic membranes and 24 and 48 hours later, ie, immediately before the subsequent dialysis session using the same membrane and at the end of the dialysis session. The same protocol was repeated 1 week later using a high-biocompatibility synthetic membrane.HCV titer decreased in all patients after dialysis (range, 3% to 95%; P = 0.001) and thereafter progressively increased and returned to basal levels within 48 hours, with a new reduction during the next dialysis treatment. There was no significant difference in the magnitude of changes in HCV titers in tests performed using cellulosic or synthetic membranes. Plasma IFN-alpha levels increased markedly after dialysis using both cellulosic (in 9 of 11 cases) and synthetic membranes (in 10 of 11 cases; P0.01) and returned to basal levels within 48 hours; thereafter, IFN-alpha levels increased again during the next dialysis session. In some patients, plasma IFN-alpha levels after HD were approximately 50% of the level observed after therapeutic administration of 6 million units of IFN-alpha to 4 HD patients with chronic hepatitis.Although without a proven direct cause-effect relationship between HCV level reduction and induction of IFN-alpha after dialysis, our observation suggests an additional new mechanism for the unusually mild course of HCV infection in HD patients.

Depletion of clusterin in renal diseases causing nephrotic syndrome. Background Clusterin is a lipoprotein that has anti-complement effects in membranous nephropathy (MN). In focal segmental glomerulosclerosis (FSGS), it inhibits permeability plasma factor activity and could influence proteinuria. Moreover, with aging, knockout mice for clusterin develop a progressive glomerulopathy with sclerosis. Methods Since little is known about clusterin metabolism in humans, we determined clusterin levels and composition in the sera and urine of 23 patients with MN, 25 with FSGS and 23 with steroid-responsive nephrotic syndrome (NS). Renal localization was evaluated by immunofluorescence and morphometry. Results Serum clusterin was markedly reduced in active MN, in FSGS and in children with NS compared to controls; after stable remission of proteinuria, nearly normal levels were restored. Among various biochemical variables, serum clusterin was inversely correlated with hypercholesterolemia. Urinary clusterin, representing a 0.01 fraction of serum, was higher in the urine from normal subjects and FSGS patients in remission with proteinuric MN, FSGS and idiopathic NS; clusterin was inversely correlated with proteinuria. In all cases, urinary and serum clusterin was composed of the same 80 kD isoforms. Finally, a decrease in focal segmental or global clusterin staining was found in FSGS glomeruli, especially in areas of sclerosis. Instead, in MN an overall increment of staining was observed that ranged from mild/focal to very intense/diffuse. Conclusions The overall pool of clusterin is reduced in glomerular diseases causing nephrotic syndrome, with hypercholesterolemia appearing as the unifying feature. Depletion of clusterin should negatively affect the clinical outcome in nephrotic patients and efforts should be aimed at normalizing clusterin overall pool.

Risk factors for late kidney allograft failure. Background While graft survival rates in the short term have improved dramatically, only a modest improvement has been shown in long-term graft survival rates. We evaluated the causes of late failure in renal allograft recipients treated with cyclosporine A (CsA). Methods A total of 864 adults with a functioning graft at one year were evaluated. The end points were dialysis or death with a functioning graft. Results The 13-year patient and graft survival probabilities were 0.82 and 0.64, respectively. The graft half-life was 20.1 years and the pure graft half-life was 31.1 years. At multivariate analysis, plasma creatinine at one year ( P = 0.0006; RR 1.72), low-density lipoproteins (LDL) at one year ( P = 0.0014; RR 1.65), older age ( P = 0.0128; RR 1.50) and delayed graft function ( P = 0.0350; RR 1.45) were associated with the end point. Chronic allograft nephropathy was the cause of failure in 97 patients, death in 70, recurrence of glomerulonephritis in 24, other events in 6. Cardiovascular complications were the most frequent cause of death. Post-transplant cardiovascular events were associated with: pre-transplant cardiovascular events ( P = 0.0012; RR 2.65), older age ( P = 0.0001; RR 2.46), pre-transplant arterial hypertension ( P = 0.0249; RR 1.57), smoking ( P = 0.0235; RR 1.29), duration of dialysis ( P = 0.0229; RR 1.28). Mean serum cholesterol, LDL and triglycerides were each significantly associated post-transplant cardiovascular events. Conclusions The graft half-life was 20 years. Chronic allograft nephropathy was the leading cause of late failure, followed by death. If the data were censored by death, the projected pure graft half-life would be 31.1 years. Pre-transplant selection and preparation of the candidate as well as appropriate life style are recommended to improve life expectancy and extend graft survival.

