Galactose-Deficient IgA1 B cells in the Circulation of IgA Nephropathy Patients Carry Preferentially Lambda Light Chains and Mucosal Homing Receptors.

BACKGROUND: IgA nephropathy (IgAN) primary glomerulonephritis is characterized by the deposition of circulating immune complexes composed of polymeric IgA1 molecules with altered O-glycans (Gd-IgA1) and anti-glycan antibodies in the kidney mesangium. The mesangial IgA deposits and serum IgA1 contain predominantly λ light (L) chains, but the nature and origin of such IgA remains enigmatic. METHODS: We analyzed λ L chain expression in peripheral blood B cells of 30 IgAN patients, 30 healthy controls (HCs), and 18 membranous nephropathy patients selected as disease controls (non-IgAN). RESULTS: In comparison to HCs and non-IgAN patients, peripheral blood surface/membrane bound (mb)-Gd-IgA1+ cells from IgAN patients express predominantly λ L chains. In contrast, total mb-IgA+, mb-IgG+, and mb-IgM+ cells were preferentially positive for kappa (κ) L chains, in all analyzed groups. Although minor in comparison to κ L chains, λ L chain subsets of mb-IgG+, mb-IgM+, and mb-IgA+ cells were significantly enriched in IgAN patients in comparison to non-IgAN patients and/or HCs. In contrast to HCs, the peripheral blood of IgAN patients was enriched with λ+ mb-Gd-IgA1+, CCR10+, and CCR9+ cells, which preferentially home to the upper respiratory and digestive tracts. Furthermore, we observed that mb-Gd-IgA1+ cell populations comprise more CD138+ cells and plasmablasts (CD38+) in comparison to total mb-IgA+ cells. CONCLUSIONS: Peripheral blood of IgAN patients is enriched with migratory λ+ mb-Gd-IgA1+ B cells, with the potential to home to mucosal sites where Gd-IgA1 could be produced during local respiratory or digestive tract infections.

Expression and 7-day time course of circulating microRNAs in septic patients treated with nephrotoxic antibiotic agents.

BACKGROUND: Through regulation of signaling pathways, microRNAs (miRNAs) can be involved in sepsis and associated organ dysfunction. The aims of this study were to track the 7-day time course of blood miRNAs in patients with sepsis treated with vancomycin, gentamicin, or a non-nephrotoxic antibiotic and miRNA associations with neutrophil gelatinase-associated lipokalin (NGAL), creatinine, procalcitonin, interleukin-6, and acute kidney injury (AKI) stage. METHODS: Of 46 adult patients, 7 were on vancomycin, 20 on gentamicin, and 19 on another antibiotic. Blood samples were collected on days 1, 4, and 7 of treatment, and miRNAs were identified using quantitative reverse transcription PCR. RESULTS: The results showed no relationship between miRNA levels and biochemical variables on day 1. By day 7 of gentamicin treatment miR-15a-5p provided good discrimination between AKI and non-AKI (area under curve, 0.828). In patients taking vancomycin, miR-155-5p and miR-192-5p positively correlated with creatinine and NGAL values, and miR-192-5p and miR-423-5p positively correlated with procalcitonin and interleukin-6 in patients treated with a non-nephrotoxic antibiotic. In patients together we found positive correlation between miR-155-5p and miR-423-5p and all biochemical markers. CONCLUSION: The results suggest that these four miRNAs may serve as diagnostic or therapeutic tool in sepsis, renal injury and nephrotoxic treatment. TRIAL REGISTRATION: ClinicalTrials.gov , ID: NCT04991376 . Registered on 27 July 2021.

Acute kidney injury due to antimicrobial therapy.

One of the common causes of acute kidney injury (AKI) is drug nephrotoxicity. A large group of drugs associated with AKI includes a considerable number of antimicrobials. Clinical manifestations range from mild forms of tubular damage to significant deterioration of renal function requiring renal replacement therapy. Several mechanisms have been described, although the most common are acute interstitial nephritis, acute tubular necrosis, crystalic nephropathy or proximal/distal tubulopathy with electrolyte abnormalities. General risk factors for antimicrobial-induced AKI include pre-existing chronic kidney disease and concomitant use of drugs with nephrotoxic potential. Prevention and early recognition of AKI are the standard approach to mitigate AKI and avoid morbidity.

Nephrotoxicity of calcineurin inhibitors as a risk factor for BK polyomavirus replication after kidney transplantation.

