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Background After renal transplantation, there is a need for immunosuppressive regimens that effectively prevent allograft rejection, while minimizing cardiovascular side effects. The TRITON study is the first randomized clinical trial that tested a strategy with autologous bone marrow derived mesenchymal stromal cell (MSC) therapy and complete withdrawal of calcineurin inhibitors (CNIs). The combination of MSC therapy and CNIs discontinuation was associated with improved blood pression control and regression of left ventricular hypertrophy. Nevertheless, the impact of this immunosuppressive strategy on left atrial (LA) structural and functional remodelling, which has been proven as an independent predictor of cardiovascular outcomes, has not been investigated. Purpose To assess the effects of MSC therapy combined with CNIs withdrawal on longitudinal changes of LA structure and function, evaluated by two-dimensional transthoracic echocardiography. Methods The TRITON trial randomized renal transplant recipients to MSC therapy – infused at week 6 and 7 after transplantation, with complete withdrawal at week 8 of tacrolimus (MSC group) – or standard tacrolimus dose (control group). Patients who underwent transthoracic echocardiography with speckle-tracking analysis at week 4 and 24 after renal transplantation were included in this sub-analysis. Changes in echocardiographic variables between 4 and 24 weeks post-transplantation were evaluated and compared between randomization arms using an analysis of covariance model, adjusted for baseline variable. Results 54 patients (MSC group =27; control group =27) were included. Between 4 and 24 weeks after transplantation, an increase in indexed minimal LA volume (LAVImin) was observed in the control group, whereas in the MSC group there were no changes in LAVImin over the time, leading to a significant difference between groups (p=0.021). Moreover, patients randomized to MSC therapy showed a benefit in LA function, assessed by a significant interaction between changes in LA emptying fraction (LAEF) and LA reservoir strain and the treatment group (p=0.012 and p=0.027, respectively) (Table 1). The association between changes in LA structural and functional parameters and the randomization arm remained significant after adjustment for changes in systolic blood pressure, diastolic blood pressure and estimated glomerular filtration rate over the time (Figure 1). Conclusion The combination of MSC therapy and early CNIs withdrawal prevents LA structural and functional remodelling in the first six months after renal transplantation. MSC therapy appears a promising approach in renal transplant recipient, effective in the prevention of graft rejection, while exerting potential cardioprotective effects. Funding Acknowledgement Type of funding sources: None.

Acute cellular rejection (ACR) occurs in 10% of renal allograft recipients and is characterized by leukocyte infiltration as observed in needle biopsies. ACR onset is subject to several risk factors, including delayed graft function (DGF). As the impact of DGF on the etiology of ACR remains unclear, this study analyzed the association between presence of leukocyte subsets and ACR onset, in DCD kidney biopsies with extensive DGF following transplantation. Immunohistochemical analysis of protocol biopsies taken 10 days after kidney transplantation revealed that patients with high levels of renal CD163

BACKGROUND: Cyst infection may occur in autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD). Antimicrobial agents often fail to control infection, leading to invasive action. We aimed to identify factors predicting escalation of care. METHODS: ADPKD and ADPLD patients were identified from local/national databases (2001-2013). Records were screened for patients meeting criteria for cyst infection (positive cyst aspirate and/or clinical findings). Factors that predict escalated care were identified with multivariate modified Poisson regression. RESULTS: We screened 1773 patients. A total of 77 patients with cyst infection (4.3%) were included for analysis (hepatic 36%; male 49%; age 54 ±; 13 years; ADPKD 95%; dialysis 9%, diabetes 18%, renal transplant 56%, eGFR [IQR 24-78] ml/min/1.73 m2 (excluding patients with a history of renal transplant or receiving dialysis)). A pathogen was identified in 71% of cases. Escherichia coli was the most common pathogen and accounted for 69% of cases. Initial treatment was limited to antibiotics in 87% of patients (n = 67), 40% included a fluoroquinolone. Ultimately, 48% of patients underwent some form of invasive action (escalation of care). Increasing white blood cell count (WBC) (RR 1.04 95%-CI 1.01-1.07, p = 0.008) was associated with escalating care, whereas an increase in time between transplant and infection (RR 0.92 95% CI 0.86-0.97, p = 0.005) and E. coli isolation (RR 0.55 95% CI 0.34-0.89, p = 0.02) were protective. CONCLUSION: High serum WBC, isolation of atypical pathogens and early infection after transplantation are factors that increase the risk of escalation of care in hepatic and renal cyst infection patients.