Background: Results of peritoneal dialysis (PD) in cirrhotic patients with renal failure are debated. The aim of the present study is to assess the outcome of PD patients with liver cirrhosis. Methods: A retrospective study based on clinical records was performed in 21 cirrhotic and 41 PD patients without liver disease followed up at our PD unit. Results: Five-year patient and technique survival were similar in the two groups. Seven cirrhotic patients (33%) died of liver failure (5 patients), liver cancer (1 patient), and peritonitis (1 patient). Ten controls (24%) died of cardiovascular complications (6 patients), pneumonia (1 patient), cachexia (1 patient), and unknown reasons (2 patients). Six cirrhotic patients discontinued PD therapy after 44.3 ± 24.7 months because of inadequate dialysis (2 patients), sclerosing peritonitis (2 patients), dementia (1 patient), or patient choice (1 patient). Twelve controls discontinued PD therapy after 33 ± 25.9 months because of peritonitis (6 patients), exit-site infection (1 patient), inadequate peritoneal clearance (3 patients), catheter malfunction (1 patient), and patient request (1 patient). The peritonitis rate was 0.31 episodes/y in cirrhotic patients and 0.53 episodes/y in controls (P = not significant). The hospitalization rate was similar (16.5 d/y in cirrhotic patients, 15.4 d/y in controls). In cirrhotic patients, complications were leakage (3 patients), symptomatic hypotension (5 patients), anemia (5 patients), severe malnutrition (14 patients), sclerosing peritonitis (2 patients), and hepatic encephalopathy (3 patients). Conclusion: The outcome of PD and risk for bacterial peritonitis or other dialysis complications are not worsened by the presence of liver cirrhosis. © 2002 by the National Kidney Foundation, Inc.

Background. Infection-associated glomerulonephritis is rare in adults and its long-term prognosis is undefined. Methods. We retrospectively evaluated the clinical course of 50 adults (30 men, 20 women) with infection-associated glomerulonephritis diagnosed in our department from 1979 to 1999. The mean follow-up was 90 ± 78 months. Patients were subdivided into two groups: group I included those without underlying disease and group 2 included those with severe underlying disease. Results. At presentation, the median age was 54 years, and 33 patients were hypertensive, 31 had nephritic syndrome, eight had nephrotic syndrome and 11 had non-nephrotic proteinuria. Patients in group 2 were significantly older and had a significantly higher proteinuria than patients of group 1. Of the 21 patients in group 2, nine had liver cirrhosis, four cancer, five diabetes, three bronchiectasis, one thalassaemia intermedia, one polymyositis and one had anti-phospholipid antibodies syndrome. At the last follow-up. five patients had died, 21 patients were in complete remission. ten had partial remission, ten had renal insufficiency and three were on chronic dialysis. Multivariate analysis showed that an underlying disease (P=0.04) and interstitial infiltration at biopsy (P=0.036) were predictors of incomplete recovery. A correlation analysis between the year of diagnosis and the clinical histological characteristics at presentation showed that age (P = 0.05), atypical infections (P = 0.01), underlying disease (P = 0.01) and interstitial infiltration at biopsy (P = 0.02) increased over time while the number of patients with complete remission significantly decreased (P = 0.001). Conclusions. Infection-associated glomerulonephritis may progress to chronic renal failure in a consistent number of adult hospitalized patients, particularly in those with an underlying disease and when associated with interstitial infiltration at biopsy.