BK polyomavirus-associated nephropathy (PyVAN) is responsible for a significant percentage of transplanted kidneys prematurely terminating their function. Its occurrence is closely related to the intensity of immunosuppressive therapy. In a group of 161 newly transplanted patients, we prospectively evaluated 457 protocol renal biopsies performed within the first year after transplantation. Using the calcineurin inhibitors (CI) nephrotoxicity score, the incidence of nephrotoxicity was monitored as a manifestation of excessive immunosuppression. Findings were correlated with clinical evidence of active BK polyomavirus (BKPyV) replication and PyVAN. Compared to the normal histology, nephrotoxicity was associated with more frequent BKPyV viremia and viruria (p = .01 and p < .01, respectively) and more common occurrence of PyVAN. The persistence of toxicity in the subsequent biopsy proved to be a negative risk factor of viremia and viruria (p = .03 and p < .01, respectively), independently of the initial BKPyV status. Toxicity could also be used as a predictor of viremia and viruria (p = .04 and p < .01, respectively) even in the absence of viral replication at the time of initial biopsy. The early histological manifestation of CI nephrotoxicity was associated with significant BKPyV reactivation in the risky first posttransplant year.

Acute Kidney Injury in Septic Patients Treated by Selected Nephrotoxic Antibiotic Agents-Pathophysiology and Biomarkers-A Review.

Acute kidney injury is a common complication in critically ill patients with sepsis and/or septic shock. Further, some essential antimicrobial treatment drugs are themselves nephrotoxic. For this reason, timely diagnosis and adequate therapeutic management are paramount. Of potential acute kidney injury (AKI) biomarkers, non-protein-coding RNAs are a subject of ongoing research. This review covers the pathophysiology of vancomycin and gentamicin nephrotoxicity in particular, septic AKI and the microRNAs involved in the pathophysiology of both syndromes. PubMED, UptoDate, MEDLINE and Cochrane databases were searched, using the terms: biomarkers, acute kidney injury, antibiotic nephrotoxicity, sepsis, miRNA and nephrotoxicity. A comprehensive review describing pathophysiology and potential biomarkers of septic and toxic acute kidney injury in septic patients was conducted. In addition, five miRNAs: miR-15a-5p, miR-192-5p, miR-155-5p, miR-486-5p and miR-423-5p specific to septic and toxic acute kidney injury in septic patients, treated by nephrotoxic antibiotic agents (vancomycin and gentamicin) were identified. However, while these are at the stage of clinical testing, preclinical and clinical trials are needed before they can be considered useful biomarkers or therapeutic targets of AKI in the context of antibiotic nephrotoxicity or septic injury.

Acute toxic kidney injury.

Substances toxic to the kidney are legion in the modern world. The sheer number and variety, their mutual interactions and, metabolism within the body are a challenge to research. Moreover, the kidney is especially prone to injury owing to its physiology. Acute kidney injury (AKI) induced by poisonous or primarily nephrotoxic substances, may be community acquired with ingestion or inhalation or nosocomial. Many nephrotoxic plants, animal poisons, medications, chemicals and illicit drugs can induce AKI by varying pathophysiological pathways. Moreover, the epidemiology of toxic AKI varies depending on country, regions within countries, socioeconomic status and health care facilities. In this review, we have selected nephrotoxic insults due to medication, plants, animal including snake venom toxicity, environmental, (agri)chemicals and also illicit drugs. We conclude with a section on diagnosis, clinical presentation and management of poisoning accompanied by various organ dysfunction and AKI.

Glucocorticoids Reduce Aberrant O-Glycosylation of IgA1 in IgA Nephropathy Patients.

BACKGROUND/AIMS: IgA nephropathy is associated with aberrant O-glycosylation of IgA1, which is recognized by autoantibodies leading to the formation of circulating immune complexes. Some of them, after deposition into kidney mesangium, trigger glomerular injury. In patients with active disease nonresponding to angiotensin-converting enzyme inhibitors or angiotensin II blockers, corticosteroids are recommended. METHODS: The relationship between the corticosteroid therapy and serum levels of IgA, aberrantly O-glycosylated IgA1, IgA-containing immune complexes and their mesangioproliferative activity was analyzed in IgA nephropathy patients and disease and healthy controls. RESULTS: Prednisone therapy significantly reduced proteinuria and levels of serum IgA, galactose-deficient IgA1, and IgA-IgG immune complexes in IgA nephropathy patients and thus reduced differences in all of the above parameters between IgAN patients and control groups. A moderate but not significant reduction of mesangioproliferative potential of IgA-IgG immune complexes and IgA sialylation was detected. CONCLUSION: The prednisone therapy reduces overall aberrancy in IgA1 O-glycosylation in IgA nephropathy patients, but the measurement of IgA1 parameters does not allow us to predict the prednisone therapy outcome in individual patients.