Background The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biologic therapies. Aims To review, from an infectious diseases perspective, the safety profile of therapies targeting different intracellular signaling pathways and to suggest preventive recommendations. Sources Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family. Content Although BCR-ABL tyrosine kinase inhibitors modestly increase the overall risk of infection, dasatinib has been associated with cytomegalovirus and hepatitis B virus reactivation. BRAF/MEK kinase inhibitors do not significantly affect infection susceptibility. The effect of Bruton tyrosine kinase inhibitors (ibrutinib) among patients with B-cell malignancies is difficult to distinguish from that of previous immunosuppression. However, cases of Pneumocystis jirovecii pneumonia (PCP), invasive fungal infection and progressive multifocal leukoencephalopathy have been occasionally reported. Because phosphatidylinositol-3-kinase inhibitors (idelalisib) may predispose to opportunistic infections, anti-Pneumocystis prophylaxis and prevention strategies for cytomegalovirus are recommended. No increased rates of infection have been observed with venetoclax (antiapoptotic protein Bcl-2 inhibitor). Therapy with Janus kinase inhibitors markedly increases the incidence of infection. Pretreatment screening for chronic hepatitis B virus and latent tuberculosis infection must be performed, and anti-Pneumocystis prophylaxis should be considered for patients with additional risk factors. Cancer patients receiving mTOR inhibitors face an increased incidence of overall infection, especially those with additional risk factors (prior therapies or delayed wound healing). Implications Specific preventive approaches are warranted in view of the increased risk of infection associated with some of the reviewed agents.

AIMS: Everolimus is a drug from the class of mammalian target of rapamycin inhibitors used for both immunosuppressant and oncological indications. We postulate that there is room for improvement of dosing, as the optimal immunosuppressive dose in calcineurin‐free regimens is unknown and since the once daily dosing regimen for oncological indications is often associated with treatment‐limiting toxicity. METHODS: We developed a mechanistic population pharmacokinetic model for everolimus in cancer and transplant patients and explored alternative dosing regimens. RESULTS: We found that formulation did not influence bioavailability and that use of >20 mg prednisolone daily increased everolimus clearance. In transplant patients, the approved dose of 0.75–1 mg twice daily (BID) results in subtherapeutic trough levels (

In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open-label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor-specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.

Pancreatic islet transplantation is performed in a select group of patients with type 1 diabetes mellitus. Immunosuppressive regimens play an important role in long-term islet function. We aimed to investigate the efficacy of islet transplantation in patients with type 1 diabetes and a previous kidney transplantation using an alemtuzumab-based induction regimen and triple maintenance immunosuppression. Patients with type 1 diabetes, who had received a kidney transplant previously, were treated with alemtuzumab as induction therapy for their first islet transplantation and basiliximab induction therapy for subsequent islet transplantations. Maintenance immunosuppression consisted of triple immunosuppression (tacrolimus, mycophenolate mofetil, and prednisolone). Thirteen patients (age 50.9 ± 9.2 years, duration of diabetes 35 ± 9 years) received a total of 22 islet transplantations. One- and 2-year insulin independence was 62% and 42%, respectively; graft function was 100% and 92%, respectively. HbA1c dropped from 57.2 ± 13.1 (7.4 ± 1.2%) to 44.5 ± 11.8 mmol/molHb (6.2 ± 0.9%) (p = 0.003) after 2 years. Six of 13 patients suffered from severe hypoglycemia before islet transplantation. After transplantation, severe hypoglycemia was restricted to the only patient who lost graft function. Creatinine clearance was unchanged. Islet-after-kidney transplantation in patients with type 1 diabetes using an alemtuzumab-based induction regimen leads to considerable islet allograft function and improvement in glycemic control.

A 62-year-old woman with a history of genetically confirmed hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) was admitted because of chronic diarrhoea. During admission she developed a rapidly progressive nephrotic syndrome. Reactive amyloid A (AA) amyloidosis was confirmed after colonic and renal biopsy which showed deposition of amyloid. After initial treatment with high-dosed corticosteroids, therapy was switched to anakinra, an IL-1 receptor antagonist, but her symptoms persisted. After cessation of anakinra, a marked exacerbation of the intestinal symptoms was noted. Nine months after the initial diagnosis of reactive amyloidosis without any amelioration of the symptoms and a decreasing quality of life, our patient declined further treatment and died soon after. This case demonstrates that AA amyloidosis does occur in patients with HIDS and can present with intestinal symptoms and proteinuria. Once amyloidosis is diagnosed the goal of treatment is to prevent further complications. In this case report we give an overview of previous cases with amyloidosis complicating HIDS with the treatments received and propose a step-up treatment plan for future cases.

Mycophenolate mofetil (MMF) is an immunosuppressive drug commonly used in the context of kidney transplantation. exposure to the active metabolite mycophenolic acid (MPA) is associated with risk of allograft rejection. MPA pharmacokinetics varies between individuals, the potential cause being the presence of genetic polymorphisms in key enzymes. We genotyped 338 kidney transplant patients for UGT1A8, UGT1A9, UGT2B7, and MRP2 polymorphisms and recorded MPA exposure and biopsy-proven acute rejections (BPARs) during a 1-year follow-up. Tacrolimus-treated patients who were UGT1A9-275T>A and/or -2152C>T carriers displayed a 20% lower MPA area under the concentration-time curve from 0 to 12 h (AUC(0-12)) (P = 0.012). UGT1A9*3 carriers displayed a 49% higher MPA AUC(0-12) when treated with tacrolimus and a 54% higher MPA AUC(0-12) when treated with cyclosporine (P < 0.005). Cyclosporine-treated UGT1A8*2/*2 (518GG) patients had an 18% higher MPA AUC(0-12) compared with noncarriers. Carrying the UGT1A9-275T>A and/or -2152C>T polymorphism significantly predicted acute rejection in fixed-dose (FD) MMF-treated patients receiving tacrolimus (odds ratio 13.3, 95% confidence interval 1.1-162.3; P < 0.05). UGT1A9-275T>A and/or -2152C>T genotyping may identify patients at risk of MPA underexposure and acute rejection when receiving treatment with MMF and tacrolimus.