In normal subjects, the gastric ionisation of calcium and phosphate seems to be a prerequisite for their intestinal absorption. We investigated the behavior of the plasma calcium and phosphate profile in 30 patients on regular dialysis treatment in the 6 h following a meal containing 1 g of calcium and 2 g of phosphate. Moreover, to assess the role of gastric acidity, the study was repeated after 3 days on omeprazole administration, to nearly abolish gastric acid secretion. Both total plasma calcium and ionized calcium peaked after the meal (at 30 and 120 min, respectively) only in basal study, while no peak was observed after the administration of omeprazole. Surprisingly, both in basal and in the omeprazole study the levels of plasma phosphate did not increase after the test meal. In conclusion, as in normal subjects, the gastric ionization of dietary calcium promotes the intestinal absorption of calcium in uremic patients on dialysis treatment, while the acute gastric acid inhibition by omeprazole reduced the intestinal calcium transport. In contrast, with the ‘trade off’ hypothesis we did not observe any postprandial phosphate peak after the dietary load, and, in contrast with normal subjects, omeprazole administration did not influence the phosphate profile.

Today, old age does not represent a formal contraindication to kidney transplantation. Rather, there is evidence that in elderly patients renal transplantation offers longer life expectancy and better quality of life in comparison with dialysis. Yet, the results of renal transplantation in recipients older than 65years are inferior to those observed in younger adults, death with functioning graft representing a major cause of failure. Therefore, the selection of aged patients is of paramount importance. Apart from the routine clinical and biological investigations, three aspects have been relatively neglected by the transplant community and may require a careful analysis in elderly candidates to transplantation: the presence and degree of frailty, the presence of comorbidities and the adherence to prescriptions. Although there are rapid and simple tests for assessing the degree of frailty in the elderly, there is no clear cut-off value to decide whether a patient should be accepted or not. With advanced age the prevalence and severity of cardiovascular events and other diseases tend to increase. The use of combined age-comorbidity indices may be helpful to identify patients at high risk of mortality. Another critical point is the poor unintentional adherence to treatment, often caused by forgetfulness and mild cognitive impairment. These drawbacks may be further enhanced by a high number of pills to take and by changes in the dosage or type of prescriptions. A careful screening of the presence and degree of frailty, comorbidity and poor compliance to treatment is highly recommended before admitting older candidates to the waiting list for transplantation.

Glomerular diseases developing in the kidney allograft are more often recurrences of the original disease affecting the native kidneys. However, in an undefined number of cases de novo, glomerular diseases unrelated to the original disease in the native kidneys can develop in the transplanted kidney. The clinical presentation and histologic features of de novo diseases are often similar to those features observed in patients with primary or secondary GN in the native kidneys. However, in transplanted kidneys, the glomerular, vascular, and tubulointerstitial changes are often intertwined with structural abnormalities already present at the time of transplant or caused by antibody- or cell-mediated allograft rejection, immunosuppressive drugs, or superimposed infection (most often of a viral nature). The pathophysiology of de novo glomerular diseases is quite variable. In rare cases of de novo minimal change disease, circulating factors increasing the glomerular permeability likely participate. Maladaptive hemodynamic changes and tissue fibrosis caused by calcineurin inhibitors or other factors may be involved in the pathogenesis of de novo FSGS. The exposure of cryptic podocyte antigens may favor the development of de novo membranous nephropathy. Many cases of de novo membranoproliferative GN are related to hepatitis C virus infection. Patients with Alport syndrome lacking antigenic epitopes in their glomerular basement membrane may develop antibodies against these glomerular basement membrane antigens expressed in the transplanted kidney. Infection may cause acute GN to have a heterogeneous clinical presentation and outcome. De novo pauci-immune GN in renal transplant is rare. Preexisting or acquired intolerance to glucose may, in the long term, cause diabetic nephropathy. The prognosis of de novo diseases depends on the type of GN, the severity of lesions caused by the alloimmune response, or the efficacy of immunosuppressive therapy. In most cases, the management of de novo glomerular diseases is empirical or elusive.

