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A large number of neurological disorders can affect renal transplant recipients, potentially leading to disabling or life-threatening complications. Prevention, early diagnosis and appropriate management of these conditions are critical to avoid irreversible lesions. A pivotal role in the pathogenesis of common post-transplant neurological disorders is played by immunosuppressive therapy. The most frequently administered regimen consists of triple immunosuppression, which comprises a calcineurin inhibitor (CNI), a purine synthesis inhibitor and glucocorticoids. Some of these immunosuppressive drugs may lead to neurological signs and symptoms through direct neurotoxic effects, and all of them may be responsible for the development of tumors or opportunistic infections. In this review, after a brief summary of neurotoxic pathogenetic mechanisms encompassing recent advances in the field, we focus on the clinical presentation of more common and severe immunosuppression-related neurological complications, classifying them by characteristics of urgency and anatomic site. Our goal is to provide a general framework that addresses such clinical issues with a multidisciplinary approach, as these conditions require.

The kidney is frequently involved by autoimmune rheumatic diseases. The renal manifestations may be variable, ranging from asymptomatic proteinuria and microscopic haematuria to nephrotic syndrome and rapidly progressive glomerulonephritis or vasculitis. In a number of cases the kidney involvement is related to the treatment of the original disease and may represent a major cause of morbidity and mortality. Thus, it is important for nephrologists and rheumatologists to remember that dysfunction of the kidney may be part of the primary systemic disorder or consequence of its pharmacotherapy. In the first part of this review we will analyse the kidney involvement in four autoimmune connective tissue diseases: systemic lupus erythematosus, Sjögren syndrome, polymyositis/dermatomyositis, and systemic sclerosis. Renal disease is common in lupus and is a main cause of morbidity and mortality. About 10% of patients with Sjögren syndrome may present interstitial nephritis or, more rarely, glomerulonephritis. Myoglobinuria and acute kidney injury is a frequent complication of polymyositis. Renal disease is one of the most serious complications of systemic sclerosis and may present with a dramatic renal crisis, characterized by malignant hypertension, oligo-anuria, and microangiopathic thrombocytopenic anaemia.

Sarcoidosis is a systemic inflammatory disease of unknown etiology. The pathogenesis rests on an aberrant T cell response to unidentified antigens in individuals predisposed by genetic and environmental factors. Increased expression of polarized macrophages and disequilibrium between effector and regulator T cells contribute to the formation of noncaseating granulomas, that are frequently found in affected organs. The main kidney abnormalities in sarcoidosis are granulomatous interstitial nephritis (GIN) and hypercalcemia-related disorders. The clinical diagnosis is difficult. The outcome is variable, ranging from spontaneous remission to end-stage kidney disease (ESKD). Early diagnosis and prompt treatment with corticosteroids can improve the prognosis. Hypercalcemia may be responsible for acute kidney injury (AKI) caused by vasoconstriction of afferent arterioles. Complications of persistent hypercalcemia include nephrocalcinosis and renal stones. In patients with ESKD, dialysis and transplantation can offer results comparable to those observed in patients with other causes of kidney failure. Based on a review of the literature, we present an overview of the etiopathogenesis, the renal manifestations of sarcoidosis and their complications, management and prognosis.

Synthetic immunosuppressive drugs are largely used in immune-related renal diseases and in kidney transplantation. Most of these drugs have a low therapeutic index (the ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is effective), which means that the drug should be dosed carefully and the patient monitored frequently. In this review, we consider the categories of synthetic immunosuppressive agents more frequently and conventionally used in clinical nephrology: glucocorticoids, Aalkylating agents (cyclophosphamide, chlorambucil), purine synthesis inhibitors (azathioprine, mycophenolate salts) and calcineurin inhibitors (cyclosporine, tacrolimus). For each category the possible side effects will be reviewed, the general and specific measures to prevent or treat the adverse events will be suggested, and the more common mistakes that may increase the risk of toxicity will be described. However, the efficacy and safety of immunosuppressive agents depend not only on the pharmacologic characteristics of single drugs but can be influenced also by the clinical condition and genetic characteristics of the patient, by the typology and severity of the underlying disease and by the interaction with other concomitantly used drugs.