We describe 2 renal transplant recipients with severe but reversible neurological manifestations related to Varicella zoster virus (VZV) cerebral vasculopathy. To the best of our knowledge, this is the first description of cerebral VZV vasculopathy in solid organ transplant recipients. We review the published literature on the clinical presentation, diagnosis and treatment. In solid organ transplant recipients presenting with neurological signs and symptoms, a diagnosis of VZV-associated vasculopathy should be considered.

Radionuclide renal diagnostic studies play an important role in assessing renal allograft function, especially in the early post-transplant period. In the past two decades various quantitative parameters have been derived from the radionuclide renogram to evaluate changes in perfusion and/or function of the kidney allograft. In this review article we discuss the quantitative parameters that have been used to assess graft condition, with emphasis on the early postoperative period. These quantitative methods are divided into parameters used for assessing renal graft perfusion and parameters used for evaluating parenchymal function. The blood flow in renal transplants can be quantified (a) by measuring the rate of activity appearance in the kidney graft, (b) by calculating the ratio of the integral activity under the transplanted kidney and arterial curves and (c) by calculating the renal vascular transit time. In this article we review a number of parenchymal uptake and excretion indices, such as the accumulation index, the graft uptake capacity at 2 and 10 min, the excretion index and the elimination index. The literature on these parameters shows that they have some practical disadvantages. In addition, values suffer from significant overlap when various graft pathologies coexist. A retrospective study was designed in our institution to evaluate the clinical usefulness of some of the frequently used previously published methods in which the graft function is quantitatively assessed in the early post-transplant period. The quantitative parameters studied which were reasonably reproducible in our hands included: global perfusion index (GPI), cortical perfusion index (CPI), vascular transit time, and the parenchymal parameters uptake capacity at 2 min (UC2) and elimination index (K3/20). The patient population in this study consisted of 43 patients with 157 technetium-99m mercaptylacetyltriglycine renograms. The perfusion indices GPI and CPI did not allow differentiation of the acute tubular necrosis (ATN) group from the acute rejection (AR) group; however, they were of value in monitoring the improvement in the condition of the graft dysfunction in both the AR and ATN groups. As for the parenchymal parameters, both UC2 and K3/20 were able to differentiate stable graft function (SGF) versus AR and ATN groups but were unable to separate AR from ATN dysfunction. The ability of these parenchymal parameters to detect improvement in the graft function was poor and statistically non-significant. From the literature data and our own findings it is concluded that radionuclide scintigraphy of renal transplants has assumed an important role, especially if performed serially, in monitoring graft function in the post-transplant period. Many quantitative parameters have been derived from the radionuclide renogram to evaluate changes in perfusion and/or function of the kidney allograft. It appears that these quantitative numerical values are unable to differentiate unequivocally between grafts with ATN and AR cases. The real value of these parameters lies in the follow-up of the dysfunction processes, which helps the clinician to determine the appropriate therapeutic regimen.

A varying percentage of cadaveric transplant recipients remain anuric or oliguric and depend on dialysis in the first weeks after transplantation. This delayed graft function group needs careful management to detect additional post-transplant events. Under these clinical circumstances, the assessment of allograft status depends to a great extent on non-invasive imaging studies. The wide variety of imaging procedures for the transplanted kidney, combined with recent technical advances in ultrasonography, scintigraphy and radiopharmaceuticals, computed tomography and magnetic resonance imaging, has created a challenging and sometimes confusing environment for clinicians, radiologists and nuclear medicine physicians. Assessing the relative merits of available procedures and choosing an optimal approach to the clinical presentation of a particular graft is sometimes difficult. The contrasting characteristics of these diagnostic methods led us to consider their relative roles and to determine their selective use. This review focuses on the value and limitations of diagnostic imaging modalities in the management of patients with impaired or delayed graft function. Our emphasis is on ultrasonography and nuclear medicine, as these are the most frequently used methods.