The term crescentic glomerulonephritis (GN) refers to a pathologic condition characterized by extracapillary proliferation in >50% of glomeruli. Clinically crescentic GN is characterized by a nephritic syndrome rapidly progressing to end stage renal disease (ESRD). Three types of crescentic GN have been identified. Type 1 includes cases of Goodpasture syndrome characterized by linear deposits of antibodies along the glomerular basement membrane (GBM) at immunofluorescence. Type 2 is a heterogeneous group of primary or secondary glomerular diseases complicated by crescentic GN. In this category there are granular deposits of immunoglobulins and complement fractions on the glomerular tuft. Type 3 includes cases of ANCA-associated small-vessel vasculitis. Immunofluorescence is negative or may show only faint deposits of immunoglobulins. The etiology and the initial pathogenetic factors are different in the three types, but the final mechanisms leading to crescent formation and the renal symptoms and signs are similar. The prognosis depends on the timeline of diagnosis and treatment. Although some patients requiring dialysis may recover a good renal function, usually the higher the serum creatinine at presentation the worse the outcome. When treatment is initiated early, most patients obtain a complete or partial remission. High-dose corticosteroids and cyclophosphamide represent the standard therapy for crescentic GN. The addition of plasma exchange may also be helpful, particularly in patients with massive alveolar hemorrhage. Anti-B monoclonal antibodies have also been used in some patients with crescentic GN, but their role in this particular area is still poorly established.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by infiltrates of lipid-laden CD68+/CD1a− histiocytes, affecting heart, lungs, central nervous system, and bones. Kidney and adjacent structures can also be affected, leading to renal failure in about 30% of cases. The diagnosis is challenging, and treatment is generally based on administration of interferon-alpha (IFNα), but preliminary results also showed the therapeutic efficacy of anakinra, an antagonist of the receptor of interleukin-1 (IL-1). We report the case of an elderly patient with ECD and severe involvement of the heart and kidneys who was successfully treated with anakinra.

Sirolimus and its derivate everolimus are two immunosuppressive drugs with similar chemical structure that inhibit the proliferation of T cells by interfering with a serine-threonine kinase, called mTOR. Apart from their immunosuppressive effects, these agents may also inhibit endothelial intimal proliferation, the replication of cytomegalovirus, and the development of certain cancers. The main dose-dependent adverse events of mTOR inhibitors are hyperlipidemia, thrombocytopenia, mucositis, edema, and proteinuria. The use of mTOR inhibitors in renal transplantation may allow to reduce the doses of calcineurin inhibitors. Withdrawal of calcineurin inhibitors is also possible and may improve renal function, but some patients do not tolerate this regimen because of side effects. Further studies are needed to assess the role of mTOR inhibitors in the long-term.

Hepatitis C virus (HCV) infection is common in the dialysis population and patients with chronic renal failure (CRF) not requiring dialysis. HCV is the most important cause of chronic liver disease in dialysis patients; however, its role has been underestimated by the lower aminotransferase activity in the dialysis population. Aminotransferase activity in patients with CRF not requiring dialysis has not been adequately addressed to date. The aim of this study is to investigate whether serum aminotransferase levels in predialysis patients with CRF are less than those obtained in healthy individuals and dialysis patients. We also analyzed the potential association between serum aminotransferase activity and demographic, clinical, and biochemical parameters. Aspartate (AST) and alanine aminotransferase (ALT) activity was greater in antibody to hepatitis C (anti-HCV)-positive than anti-HCV-negative patients with CRF not requiring dialysis (AST, 32.3 +/- 19 versus 18.1 +/- 8 IU/L [P = 0.0001]; ALT, 32.9 +/- 28 versus 17.7 +/- 11 IU/L [P = 0.00001], respectively). Predialysis patients with CRF had lower AST and ALT activity in comparison to healthy individuals (AST, 19.7 +/- 11.2 versus 20.4 +/- 6.8 IU/L [P = 0.00001]; ALT, 19.5 +/- 15.1 versus 21.7 +/- 11.3 IU/L [P = 0.00001], respectively). The difference was much greater after correction for viral markers: AST and ALT levels in hepatitis B surface antigen (HBsAg)-negative anti-HCV-negative predialysis patients with CRF were less than those in the healthy population (AST, 17.9 +/- 8 versus 20.4 +/- 6.8 IU/L [P = 0.00001]; ALT, 17.5 +/- 10 versus 21.7 +/- 11.3 IU/L [P = 0.00001], respectively). Comparison of AST and ALT activity between age-matched healthy and predialysis seronegative CRF groups showed lower AST and ALT values in the study population. HBsAg-negative anti-HCV-negative dialysis patients had lower AST and ALT activity than seronegative predialysis patients with CRF (AST, 16.6 +/- 11.6 versus 17.9 +/- 8 IU/L [P = 0.01]; ALT, 16.3 +/- 9.4 versus 17.5 +/- 10 [P = 0.041], respectively). Multivariate analysis in the predialysis CRF population showed an independent association between AST (P = 0.00001) and ALT (P = 0.00001) activity and anti-HCV positivity, and age was negatively linked to AST (P = 0.011) and ALT levels (P = 0.001). AST level was negatively related to serum creatinine level (P = 0.0001). In conclusion, HCV infection causes significant liver injury in predialysis patients with CRF. These patients have decreased aminotransferase activity compared with the general population. Dialysis patients show lower aminotransferase activity than predialysis patients with CRF. Because serum aminotransferase levels are commonly used to screen for liver disease in the dialysis and predialysis CRF population, recognition of liver damage may be hampered by the reduction in aminotransferase values in these patients. Studies aimed to clarify the pathogenesis of this phenomenon are in progress.