There is agreement that early diagnosis and aggressive treatment of lupus nephritis exacerbations are of paramount importance to achieve remission and prevent the development of irreversible lesions. There is less agreement about the optimal duration of maintenance treatment. Instead, the prolonged exposure to corticosteroids and/or immunosuppressive drugs can cause invalidating or even life-threatening complications. It is still unclear if these drugs can be safely withdrawn in lupus patients. We were able to completely withdraw therapy in around 1/3 of our patients after a follow-up of 5 years or more; 60 % of them never had to start therapy again. Based on our own experience, discontinuation of therapy should be applied only in selected cases, i.e. patients who received maintenance therapy for at least 5 years and are in complete renal remission for at least 3 years. Antimalarial agents are helpful in maintaining the remission after withdrawal of therapy. However, to achieve these goals, drugs should be tapered off very slowly and under strict surveillance. If all these prerequisites are satisfied, the withdrawal of therapy in patients with lupus nephritis may be considered safe, may improve the patients' quality of life and may reduce the damage accrual.

Morbidity and mortality due to skin cancer is excessively high in renal transplant recipients compared to the general population. This epidemiologic difference is mainly due to the severe immunosuppression that enhances ultraviolet-induced DNA damage and leads to reactivation of potential oncogenic viruses. The most common skin cancer in transplant recipients is squamous cell carcinoma followed by basal cell carcinoma, while in the general population this ratio is reversed. Melanoma and cutaneous lymphoma are relatively rare although they occur more frequently in transplant patients than in the general population. Notably some tumors, such as Kaposi's sarcoma, are seldom encountered in the general population while they are frequently observed in transplant recipients. Local recurrences and visceral spreading are not so uncommon and pose a major issue for quality of life and overall prognosis of these patients. Timely diagnosis is essential and may be challenging, since the accuracy of clinical diagnosis is modest; thus skin biopsy is an essential tool for appropriate management. In this review, we describe the most common types of skin cancer in renal transplant recipients, with a focus on pathogenic issues that account for the different epidemiology and clinical expression of these neoplasms in this population.

Focal and segmental glomerular sclerosis (FSGS) is a histological pattern characterized by the partial sclerosis of some, but not all, glomeruli. It may be secondary to diverse etiologies such as mutations of podocyte key genes, loss of nephrons, drugs, and virus infection. However, in most cases of FSGS, the etiology is unknown and these forms are called idiopathic (primary) FSGS. A number of different pathogenic hypotheses have been proposed. The frequent recurrence of nephrotic proteinuria after renal transplantation has attracted the attention to search for plasma factors eventually implicated in the pathogenesis. However a decisive and unifying hypothesis is still lacking. On the other hand, recent findings indicate the involvement of cellular immunity and possibly autoantibodies in the pathogenesis of some forms of FSGS. In this paper we report on the recent advances in the pathophysiology of idiopathic FSGS and suggest the possibility that at least some forms of idiopathic FSGS may be caused by autoimmune reactivity.

A large number of factors can influence the clinical out- come of kidney transplant recipients, but the active role of the patient to prevent the possible complications re- lated to transplant and its treatment is often neglected. Poor adherence to prescriptions is frequent in transplant recipients and represents a major contributor to the de- velopment of graft failure, cardiovascular disease, infec- tion and/or malignancy. Smoking can render the patient more susceptible to cancer, cardiovascular disease and infection, and can also impair renal allograft func- tion. The risk of malignancy is increased in transplant recipients. Therefore screening for cancer is of para- mount importance. Measures that can enable preven- tion or early detection of cancer include self-exams and screening, physical activity, avoidance of smoking and sun exposure, and a diet rich in fruits and vegetables but limited in fats, red meats, salt and alcohol. Regu- lar exercise can help to prevent cardiovascular disease, diabetes, obesity, osteoporosis and even some forms of cancer. Thus regular exercise is recommended. Yet, too many transplant patients remain sedentary. Weight gain is common in renal allograft recipients and may be asso- ciated with hypertension, hyperlipidemia and/or glucose intolerance or overt diabetes. To prevent these compli- cations, patients should follow diet regimens based on low fat and normal/low caloric intake. Small amounts of alcohol may be permitted in view of its potential car- dioprotective effect, but a large consumption of alcohol can be responsible for devastating side effects. Last but not least, abidance by hygienic measures may help in preventing cardiovascular and infectious complications.