Radionuclide renal diagnostic studies play an important role in assessing renal allograft function especially in the early post transplant period. In the last two decades various quantitative parameters have been derived from the radionuclide renogram to facilitate and confirm the changes in perfusion and/or function of the kidney allograft. In this review article we discuss the quantitative parameters that have been used to assess graft condition with emphasis on the early post-operative period. These quantitative methods were divided into parameters used for assessing renal graft perfusion and parameters used for evaluating parenchymal function. The blood flow in renal transplants can be quantified by measuring (a) the rate of activity appearance in the kidney graft; (b) the ratio of the integral activity under the transplanted kidney and arterial curves e.g. Hilson's perfusion index and Kircher's kidney/aortic ratio; (c) calculating the renal vascular transit time by deconvolution analysis. The literature overview on these parameters showed us that they have some practical disadvantages of requiring high quality bolus injection and numerical variations related to changes in the site and size of regions of interest. In addition, the perfusion parameter values suffer from significant overlap when various graft pathologies coexist. Quantitative evaluation of the graft parenchymal extraction and excretion was assessed by parameters derived from 123I/131I-OIH, 99mTc-DTPA or 99mTc-MAG3 renograms. We review in this article a number of parenchymal parameters which include (1) plasma clearance methods like glomerular filtration rate (GFR) and effective renal plasma flow (ERPF); (2) renal transit times such as parenchymal mean transit time, Tmax, T1/2; (3) parenchymal uptake and excretion indices as the accumulation index, graft uptake capacity at 2 and 10 min, excretion index and elimination index. These indices, however, are non-specific and far from defining a specific cause for graft parenchymal dysfunction. In conclusion, despite that the literature is replete with mathematical strategies for quantitating perfusion and parenchymal functions, none of these have enough diagnostic power for specific diagnosis of graft dysfunction. In addition, no universal agreement on the use of certain quantitation parameters in transplant patients has been reached.

Summary: Although a genetic predisposition to IgA nephropathy can be documented in a minority of patients, the majority of cases are sporadic. The frequent association with mucosal infections suggest the aetiologic involvement of microbial antigens. However, no particular bacterial or viral strain has clearly been implicated. The involvement of mesangial or endothelial autoantigens has been suggested but not proven in a majority of cases. Most patients have a significantly higher memory repertoire of IgA forming B-lymphocytes in their bone marrow associated with high plasma levels of IgA1 while the mucosally stimulated IgA response against recall antigens is augmented, the mucosal and plasma IgA response after mucosal stimulation by neoantigen is significantly reduced or absent. These observations suggest that IgA nephropathy patients have a defect in raising a mucosal IgA response against novel microbial antigens and that they will suffer from recurrent mucosal infections until they have developed a large enough repertoire of memory B-cells to protect their mucosal surfaces. As a consequence of the recurrent stimulation of the IgA immune system, high levels of plasma IgA are found. The mechanism of IgA deposit formation in the mesangium is unknown. The ensuing inflammatory reaction in the glomeruli may vary from mild to severe, but usually the disease has an indolent course. The progression of IgA nephropathy to renal failure is clinically the most important complication. Recent observations on the role of cytokines in the pathogenesis of interstitial infiltration, interstitial fibrosis and tubular atrophy have created the opportunity to study and manipulate the process of renal scarring and the progression to renal failure.

Early pancreas graft loss is usually attributed to technical failure while the possibility of antibody-mediated rejection (AMR) is generally overlooked. To investigate the role of AMR in early pancreas graft loss, we retrospectively assessed 256 patients with simultaneous pancreas-kidney transplantation (SPK) between 1985 and 2010 at our institute. We included 33 SPK patients who lost their pancreas graft1 year after transplantation. AMR was diagnosed based on donor-specific antibodies, C4d and histology in 7 cases, 8 cases were suspicious for AMR and 18 pancreas graft losses were not due to AMR. Acute AMR occurred1 month after transplantation in 6/7 cases, whereas all other causes typically led to loss1 month after transplantation. Thrombotic lesions occurred equally among the 33 cases. In 12/18 concurrent kidney specimens, the diagnostic results paralleled those of the pancreas graft. All patients with acute AMR of the pancreas graft lost their renal grafts1 year after transplantation. In the setting of a thrombotic event, histopathological analysis of early pancreas graft loss is advisable to rule out the possibility of AMR, particularly because a diagnosis of acute AMR has important consequences for renal graft outcomes.

Risk stratification-based duration of trimethoprim-sulfamethoxazole (TMP-SMX) chemoprophylaxis to prevent Pneumocystis pneumonia (PCP) in kidney transplant recipients is not a universally adapted strategy and supporting evidence-based sources are limited. We performed a large retrospective study to identify risk factors for PCP in kidney transplant recipients and to define parameters for use in clinical prophylaxis guidelines. Fifty consecutive patients with confirmed PCP and 2 time-matched controls per case were enrolled. All patients were participants of the kidney transplantation program of the Leiden University Medical Center, a tertiary care hospital in the Netherlands. Potential risk factors were compared between groups by uni- and multivariate matched analyses. At transplantation, age55 years (adjusted odds ratio [OR] 2.7, 95% confidence interval [CI] 1.3-5.9) and not receiving basiliximab induction therapy (adjusted OR 4.3, 95% CI 1.1-17.1) predicted development of PCP. In the final multivariate analysis, only cytomegalovirus infection (adjusted OR 3.0, 95% CI 1.2-7.9) and rejection treatment (adjusted OR 5.8, 95% CI 1.9-18) were found to be independently associated with PCP. Using the variables identified by the multivariate analyses, effects of different hypothetical chemoprophylaxis strategies were systematically evaluated. Exploring different scenarios showed that chemoprophylaxis in the first 6 months for all renal transplant patients - and during the first year posttransplantation for patients55 years of age or those treated for rejection - would result in very low PCP incidence and optimal avoidance of TMP-SMX toxicity. The results provide a rationale for further prospective study on targeted provision of chemoprophylaxis to prevent PCP in kidney transplant patients.