With the success of organ transplantation, liver disease has emerged as an important cause of morbidity and mortality of renal transplant (RT) recipients. Numerous studies performed during the 1990s have shown that hepatitis C virus (HCV) infection is the leading cause of chronic liver disease among RT recipients. The transmission of HCV by renal transplantation of a kidney from an HCV-infected organ donor has been shown unequivocally. Liver biopsy is essential in the evaluation of liver disease of RT recipients, and histological studies have shown that HCV-related liver disease after renal transplantation is progressive. The outcome of HCV-related liver disease is probably more aggressive in RT recipients than immunocompetent individuals. Various factors can affect the progression of HCV in the RT population: coinfection with hepatitis B virus, time of HCV acquisition, type of immunosuppressive treatment, and concomitant alcohol abuse. The role of virological features of HCV remains unclear. The natural history of HCV infection after renal transplantation is under evaluation; however, recent surveys with long follow-ups have documented adverse effects of HCV infection on patient and graft survival in RT recipients. Use of renal grafts from HCV-infected donors in recipients with HCV infection does not appear to result in a greater burden of liver disease, at least for a short period. The association between HCV and de novo or recurrent glomerulonephritis after RT has been hypothesized and is an area of avid research. Reported studies do not support interferon (IFN) treatment for RT recipients with chronic hepatitis C because of the frequent occurrence of graft failure, and information on the use of other types of IFN or combined therapy (IFN plus ribavirin or amantadine) is not yet available in the RT population.

Kidney transplantation in patients with IgA mesangial glomerulonephritis.BackgroundStrategies for treating IgA glomerulonephritis (IgAGN) are controversial, particularly with regards to the long-term results of kidney transplantation, including the risk of recurrence of IgAGN post-transplant and the impact of this recurrence on graft survival.MethodsThe outcomes of 106 adults transplanted because of a biopsy-proven IgAGN and of 212 patients without IgAGN transplanted during the same period were analyzed. To evaluate the risk of recurrence, patients with hematuria, proteinuria, or an increase in plasma creatinine were submitted to allograft biopsy. Factors influencing recurrence and the impact of recurrence on graft survival were analyzed.ResultsThe ten-year patient (0.93 vs. 0.92) and graft survival (0.75 vs. 0.82) probabilities were not significantly different between IgAGN patients and controls. Only plasma creatinine and proteinuria at six months were associated with an increased relative risk (RR) of graft failure (RR 2.79 and 5.94, respectively). Histological recurrence of IgA glomerulonephritis was diagnosed in 37 patients. Younger age (RR 2.63), increased plasma creatinine (RR 2.39), and proteinuria (RR 6.02) at six months were associated with the risk of recurrence. If proteinuria and plasma creatinine at six months were considered in the Cox model, IgA recurrence per se was not associated with an increased risk of graft failure (P = 0.181). The main causes of graft failure were glomerulonephritis in patients with recurrence of IgAGN and chronic rejection in patients without recurrence.ConclusionsThe ten-year graft survival rate was similar in patients with IgAGN or other renal diseases. At least 35% IgAGN patients had biopsy-proven recurrence, and younger patients were more prone to the risk of recurrence. Recurrence did not affect the ten-year graft survival.