For many years, acute rejection has been considered as a typical response of the adaptive immunity system. However, recent investigations have revealed a critical role for innate immunity as a pivotal trigger in adaptive immune responses. Danger signals released by cells damaged or killed by injury or disease may be intercepted by Toll-like receptors (TLRs) that alarm the dendritic cells (DCs) through the activation of transcription factors. In the presence of an inflammatory milieu created by other components of the innate immunity, DCs become mature and present the antigen to naive T cells. The activation of T cells requires both a signal engendered by the presentation of the antigen to the T cell receptor and costimulatory signals generated by the contact between molecules displayed by antigen-presenting cells (APCs) and by T cells. Once activated, T cells encode and synthesize interleukin 2 (IL-2) and other cytokines that provide the signals for cell differentiation and proliferation. Until recently, little attention was paid to the role of antibodies in renal transplantation. However, there is mounting evidence that a number of kidney allografts fail as a consequence of a rejection caused by antibodies specifically directed against major histocompatibility complex antigens, class I or II, of the recipient. A critical role in antibody-mediated rejection (AMR) is played by complement. A number of therapeutic attempts have been tried to prevent or treat AMR. The still open question is whether the antibodies we detect are those responsible for tissue damage or not.

Chyluria results from an abnormal connection between lymphatic bed and urinary tract, causing lymph leakage into the urine. The clinical picture often begins with the appearance of cloudy, milky urines accompanied by monolateral flank pain, malnutrition, weight loss and weakness. We report a case of chyluria that occurred in a young woman who was referred to our unit for nephrotic-range proteinuria. Before performing a renal biopsy, we found that urine analysis demonstrated a massive lipiduria. Therefore, we collected urine samples from each kidney with a selective ureteral catheterization, demonstrating a monolateral source of lipids and proteins. We suspended the renal biopsy and performed a lymphography that showed an inherited lymphangioma on the left lumbar lymphatic bed. Sclerosing solution instillation, renal pedicle lymphatic disconnection or laser therapy are invasive therapeutical options that may cause severe adverse effects. Instead of these procedures, a conservative therapy based on a low-fat diet supplemented with medium-chain triglycerides was chosen. This dietetic schedule was followed by complete resolution of proteinuria and lipiduria. The patient progressively gained body weight and improved quality of life. No relapses were observed after 3 years of follow-up. This case emphasizes the possible role of a noninvasive therapeutical option for patients with chyluria.

Idiopathic membranous nephropathy (IMN) may have a variable course, with some patients entering spontaneous remission and others slowly progressing to renal failure. The disease is treatable, but the available treatments are not devoid of potential morbidity. We review the studies dedicated to finding prognostic markers. Although a number of clinical and histologic markers are associated with an increased risk of progression to renal failure, in many cases it is still impossible to recognize at presentation what will be the long-term outcome for a patient with IMN. More reliable are time-dependent predictors, such as the amount of proteinuria over time and complete or partial remission. However, this means that a physician should wait for months or even years before taking therapeutic decisions, with the risk of starting after renal or extrarenal complications have already developed. How to proceed will have to be dictated by a careful evaluation of the patient: Taking into consideration not only the risk of renal progression but also the possible extrarenal complications, we suggest starting a "specific" treatment for patients presenting with full-blown nephrotic syndrome or with increasing levels of serum creatinine, while specific treatment is not necessary for asymptomatic patients with subnephrotic proteinuria.

Treatment of proliferative lupus nephritis (PLN) consists of an initial aggressive treatment aimed to quench the hectic activity of the disease (induction phase) followed by a milder therapy aimed to prevent flares (maintenance treatment). There are a number of possible options for induction treatment. Intravenous (i.v.) pulses of cyclophosphamide plus oral or i.v. steroids is very effective but can be accompanied by severe adverse events. Alternatively, i.v. pulses of methylprednisolone (MPP) followed by a 2-3-month course of oral cyclophosphamide, or mycophenolate mofetil (MMF) plus prednisone, seem to be as effective as i.v. cyclophosphamide and may be better tolerated. In cases refractory to these treatments, rituximab has been used successfully. However, the exact role of rituximab is difficult to ascertain as in most cases the drug was administered together with glucocorticoids or cyclophosphamide. Intravenous cyclophosphamide has also been prescribed for maintenance therapy with good results. However, recent trials showed that similar or even better results can be obtained with azathioprine or MMF associated with moderate doses of prednisone. Also cyclosporine can achieve good results while sparing steroids, particularly in patients with persistently elevated proteinuria. In summary, modern immunosuppression today allows us to reduce the dosage of steroids and to avoid the prolonged use of cyclophosphamide. These newer strategies may result in fewer adverse effects, better quality of life and better survival for patients with proliferative lupus nephritis.