Skin diseases are frequently observed in organ-transplant recipients (OTRs).To count the registered skin diseases in all 2136 OTRs who had been transplanted in a single centre between 1966 and 2006 and to calculate their relative contribution in relation to the number of years after transplantation.All registered skin diseases which were entered into a computerized system between 1994 and 2006 at the Leiden University Medical Centre were counted and their relative contributions were calculated.Between 1994 and 2006, 2408 skin diseases were registered in 801 of 1768 OTRs who were at risk during this specific time period. The most commonly recorded diagnoses were skin infections (24.0%) followed by benign skin tumours (23.3%) and malignant skin lesions (18.2%). The relative contributions of infectious and inflammatory disorders decreased with time after transplantation, whereas the contribution of squamous cell carcinomas strongly increased with time.This study gives a systematic overview of the high burden of skin diseases in OTRs. The relative distributions of skin diseases importantly changed with time after transplantation, with squamous cell carcinoma contributing most to the increasing burden of skin diseases with increasing time after transplantation.

In this report, we describe a bladder-drained simultaneous pancreas-kidney transplant (SPKT) recipient with a polyoma virus-associated nephropathy (PVAN) in whom the urine cytology failed to detect decoy cells despite repeated attempts. Several tests were performed to confirm our hypothesis that pancreatic enzymes can degrade decoy cells and granulocytes. This case illustrates an important pitfall in the urinary screening for PVAN with cytology and for urinary tract infections with urine sediment in bladder-drained SPKT recipients.

Summary Secretory immunoglobulin A (SIgA), although generated at mucosal surfaces, is also found in low concentrations in the circulation. Recently, SIgA was demonstrated in mesangial deposits of patients with immunoglobulin A nephropathy (IgAN), suggesting a role in the pathogenesis. This finding is in line with the belief that high molecular weight (HMW) immunoglobulin A (IgA) is deposited in the kidney. However, there is little information on the size distribution of antigen-specific IgA in circulation upon mucosal challenge. In this study we measured antigen-specific IgA, including SIgA, in serum following challenge of IgAN patients and controls via intranasal vaccination with a neoantigen, cholera toxin subunit B (CTB). We size-fractionated serum and nasal washes to study the size distribution of total IgA, SIgA and CTB-specific IgA. Finally, we compared the size distribution of antigen-specific IgA after mucosal immunization with the distribution upon systemic immunization. A significant induction of antigen-specific SIgA was detectable in serum of both patients with IgAN and controls after mucosal immunization with CTB. Independent of the route of immunization, in both groups the antigen-specific IgA response was predominantly in the polymeric IgA fractions. This is in contrast to total IgA levels in serum that are predominantly monomeric. We conclude that mucosal challenge results in antigen-specific SIgA in the circulation, and that the antigen-specific IgA response in both IgAN patients and in controls is of predominantly HMW in nature. No differences between IgAN patients and controls were detected, suggesting that the size distribution of antigen-specific IgA in the circulation is not disturbed specifically in IgAN patients.

Solid organ transplant patients have an increased risk of cutaneous squamous cell carcinomas compared to the immunocompetent population, and often develop multiple and sometimes aggressive tumours. There are few published studies or reviews, which provide guidance to the clinician in the management of these patients. In the prevention of skin cancer in organ transplant patients, patient education about the harmful effects of ultraviolet radiation, sun protection, and the early recognition of (pre)malignant skin lesions should be emphasised. Furthermore, close follow-up by a dermatologist and treatment of (pre)malignant lesions in an early stage are necessary. Chemoprevention of skin cancer can be achieved through systemic retinoids. Reduction of the dose of immunosuppressive agents can be considered. Excision is the first treatment of choice for squamous cell and basal cell carcinomas. In selected rumours curettage and electrodessication can be performed.

Whole pancreas transplantation can effectively restore endogenous insulin secretion in type 1 diabetes mellitus, and prevent, retard, or reverse diabetic complications. The effect of a simultaneous pancreas and kidney transplantation (SPKT) on diabetic complications is variable. These reports must be interpreted in the light of the fact that most recipients received a pancreas in combination with a kidney graft after having already had diabetes for over two decades. Nevertheless, the potential benefits should also be balanced against the risk of peroperative morbidity and the requirement of long-term immunosuppressive medication. Transplantation of a whole pancreas is currently the only reliable option to achieve long-term normoglycaemia. The success of pancreatic islets transplantation will ultimately depend on the longevity of pancreatic islets, requiring further development of immunosuppressive regimens which are not toxic to the islets and prevent recurrent autoimmune destruction of transplanted pancreatic beta-cells.