Serum protein pattern associated with organ damage and lupus nephritis in systemic lupus erythematosus revealed by PEA immunoassay.

BACKGROUND: Systemic lupus erythematosus (SLE) is a remarkably heterogeneous autoimmune disease. Despite tremendous efforts, our knowledge of serum protein patterns in severe SLE phenotypes is still limited. We investigated the serum protein pattern of SLE, with special emphasis on irreversible organ damage and active lupus nephritis (LN) as assessed by renal Systemic Lupus Erythematosus Disease Activity Index. METHODS: We used proximity extension immunoassay (PEA, Proseek Multiplex, Olink) to assess the serum levels of ninety-two inflammation-related proteins in Czech patients with SLE (n = 75) and age-matched healthy control subjects (n = 23). Subgroup analysis was carried out on the basis of organ damage (with/without, 42/33) and biopsy-proven LN (with/without, 27/48; active LN, n = 13; inactive LN, n = 14). RESULTS: Of thirty deregulated proteins between SLE and the healthy controls (Pcorr  < 0.05), the top upregulated proteins in SLE were sirtuin 2, interleukin 18 (IL18), and caspase 8 (Pcorr  < 0.0006). Of these, sirtuin 2 and caspase 8 had not yet been reported with SLE. Elevated levels of IL8, CCL2/MCP1, CCL11, and MMP10 (Pcorr  < 0.05) were detected in patients with organ damage for which the serum levels of CCL11 and MMP10 were particularly informative in organ damage prediction. Comparing patients based on LN, elevated levels of CSF1, sIL15RA, sCD40, sCX3CL1, caspase 8, sIL18R1, bNGF, and GDNF (Pcorr  < 0.05) were detected in active LN. Except GDNF, all LN-associated markers showed usefulness in prediction of active renal disease. CONCLUSIONS: This highly sensitive PEA analysis identified the serum pattern of SLE, organ damage, and active LN, with many novel candidate proteins detected. Their exact role and suitability as biomarkers in SLE deserve further investigation.

Late Rupture of Lumbar Artery as an Unusual Complication after Renal Biopsy - Case Report.

The most serious complication of renal biopsy is vascular damage with subsequent haemorrhage. To our knowledge, we present a first ever case of lumbar artery (LA) rupture accompanied by massive retroperitoneal bleeding, which developed after a significant amount of time following the biopsy itself. In a 63-year-old Caucasian female patient, a percutaneous left kidney biopsy was performed under continuous ultrasound guidance. On the fourteenth day after the procedure, she was examined for a sudden onset of left lumbar region pain. Computed tomography angiography showed a large retroperitoneal hematoma with active bleeding from the fourth left LA. Successful endovascular superselective embolization was performed immediately. The predisposing factor for the late haemorrhage could have been anticoagulation therapy, renal insufficiency and older age. Our case report highlights the need for caution, especially when performing kidney biopsy in a group of high-risk patients, particularly if they are indicated for subsequent anticoagulant therapy.

[IgA nephropathy - research-generated questions]. / IgA nefropatie - otázky, které nastolil výzkum.

IgA nephropathy (IgAN) is the most common type of glomerulonephritis. Its etiology involves an increased production of polymeric immunoglobulin A1 with an abnormal composition of some carbohydrate chains. The reaction of these abnormal forms of IgA1 with specific autoantibodies while circulating immune complexes arise and settle in the renal mesangium with subsequent inflammatory activation of mesangial cells which in up to 50% of cases results in end-stage kidney failure. Pathogenesis involves an interplay of genetic predisposition and environmental effects, mainly of microbial nature. Current therapy is not sufficiently effective and lacks the focus on the cause of the disease, therefore more efficient and specific ways of therapy are being sought to target the individual stages of the pathogenetic process of IgAN development. With the accumulation of knowledge, new questions arise, concerning detailed mechanisms of the pathological processes, as discussed in the text.Key words: autoimmunity - glycosylation of IgA hinge region - IgA nephropathy - immunoglobulin IgA - IgA1 hinge region.

Cutaneous bacillary angiomatosis due to Bartonella quintana in a renal transplant recipient.