Membranous nephropathy (MN) is a glomerular disease characterized by proteinuria, usually in a nephrotic range, and variable natural course. The etiology is unknown in many cases, while in some patients, MN may be secondary to infection, to other diseases, or to exposure to drugs and toxic substances. In idiopathic MN, the antigens are probably located at the base of podocytes, and the glomerular lesions occur by the local formation of immune complexes, with consequent activation of complement and inflammation triggered by the membrane attack complex C5b-9. Patients with severe proteinuria, those with advanced tubulointerstitial changes at renal biopsy and those with increased serum creatinine at presentation have a poorer prognosis, while patients showing complete or even partial remission of proteinuria have a favorable prognosis. The indications for and types of treatment are controversial. There is no good evidence in favor of therapies based on corticosteroids alone. Cyclophosphamide and chlorambucil may increase the probability of remission, but the prolonged use of these agents may cause disquieting adverse effects. Good results have been obtained by alternating corticosteroids and a cytotoxic agent every other month for 6 months. Other potential treatments are represented by cyclosporine, synthetic adrenocorticotropic hormone (ACTH), mycophenolate mofetil, rituximab and intravenous immunoglobulins. Further studies addressed to recognizing the responsible antigen(s), and interventions directed to interfere with the specific antibodies, with regulators of glomerular permeability, and/or with factors regulating the complement activity might allow us to better understand the physiopathology of MN and to organize more specific and effective treatments in the near future.

Neurological complications are frequent in renal transplant recipients and may largely contribute to morbidity and mortality. The postransplant neurological complications may be categorized into five areas: 1) Immunosuppressive medications, 2) stroke, 3) peripheral neuropathies, 4) infection, and 5) malignancies. A number of complications are directly caused by the neurotoxicity of immunosuppressive agents. Calcineurin-inhibitors may cause mild symptoms, such as tremors and paresthesia, or severe symptoms, such as disabling pain syndrome and leukoencephalopathy. Severe neurological syndromes may also be caused by the monoclonal antibody OKT3. Stroke may occur in about 8% of renal transplant patients. It may be favored by hypertension, diabetes, and accelerated atherosclerosis which may be acquired during dialysis or after transplantation. Peripheral mononeuritis and polyneuritis may also occur. An acute femoral neuropathy may occur in about 2% of patients as a result of nerve compression after operation. Guillain-Barré syndrome may also develop, triggered in some cases by cytomegalovirus (CMV) or Campylobacter jejuni infection. Lymphomas are the most frequent brain tumors. They are usually associated to a Epstein Barr virus (EBV) infection and are more frequent in patients who received an aggressive immunosuppressive therapy. Infection represents the most frequent neurological complication. Acute meningitis usually caused by Listeria monocytogenes, subacute and chronic meningitis caused by Cryptococcus neoformans, focal brain infection caused by Aspergillus fumigatus, Toxoplasma gondii or Nocardia asteroids, and progressive dementia caused by polyoma J virus or other viruses are the most frequent types of neurological infections.

Cyclosporine (CsA) has been the cornerstone of immunosuppression for organ transplantation since its introduction. However, CsA is a critical drug as it has low therapeutic index and high inter- and intra-individual variations in bioavailability. The new microemulsion Neoral has increased bioavailability and is not influenced by bile or food. When compared with the old formulation, Neoral was able to significantly reduce rejection and to allow a better long-term graft survival in renal transplant patients. Moreover, the measurement of CsA at peak, around 2 hours after Neoral administration, proved to be a reliable index of the drug exposure, thus allowing efficient drug monitoring. Recently, different CsA galenics have been approved on the basis of bioequivalence tests performed in a small number of healthy volunteers after a single administration. Transplant experts expressed their concern about the adequacy of these tests in organ transplantation. The few short-term studies of bioequivalence in renal transplant recipients reported conflicting results. Certainly, the bioequivalence tests used, cannot capture a subset of low-absorbers who are exposed to the risk of underimmunosuppression. Another matter of concern is the lack of studies with galenic CsA to evaluate the role of C2 measurement for therapeutic drug monitoring. Observational studies reported a lower 1-year renal allograft survival in patients treated with galenic CsA than in patients given Neoral. A main problem is the absence of long-term studies with generic CsA, in the complex setting of organ transplantation.

mTOR is a downstream effector of phosphatidylinositol-3-kinase pathway, which is involved in the regulation of protein synthesis and interacts with cell cycle progression. Sirolimus and everolimus may interfere with mTOR activity after their binding with FK binding protein. These drugs may prevent rejection of organ transplants by inhibiting the proliferation signals provided by interleukins 2 and 15, so causing lymphocyte cycle arrest in the G1 phase. Experimental studies have also shown that some oncoproteins may derive either from an overactivity of phosphatidylinositol-3-kinase or from a loss of the tumor suppressor PTEN. As mTOR is an important mediator of the kinase cascade and may also be antiangiogenic, it has become an attractive target in some malignancies. In organ transplant recipients some retrospective studies have shown that patients treated with mTOR inhibitors for immunosuppression had a reduced incidence of neoplasia in comparison with patients treated with calcineurin inhibitors. mTOR is also involved in the replication of cytomegalovirus in the host cells, as it favors transcription and translation signals necessary for virus replication. Recent studies reported a very low incidence of cytomegalovirus infection in organ transplant patients treated wih either sirolimus or everolimus. Finally, mTOR inhibitors may offer vascular protection, as they mediate vascular endothelial growth factor. In cardiac transplants treated with everolimus, cyclosporine, and steroids the average increase in maximal intimal thickness and the incidence of vasculopathy were significantly lower than in patients treated with azathioprine, cyclosporine, and steroids.