Ultraviolet radiation (UVR) is an important risk factor for skin cancer in transplant recipients. In view of the potential suppressive effect of UVR on host resistance it was examined whether exposure to UVR was also associated with the occurrence of various skin infections.In a cohort of renal transplant recipients (n = 137), lifetime exposure was assessed by means of a retrospective questionnaire on cumulative sunlight exposure. Diagnosed skin infections since renal transplantation were extracted from the patient's medical charts. Season of diagnosis was regarded as indicative of short-term exposure.In comparison with winter a high rate of herpes simplex infections was found in spring [rate ratio (RR) = 4.09, 95% confidence interval (CI) 1.2-14.5], and high rates of herpes zoster infections (RR = 1.6, 95% CI: 0.8-3.5) and fungal/yeast infections in summer (RR = 2.1, 95% CI: 1.3-3.4). A higher lifetime exposure (RR = 2.31, 95% CI: 1.04-5.1) and a greater cumulative number of reported sunburns (RR = 2.3, 95% CI: 1.1-5.1) were independently associated with a higher risk of bacterial infections.The seasonal association with the occurrence of clinical herpes infections indicates an effect of short-term UVR. Our data suggest that the number of sunburn episodes in the past is also relevant for the susceptibility to certain skin infections.

In the current paper we will review the evidence that drug therapy may be of value to prevent or treat chronic allograft nephropathy. We will review the immunosuppressive therapy and non-immune therapies in use to treat risk factors associated with chronic allograft nephropathy and evaluate their efficacy with respect to long term outcome as well as their effect on markers of long-term survival. In the last part of this review, we will indicate possible benefits of new approaches being explored but most of these data are obtained in in vitro test systems and rodent models.

Many patients with end-stage renal disease are eligible for renal transplantation. To enable a patient to choose between transplantation or to remain on dialysis comparable data on morbidity and mortality should be available.Data were collected retrospectively from the medical records of all patients on the waiting list for renal transplantation and of transplanted patients during the period January 1, 1990, to January 1, 1997. All patients were dialyzed in the Kennemer Gasthuis and renal transplantation was performed in the Leiden University Medical Center (LUMC). Morbidity and mortality in both groups were compared. Morbidity was assessed by studying number, length and cause of hospital admissions.During the study period 102 patients had been on the waiting list and 54 patients had been transplanted in the LUMC. Mean length of stay on the waiting list before transplantation was 37 months. During the follow-up period 11 patients (10.8%) died on the waiting list and 6 patients (11.1%) died after renal transplantation. The mean length of stay on the waiting list of these two groups was much longer, being 55 months and 62 months, respectively. Length of hospitalization was significantly different between both patient groups during the first 6 months of treatment (13.24 days for those on the waiting list versus 40.75 days transplanted patients) and after 6 months (32.4 days for those on the waiting list versus 13.1 days transplanted patients). The number of hospital admissions did not differ significantly. Dialysis-related admissions constituted 47% of the total of admissions in the waiting list group and transplantation-related admissions were 43% in the transplanted group.In the present study we revealed no difference in overall mortality. However, mortality was influenced by length of stay on the waiting list. Morbidity was increased during the first 6 months after transplantation. Therapy modality greatly influenced the specific cause of morbidity.

In 1995 - 1996, we switched from a once-daily Sandimmune dose to a twice-daily dose regimen of Neoral. Concurrent with the switch we changed our target trough level from 100 microg/l at 24 hours to the generally accepted 12-hour level of 150 microg/l. We performed a retrospective cohort study to assess cyclosporine toxicity following this switch and to identify risk factors for nephrotoxicity.Of 212 patients with a stable graft function pre-conversion clinical parameters at 1 and 12 months post-conversion were compared with those at time of conversion. Cyclosporine nephrotoxicity was defined as a significant decline of the reciprocal of the serum creatinine concentration over time post-conversion in the absence of other obvious causes for declining graft function. Risk factors of cyclosporine nephrotoxicity were assessed using logistic regression analysis.The mean cyclosporine trough level rose from 87 microg/l at the time of conversion to 139 microg/l at 12 months post-conversion whereas the daily drug dose increased over the same period from 233 mg to 252 mg. Mean serum creatinine increased by 10% from 135 to 148 micromol/l (p0.001). Cyclosporine nephrotoxicity was present in 42 patients (20%). Cyclosporine dose and trough level did not predict nephrotoxicity but beta-blockers (OR 0.35, 95% CI 0.17-0.72) and calcium channel blockers (OR 0.35, 95% CI 0.19-0.82) reduced the risk of nephrotoxicity, independent from an effect on blood pressure.20% of stable renal transplant patients experienced chronic cyclosporine nephrotoxicity after conversion from a once-daily Sandimmune regimen to a twice-daily Neoral regimen with dose adjustments to a trough level of 150 microg/l. beta-blockers and calcium channel blockers reduced the risk of nephrotoxicity.

Skin infection is a frequent complication in renal transplant recipients. The purpose of the study was to acquire long-term, period-specific incidence data on the most commonly occurring skin infections in renal transplant recipients.A retrospective analysis was performed using medical records of 134 patients, covering a period between 10 and 29 yr. Cumulative incidences of the skin infections were calculated by counting the infections per patient for different time periods and were expressed as a percentage of the total group of patients. The incidence of the skin infections was determined for different post-transplant time periods.A total of 340 skin infections in 105 out of 134 patients were recorded. Some infections, such as candidal infection, herpes simplex infection, and impetigo were most prominent during the first post-transplant year and did not affect many new patients after the first year. Other infections, such as dermatomycoses, herpes zoster, and folliculitis were also affecting a substantial number of new patients after the first post-transplant year.This study confirms that skin infections among renal transplant recipients are very common and that the spectrum of skin infections differs according to the post-transplant time period.