Bacillary angiomatosis (BA) is a disorder of neovascular proliferation involving skin and other organs of immunosuppressed patients caused by Bartonella species. BA has been recognized in both immunocompetent and immunodeficient patients, mostly in human immunodeficiency virus (HIV)-infected persons, much more rare in those with other immunodeficiencies, including organ transplantation. Diagnosis is based on serologic analysis, culture and molecular biology [detection of Bartonella species deoxyribonucleic acid (DNA) in tissue biopsy extracts by real-time polymerase chain reaction (PCR)]. All immunosuppressed patients with BA should be treated with antibiotics because of potentially life-threatening course of the disease. We report the first case of cutaneous bacillary angiomatosis due to Bartonella quintana in renal transplant recipient. This presentation demonstrates that BA should be considered a differential diagnosis in immunocompromised patients presenting with fever and cutaneous angioma-like lesions.

Prognostic value of myocardial perfusion imaging and coronary artery calcium measurements in patients with end-stage renal disease.

OBJECTIVE: Coronary artery disease (CAD) is highly prevalent in patients with end-stage renal disease (ESRD), owing to clustering of traditional and uremic-specific risk factors. However, in this population asymptomatic course of CAD is common and it has been reported that myocardial perfusion imaging (MPI) with single-photon emission tomography (SPET) has lower sensitivity. In the current study, we assessed the value of MPI gated-SPET and its combination with coronary artery calcium (CAC) score measurements in risk stratification of ESRD patients. MATERIALS AND METHODS: MPI gated-SPET was performed with dual-headed SPET camera and CAC score measured by multi-detector computed tomography (MDCT) system.There were tested 77 ESRD individuals. During the follow-up study, cardiac events (CE) defined as cardiac death or nonfatal myocardial infarction (MI) or the necessity for coronary revascularization were recorded. Univariate and stepwise multivariable Cox proportional hazards-models were used to identify the predictors of CE. RESULTS: Eighteen CE were recorded during the follow-up. They were significantly associated with higher summed stress scores on MPI, higher percentage of ischaemic myocardium, higher occurrence of defects in multiple territories and higher CAC score (all with P<0.05). Univariate Cox proportional hazard-models showed that severe perfusion abnormalities as well as CAC score ≥1000 were significantly associated with cardiac events (P<0.0001, P=0.0056). In stepwise Cox proportional hazards-models considering age, gender, history of diabetes mellitus, post-stress left ventricular stunning, the degree of perfusion abnormality and CAC score, only severe perfusion abnormalities and CAC score ≥1000 were independent predictors of CE. There was no CE in patients with normal perfusion, normal function and zero CAC score. CONCLUSION: This study suggests that combined evaluation of MPI and CAC can predict the outcome in ESRD individuals, while severe perfusion abnormality on gated-SPET and high CAC score ≥1000 are predictors of future cardiac events.

IgA nephropathy in Czech patients--are we able reliably predict the outcome?

BACKGROUND/AIMS: The aim of our study was to retrospectively analyse data of 520 Czech patients with IgA nephropathy (IgAN) and to specify the risk factors affecting renal survival of IgAN patients. METHODS: Cox proportional hazards regression model was used to evaluate the effects of different variables on renal survival during a median follow up of six years. McNemar´s test was used to analyse the progression of renal function according to Bartosik´s formula. RESULTS: In our retrospective analysis of 520 Czech IgAN patients Cox proportional hazards regression model with five variables [hypertension, sex, GFR, proteinuria, age] was used. Significant regression coefficient was found for GFR, hypertension and proteinuria. Using stepwise algorithm GFR (OR = 3.09), hypertension (OR = 2.09) and proteinuria (OR = 1.97) were found as the most important factors for renal survival in our group of IgAN patients. Among patients with CKD 3 we found significantly better renal survival in patients with proteinuria < 1g/day compared to patients with higher proteinuria. We did not find the significant difference between predicted progression of renal function due to Bartosik´s formula and real progression of renal parametres assessed by GFR at the end of the follow up in our group of IgAN patients. CONCLUSION: Our retrospective study of 520 Czech IgAN patients confirmed GFR, hypertension and proteinuria as the most important factors affecting the prognosis of IgAN patients. We validated Toronto Bartosik´s formula to predict prognosis of IgAN patients.

[Bortezomib-based therapy in patients with light chain deposition disease]. / Lécba bortezomibem u pacientu s onemocnením z depozice lehkých retezcu imunoglobulinu.