Background A double-blind, placebo-controlled, randomized study was performed to assess whether immunoprophylaxis with basiliximab (Simulect) could reduce the incidence of acute rejection in kidney transplant recipients treated with cyclosporine (Neoral), steroids, and azathioprine. Methods Three hundred forty patients received either placebo or basiliximab at a dose of 20 mg, given intravenously on days 0 and 4. All patients received cyclosporine, steroids, and azathioprine. The primary endpoint was the incidence of acute rejection at 6 months. Secondary endpoints included the safety and tolerability of basiliximab and placebo, 1-year patient and graft survival, and significant medical events up to 12 months. Results During the first 6 months posttransplantation, acute rejection occurred in 20.8% of patients given basiliximab versus 34.9% of patients administered placebo (P=0.005). Similarly, there was a reduction in biopsy-proven acute rejection at 6 months in the patients receiving basiliximab (P=0.023). One-year patient survival was 97.6% with basiliximab and 97.1% with placebo, graft survival was 91.5% versus 88.4%, respectively (NS). The adverse-events profile of patients treated with basiliximab was indistinguishable from that of patients treated with placebo. The number of patients with infections was similar (65.5% for basiliximab vs. 65.7% for placebo), including cytomegalovirus infections (17.3% vs. 14.5%, P=0.245). Nine neoplasms (three in the basiliximab group, six in the placebo arm) were recorded up to 1 year from transplantation. Conclusions Basiliximab in combination with cyclosporine, steroids, and azathioprine triple therapy was highly effective in reducing the incidence of acute renal allograft rejection without increasing the incidence of infections and other side effects.

Proteinuria has been shown to play a causal role in the progression towards ESRD of IgA nephropathy (IgAN). We demonstrated that steroids are effective in reducing proteinuria and preserving renal function.to evaluate the long-term effect of steroids in IgAN patients (6th year evaluation) and better clarify the role of proteinuria reduction in slowing down the progression.multicenter randomized controlled trial of 86 adult IgAN patients with serum creatinineor = 1.5 mg/ dL and moderate proteinuria. They received either supportive therapy or methylprednisolone 1-g i.v. for three days at months 1, 3, and 5, plus oral prednisone (0.5 mg/kg every other day for six months).Proteinuria significantly decreased in the treated patients (from 2.0+/-0.60 g/24 h at baseline to 1.0+/-0.68 g/24 h at six months) and remained stable till the 6th year (0.67+/-0.5 g/24 h), it slightly decreased in the control group. Six-year renal survival was significantly better in the steroid than in the control group: 9 patient (20.9%) in the steroid group and 15 (34.8%) in the control group reached the primary end-point of a 50% increase in serum creatinine from baseline. Five controls and none of the steroid-treated patients started dialysis. Steroid-treated patients did not experience any major side effects during follow-up.Steroids significantly reduce proteinuria and protect against renal function deterioration in IgAN patients. Early reduction of proteinuria could also be marker of a persistent reduction in its levels over time and of a better outcome in the long term.

There is little information on the long-term outcome of patients initially assigned to cyclosporine (CsA) monotherapy and requiring the addition of steroid therapy during follow-up. The aim of this report is to describe our experience with 143 first renal transplant recipients (120 cadaver transplants, 23 living donor transplants) randomized to receive CsA monotherapy as a treatment arm of three consecutive controlled clinical trials. Median follow-up was 86 months. Thirty-four percent of the patients remained on the original CsA monotherapy, whereas the remaining 66% required the addition of steroid therapy. Cumulative patient and graft survivals at 11 years were 0.89 (95% confidence interval [CI], 0.83 to 0.95) and 0.62 (95% CI, 0.52 to 0.72), respectively. The 11-year graft survival for converted patients was 0.53 (95% CI, 0.39 to 0.67). Cumulative graft half-life was 19.9 +/- 3.47 (SE) years. According to the Cox model, variables at transplantation that correlated with a lower 11-year graft survival were yearly increases in age (relative risk [RR], 1. 04; P = 0.039), monthly increases in hemodialysis duration (RR, 1.01; P = 0.029), no blood transfusion before transplantation (RR, 1.99; P = 0.043), CsA administration in a double daily dose (RR, 2.35; P = 0.008), and a cadaver donor transplant (RR, 4.76; P = 0.039). Multivariate analysis of time-dependent variables showed that delayed graft function recovery (RR, 2.20; P = 0.019) and the need to add steroid and/or azathioprine therapy (RR, 5.28; P = 0.000) were also correlated with a lower graft survival. Patients who added steroid therapy developed infections (P < 0.001), cataracts (P < 0.001), cardiovascular complications (P = 0.004), and arterial hypertension (P = 0.024) more frequently than patients remaining on CsA monotherapy. Patients administered CsA in a single daily dose received significantly less CsA over the years (P = 0.0042) than patients administered CsA in two divided doses. They also showed a trend toward greater creatinine clearance levels, although not statistically significant. In conclusion, this analysis showed that in patients assigned to CsA therapy alone, good long-term patient and graft survival probabilities can be obtained. In approximately one third of the patients, the use of steroids could be avoided for up to 11 years, and these patients had a better long-term outcome than those who required the addition of steroid therapy. Finally, in patients administered CsA in a single daily dose, the possibility of reducing CsA dosage probably led to better intrarenal hemodynamics with improving creatinine clearances.