Living donor renal transplantation can not only reduce the increasing gap between demand and supply of renal transplants, but when compared with cadaveric renal transplants can also allow better results, particularly in the long-term. With the exception of HLA-identical siblings, there are no differences in long-term graft survival between HLA-related and HLA-unrelated living donor transplants. The possibility of a early transplantation, ideally before dialysis, can strongly improve patient and graft survival. The post-operative mortality and morbidity of the donor are minimal and may be furtherly reduced by an appropriate work-up. At present, there is no evidence that mononephrectomy in healthy subjects can expose them to an increased risk of renal failure, even in the long-term.

Hemolytic-uremic syndrome (HUS) is a rare complication in organ transplantation, characterized by hemolytic microangiopathic anemia, thrombocytopenia, and severe renal failure. The syndrome is a well-recognized complication in bone marrow transplantation, and has been likewise described in several cases of solid organs transplantation, but never in patients receiving combined liver and kidney transplantation.We describe a case of HUS in a 59-year-old woman who underwent combined liver-kidney transplantation for hepato-renal polycystic disease. Clinical and laboratory manifestations of the syndrome were severe and included renal failure, hemolytic anemia, severe thrombocytopenia, hypertension, and neurological damage. The initial treatment consisted of withdrawal of cyclosporine, introduction of low-dose tacrolimus, and administration of fresh frozen plasma (FFP) transfusion and heparin. Since there was no improvement in clinical or biochemical features, plasmapheresis with FFP replacement (2000 mL/day) followed by intravenous immunoglobulin (0.4 mg/Kg/day) was started. A rapid improvement in renal function, platelet count, and hemolytic anemia was observed.Based on the good response observed in our patient, we feel that an aggressive treatment with plasmapheresis and intravenous immunoglobulin should be offered to organ transplant recipients with severe HUS.

Since many women with systemic lupus erythematosus (SLE) are of child-bearing age and have normal fertility, the clinician must often face many problems relating to pregnancy in patients with lupus nephritis. These include the influence of lupus nephritis on fetal outcome, obstetric complications, and the influence of pregnancy on SLE. Studies published in the 1960s underlined the increased fetal and maternal risk and recommended against pregnancy in lupus patients. The prognosis for non-pregnant SLE active patients was also poor, making it difficult to know whether pregnancy altered the prognosis of the disease. Recent prospective studies indicate that the majority of lupus mothers can sustain pregnancy without detrimental effects, providing that the pregnancy is planned during the inactive phase of the disease. Nevertheless the fetal risk, although progressively reduced during the last 40 years, continues to be higher than in pregnancies of healthy women particularly in patients with antiphospholipid antibodies.

A renal transplant patient treated with tacrolimus and mycophenolate-mofetil (MMF) developed progressive graft function deterioration 10 months after transplantation. Biopsy of the graft showed severe, focally accentuated interstitial inflammation with focal tubulitis and tubular necrosis, and medium-severe interstitial fibrosis with focal tubular atrophy. Glomerular and vascular structures were preserved. On careful examination, in some sections, tubular epithelial cells showed a definite increase with deformation of the nuclear shape, chromatin irregularities with peripheral dislocation and inclusion bodies. These cytopathic changes suggested polyoma virus infection ("decoy cells"). Subsequent screening of the urinary sediment confirmed the presence of many "decoy cells". Immunohistochemical analysis of the biopsy showed many tubular cells were strongly positive for the SV 40 antigen, specific for BK polyoma virus. A diagnosis of interstitial nephritis due to BK polyoma virus was made, though the coexistence of cellular rejection could not be excluded. At variance with previous reports, our patient had not had repeated episodes of rejection before biopsy or heavy immunosuppressive treatment, such as ALG, OKT3, after transplantation. This case shows that even in the absence of vigorous anti-rejection therapy an immunosuppressive regimen based on tacrolimus and MMF may involve the risk of BK polyoma virus- associated interstitial nephritis.