After successful kidney transplantation patients may suffer from the adverse effects due to the use of calcineurin inhibitors. Calcium channel blockers are effective in the treatment of hypertension and may ameliorate cyclosporine- (CsA) induced impairment of renal function after kidney transplantation. Calcium channel blockers may also modulate the immune-system which may result in reduction of acute rejection episodes.From June 1995 till 1997 the effect of isradipine (Lomir) on renal function, incidence and severity of delayed graft function (DGF), and acute rejection after kidney transplantation, was studied in 210 renal transplant recipients, who were randomized to receive isradipine (n=98) or placebo (n=112) after renal transplantation in a double-blind fashion.In the isradipine group renal function was significantly better at 3 and 12 months (P=0.002 and P=0.021) compared with the placebo group. DGF was present in both groups: isradipine: (28+6)/98 (35%); placebo: (35+9)/112 (40%), P=0.57. Severity of DGF was comparable in both groups (isradipine: 9.1+/-8.7 vs. placebo: 9.3+/-8.1 days). No statistical difference was found in incidence or severity of biopsy-proven acute rejection [isradipine: (42+6)/98 (49%) versus placebo: (46+9)/112 (49%), P=1.00]. Renal vein thrombosis was observed in eight patients. This proved to be associated with the route of administration of the study medication [6/45 (13%) on i.v. medication versus 2/165 (1%) on oral medication, P0.001].Addition of isradipine results in a better renal function after kidney transplantation, without effect on incidence or severity of DGF or acute rejection.

DNA of the epidermodysplasia-verruciformis associated subgroup of HPV (EV-HPV) is frequently detected in biopsies of premalignant lesions and nonmelanoma skin cancers of renal transplant recipients. The prevalence of EV-HPVs, however, has never been systematically studied in benign keratotic skin lesions of patients with or without a history of skin cancer. This study included 42 renal transplant recipients with and 36 without a history of skin cancer. A total of 176 skin biopsies were tested for the presence of EV-HPV DNA, using a nested polymerase chain reaction (PCR).EV-HPV typing was done by comparison of the sequence of the amplified PCR products with the sequence of all known EV-HPVs. The natural history of the development of keratotic skin lesions was studied. The number of keratotic skin lesions rapidly increased after transplantation. This increase was most pronounced in patients who developed skin cancer. The prevalence of EV-HPV DNA in benign keratotic skin lesions was equally high in patients with and without a history of skin cancer, i.e., 55 and 53% in the two groups, respectively. A large variety of EV-HPV types was found, but of these none were predominantly present in either patient groups. A higher prevalence of EV-HPV DNA was found in benign skin lesions from sun-exposed sites, but only in patients with a history of skin cancer. The association between the number of keratotic skin lesions and the development of skin cancer strongly supports the hypothesis that EV-HPVs play a role in cutaneous oncogenesis. The equally high prevalence of EV-HPV infection in patients with and without a history of skin cancer, however, may indicate that besides EV-HPV infection, other factors, such as sun exposure may also be important.

Adding a fixed dose of 1 g b.i.d. of mycophenolate mofetil (MMF) to an immunosuppressive regimen consisting of cyclosporine and prednisone results in a 50% reduction in the incidence of acute rejection after kidney transplantation. This study was designed to investigate the relationship between pharmacokinetic data (mycophenolic acid area under the curve; MPA AUC) and the prevention of rejection after kidney transplantation.A total of 154 adult recipients of a primary or secondary cadaveric kidney graft were randomly allocated, in this double-blind trial, to receive MMF treatment aimed at three predefined target MPA AUC values (16.1, 32.2, and 60.6 microg x hr/ml). During the first 6 months after transplantation, plasma samples for nine AUCs were collected. After analysis of the samples, a coded dose adjustment advice was generated using a Bayesian algorithm, maintaining the double blinding. Immunosuppressive therapy further consisted of cyclosporine and prednisone. The primary end point of this study was the occurrence of biopsy-proven acute rejection within the 6-month study period.A total of 150 patients were eligible for analysis. Although after day 21, the mean MMF dose was reduced, the mean MPA AUC gradually increased and target MPA AUC values were exceeded in all three groups. The incidences of biopsy-proven acute rejection in the low, intermediate, and high target MPA AUC groups were 14 of 51 (27.5%), 7 of 47 (14.9%), and 6 of 52 (11.5%), respectively. The incidences of premature withdrawal from the study due to adverse events in the three groups were 4 of 51 (7.8%), 11 of 47 (23.4%), and 23 of 52 (44.2%), respectively. Logistic regression analysis showed a highly statistically significant relationship between median ln(MPA AUC) and the occurrence of a biopsy-proven rejection (P0.001). The logistic regression using median ln(Cpredose) was also statistically significant for this relationship (P=0.01), whereas it was not when using mean MMF dose (P=0.082). In contrast, the logistic regression using mean MMF dose for comparison of patients who successfully completed the study versus patients experiencing premature withdrawal due to adverse events was highly significant (P0.001), whereas this was not significant when using median ln(Cpredose) (P=0.512) or median ln(MPA AUC) (P=0.434).MPA Cpredose and MPA AUC are significantly related to the incidence of biopsy-proven rejection after kidney transplantation, whereas MMF dose is significantly related to the occurrence of adverse events.