ObjectiveSeveral experimental and clinical studies indicate that the renin system may play a pivotal role in progressing renal disease. The combination of an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker could provide a higher degree of blockade of the renin-angiotensin

Eighty nephrotic adults with focal segmental glomerulosclerosis (FSGS) and plasma creatinine lower than 3 mg/dL were given corticosteroids (53 patients) or immunosuppressive agents (27 patients) for a median of 16 and 75 weeks, respectively. Forty-two patients responded with complete remission (29 patients, 36%) or partial remission (13 patients, 16%). Twenty-six patients who did not respond were treated again. Two patients obtained complete remission and 13 partial remission. The probability of remission was associated with treatment with corticosteroids (P = 0.0001; RR, 3. 93; 95% CI, 2.00 to 7.72), absence of arterial hypertension (P = 0. 0023; RR, 2.59; 95% CI, 1.41 to 4.79), and a percentage of hyaline glomeruli lower than 5% (P = 0.0152; RR, 2.04; 95% CI, 1.15 to 3.64). The probability of being alive at 110 months without doubling of plasma creatinine was 69%. The risk of renal insufficiency was correlated with mesangial proliferation (P = 0.0025; RR, 5.50; 95% CI, 1.82 to 16.60) and with interstitial fibrosis (P = 0.0231; RR, 4. 44; 95% CI, 1.23 to 16.08) at initial biopsy. Considering partial or complete remission as a time-dependent variable, only the lack of remission (P = 0.0027; RR, 7.23; 95% CI, 1.98 to 26.33) and mesangial proliferation (P = 0.0069; RR, 4.59; 95% CI, 1.52 to 13. 88) were correlated with renal failure. Major side effects were observed in 11 patients (5 infections, 1 peptic ulcer, 2 diabetes, 3 neoplasias). This study shows that 70% of nephrotic adults with FSGS may obtain complete or partial remission and maintain stable renal function for about 10 years when given a prolonged therapy with corticosteroids or immunosuppressive drugs.

Little information is available about the role of repeated renal biopsies in lupus nephritis. We analyzed retrospectively the prognostic significance of serial renal biopsies in patients with lupus nephritis. Thirty-one patients with lupus nephritis underwent two or more renal biopsies during follow-up. The indications for repeated biopsy were as follows: improvement of renal disease but persistence of nonnephrotic proteinuria (group A, 7 patients); persistent or relapsing nephrotic syndrome (group B, 12 patients); and worsening of renal function (group C, 19 patients). After a median follow-up of 10.5 years, 17 patients reached the end point (persistent doubling of plasma creatinine level). At repeated renal biopsy, there was a correlation between improved clinical and histological features for group A. In these patients, treatment was reduced or stopped successfully. Histological features remained almost unchanged in group B. All patients showed an improvement of proteinuria after reinforcement of therapy. In group C, the worsening of renal function was associated with a variable and clinically unpredictable combination of active and chronic lesions. Only the few patients with an elevated activity index and moderate chronicity index showed a favorable and persistent improvement of renal disease after reinforcement of therapy. At multivariate analysis of clinical and histological data at presentation, only male sex was predictive of an adverse outcome (P = 0.015). At repeated renal biopsy, crescents in more than 30% of glomeruli (P = 0.0009) and chronicity index of 5 or greater (P = 0.00006) were associated with the probability of reaching the end point at multivariate analysis. Repeated renal biopsy may be helpful for establishing the prognosis in patients with lupus nephritis, particularly in the presence of worsening of renal function.

In this paper we assessed the clinical status of 150 cadaveric renal transplant patients who received cyclosporine without interruption for 10 yr. The mean creatinine clearance was 59.2 +/- 15.71 at 1 yr and 55.6 +/- 24.91 mL/min at 10 yr (p = 0.039). Patients were subdivided into four quartiles according to the mean creatinine clearance at 1 yr. The 14 patients with the lowest quartile showed a significant decrease of creatinine clearance from the 1st to 10th year (from 31.5 +/- 5.83 to 24.8 +/- 14.00 mL/min; p = 0.038) while no difference between the mean creatinine clearance at 1 and at 10 yr was found in the other three quartiles. At 10 yr, 84.6% patients needed antihypertensive therapy, a rate similar to that seen at 1 yr (81.4%). The mean plasma cholesterol (253 +/- 57.8 mg/dL) and triglyceride (197 +/- 113.1 mg/dL) at 10 yr were similar to those found at +/- yr (243 +/- 48.2 and 201 +/- 143.0 mg/dL, respectively). Most patients have a high degree of rehabilitation 10 yr after uninterrupted cyclosporine therapy and all patients but 3 were able to work.

The 3 main causes of primary nephrotic syndrome are minimal change nephropathy, focal segmental glomerulosclerosis and membranous nephropathy. Corticosteroids result in remission of proteinuria in most patients with minimal change nephropathy. Many patients, however, develop corticosteroid dependency. A course of cytotoxic drugs can also achieve remission but these agents cannot be administered for prolonged periods or in repeated cycles because their toxicity is cumulative. Review of the available literature indicates that cyclosporin may maintain remission of nephrotic syndrome in about 80% of patients with corticosteroid-sensitive disease, indicating an important role for this drug in patients with frequent relapses or corticosteroid dependency. Although cyclo-sporin is less effective in patients with focal segmental glomerulosclerosis, which is often corticosteroid-resistant, a number of studies indicate that it may be successful both in the few steroid-sensitive patients with frequent relapses and in some corticosteroid-resistant patients. In patients with membranous nephropathy, a 6-month course of corticosteroids and cytotoxic agents may favour remission of nephrotic syndrome and protect renal function. Several studies have shown that cyclosporin can improve proteinuria, and there is a tentative suggestion that it might also protect against renal function deterioration. The risk of nephrotoxicity can be minimised if cyclosporin is used at the correct doses and if renal function is carefully monitored during treatment. In summary, cyclosporin can be considered a useful tool for treating patients with nephrotic syndrome associated with primary glomerulonephritis.

Promising immunosuppressive drugs designed to prevent rejection have been developed recently. Two monoclonal antibodies directed against the interleukin-2 (IL-2) receptor, daclizumab and basiliximab, have been shown to significantly reduce the incidence of acute rejection without increasing adverse events. Sirolimus (rapamycin), an agent that inhibits T- and B-response at a later stage than cyclosporin, has been shown to be synergistic with cyclosporin in experimental and clinical studies. Ongoing clinical trials have reported that in renal transplantation high doses of sirolimus are as effective as cyclosporin. SDZ-RAD, a derivative of sirolimus, is also under investigation. FTY-720 another promising drug, prolonged the survival of allografts and synergised with cyclosporin and sirolimus in experimental models. Gusperimus (deoxyspergualin), which inhibits IL-1 synthesis, was useful in reversing early and late acute rejection in clinical trials. Antisense oligonucleotides which interfere with intercellular adhesion molecules which are important in rejection, gave encouraging results in primate renal allografts. The availability of these new drugs will be able to further abate the risk of rejection in organ transplantation. However, caution is warranted with their use in order to avoid the risks of over immunosuppression. Today excellent results can be obtained with the available drugs. Newer immunosuppressive schedules should be designed, not only to reduce the risk of rejection, but also to obtain a better therapeutic index that allows a further improvement of the graft survival while minimising the comorbidity and drug-related toxicity.