With time recurrence of IgA nephropathy in renal allografts may be found in most, if not all patients. However, at the present graft loss due to recurrent IgA nephropathy appears to be of limited importance as compared to other causes. No definite risk factors for recurrent disease and/or graft failure have been identified yet. Although recurrence rates appear to be higher in allografts from living related donors, graft loss rates due to IgA nephropathy are not significantly different. More important, sporadic cases of IgA nephropathy should be excluded in all living related donors.

It is generally accepted that the severity of renal insufficiency in patients correlates with the severity of tubulointerstitial abnormalities, but not with the severity of glomerular abnormalities in kidney biopsies. We recently challenged this view by demonstrating significant correlations of glomerular structural abnormalities with renal function in a histomorphometric study of biopsies from patients with various kidney diseases. We set out to confirm these findings in biopsies from patients with a single disease entity. IgA nephropathy was selected. An additional objective of the study was to determine the prognostic value of our histological predictors of renal function. Histomorphometric measurements were done in silver- and PAS-stained paraffin sections of biopsies from 83 patients with primary IgA nephropathy. The results were correlated with creatinine clearance at the time of biopsy. The prognostic value of the histomorphometric parameters and of several clinical characteristics were determined in a Cox proportional hazard model. All glomerular histomorphometric indices correlated with the severity of renal insufficiency, but quantitative estimates of the glomerular deposition of periodic acid-Schiff positive extracellular matrix (PAS-index) seemed to be the most important glomerular structural-functional correlate (r = 0.53, p0.001). However, the correlation of quantitative estimates of the severity of interstitial extracellular matrix accumulation with renal function (quantitative interstitial index) was superior (r = 0.76, p0.001). Creatinine clearance at biopsy and initial proteinuria were the strongest clinical predictors of renal survival. The severity of tubulointerstitial extracellular matrix accumulation was the strongest histological predictor of an adverse outcome. In conclusion, quantitative estimates of the severity of glomerular and tubulointerstitial extracellular matrix accumulation both correlate well with the severity of renal failure in biopsies from patients with IgA nephropathy. Creatinine clearance at biopsy, initial proteinuria and the severity of tubulointerstitial extracellular matrix accumulation are the best predictors of renal survival. On a more general note, the paradigm of the absence of correlation of glomerular pathology with renal function should be abandoned.

In IgA nephropathy (IgAN), the abnormalities in the IgA immune system are apparently restricted to the IgA1 subclass in the systemic compartment, as evidenced by the antigen-specific responses to recall antigens. Since precursors of IgA producing B cells in human peripheral blood belong predominantly to the mucosal compartment, we took the opportunity to assess the capacity of circulating B cells in peripheral blood (PBMC) of 20 IgAN patients and matched controls to produce IgA, IgA1, and IgA2.Supernatants from T cell- (immobilized anti-CD3) and B cell-specific (CD40 ligation) activated cultures were assessed for immunoglobulin isotypes by ELISA. In addition, we compared the sensitivity of T and B cells to various cytokines (IL-2, IL-10, TGF-beta) in both culture systems.In contrast to significantly higher plasma IgA1 levels (P0.01), no significant differences in salivary IgA1 (P = 0.73) and IgA2 (P = 0.96) levels or ratios (P = 0.91) were found. In the absence of exogenous cytokines, none of the different culture systems led to significant differences in IgA or IgA subclass synthesis by PBMCs of patients and controls. However, in IgAN patients, the addition of IL-2 did not enhance the production of the IgA subclasses as was found in controls. Furthermore IL-10 led to significantly (P0.05) lower IgA1 and IgA2 synthesis in patients than in controls. TGF-beta induced suppression of all isotypes in patients and controls. None of the different conditions resulted in a selectively enhanced production of any one of the IgA subclasses. When both IL-10 and TGF-beta were added to the cultures, IgM was the predominant immunoglobulin synthesized both in patients and controls with a significantly (P0.05) lower synthesis of IgM, IgG, IgA1, and IgA2 in patients.These in vitro data suggest that PBMCs from patients contain more mature and further differentiated B cells. However, there was no selective IgA or IgA1 dysregulation of circulating B cells in IgAN. These results do not confirm the widely believed paradigm that patients with IgAN are primary hyperresponders.

Aims: A case report is presented in which an unexpected pathological diagnosis raised the possibility that biopsies of two patients were mixed-up. Since these biopsies were obtained from kidney transplant patients, the HLA-typings of both patients were known. Methods and results: We developed an immunohistochemical method using HLA-class I specific monoclonal antibodies to recognize the donor and recipient antigens in these biopsies. Using this method we could confirm the identity of the patients of whom the biopsies had been taken. Conclusions: This method, which uses the highly polymorphic HLA-system, is potentially useful for rapid and easy verification of the identity of specimens if a mix-up is suspected.