Light chain deposition disease (LCDD) is a rare systemic condition caused by monoclonal proliferation of terminally differentiated B-lymphocytes with production of free light chains and their deposition in kidneys or other organs. The aim of our study is to show the pitfalls of the diagnostics, and to demonstrate the effect of bortezomib-based therapy on a series of 4 patients with LCDD, from the point of hematological and organ therapeutic response. We include that bortezomib based treatment provides rapid and effective hematological response. It is, however, often accompanied by adverse events, especially within intensive treatment schedules. The most serious adverse effects includes peripheral neuropathy, which might be dose or treatment-limiting. Less intensive regimens ("bortezomib weekly") suggest an alternative with expectation of lower incidence of adverse effects. Autologous stem cell transplantation is a recommended and relatively safe approach in convenient candidates. Organ response is significantly delayed after hematological response, and organ damage by light chain deposits might not be fully reversible.

GalNAc-T14 may Contribute to Production of Galactose-Deficient Immunoglobulin A1, the Main Autoantigen in IgA Nephropathy.

Introduction: Immunoglobulin A1 (IgA1) with galactose-deficient O-glycans (Gd-IgA1) play a key role in the pathogenesis of IgA nephropathy (IgAN). Mucosal-tissue infections increase IL-6 production and, in patients with IgAN, are often associated with macroscopic hematuria. IgA1-secreting cell lines derived from the circulation of patients with IgAN, compared to those of healthy controls (HCs), produce more IgA1 that has O-glycans with terminal or sialylated N-acetylgalactosamine (GalNAc). GalNAc residues are added to IgA1 hinge region by some of the 20 GalNAc transferases, the O-glycosylation-initiating enzymes. Expression of GALNT2, encoding GalNAc-T2, the main enzyme initiating IgA1 O-glycosylation, is similar in cells derived from patients with IgAN and HCs. In this report, we extend our observations of GALNT14 overexpression in IgA1-producing cell lines from patients with IgAN. Methods: GALNT14 expression was analyzed in peripheral blood mononuclear cells (PBMCs) from patients with IgAN and from HCs. Moreover, the effect of GALNT14 overexpression or knock-down on Gd-IgA1 production in Dakiki cells was assessed. Results: GALNT14 was overexpressed in PBMCs from patients with IgAN. IL-6 increased GALNT14 expression in PBMCs from patients with IgAN and HCs. We used IgA1-producing cell line Dakiki, a previously reported model of Gd-IgA1-producing cells, and showed that overexpression of GalNAc-T14 enhanced galactose deficiency of IgA1, whereas siRNA-mediated GalNAc-T14 knock-down reduced it. GalNAc-T14 was localized in trans-Golgi network, as expected. Conclusions: Overexpression of GALNT14 due to inflammatory signals during mucosal infections may contribute to overproduction of Gd-IgA1 in patients with IgAN.

Stabilization of oxidative stress 1 year after kidney transplantation: effect of calcineurin immunosuppressives.

Kidney transplantation (KT) is one of the best treatments for patients with chronic renal disease. It leads to improved kidney function, but the oxidative stress (OS) is only partially eliminated after KT. This study evaluated the effect of KT on outcomes, such as (a) specific kidney functions, (b) metabolic parameters, as well as (c) OS-related markers in 70 patients (46 males, 24 females; mean age = 54 ± 11) before and 1 year after KT. Post KT, the patients were divided into two groups: those receiving only cyclosporine A (N = 36) and those receiving only tacrolimus (N = 34). Improved kidney function (creatinine, urea, and glomerular filtration rate) and biochemical and hematological parameters were found 1 year after KT. OS-related markers (total antioxidant capacity, advanced oxidation protein, and lipid peroxidation products) decreased, but glutathione level increased after KT. Alterations in superoxide dismutase and catalase activities were also found. Glutathione peroxidase levels were unchanged. The level of oxidized low-density lipoprotein was surprisingly, not significantly increased. There was no significant difference between calcineurin inhibitors in any of the measured parameters. Improved renal function after KT is linked to reduction in OS but independent of immunosuppressive therapy.

Time-course evaluation of oxidative stress-related biomarkers after renal transplantation.

Patients with chronic renal disease have a high prevalence of oxidative stress (OS), which is associated with the cardiovascular complications occurring in this population. The restoration of kidney function after kidney transplantation (KT) can lead to reduction in the metabolic abnormalities and elimination of the OS. Time-dependent changes in OS-related markers and specific kidney function and metabolic parameters were evaluated in patients (N = 39; 23 males; 16 females; mean age = 57 ± 10 years) before (day 0) and after KT (day 1, 7, 30, 90, and 180) to monitor the graft. In particular, total antioxidant capacity (TAC), levels of advanced oxidation protein products (AOPP), lipid peroxidation as thiobarbituric acid-reactive substances (TBARS) and reduced glutathione (GSH); activities of glutathione peroxidase, catalase, and superoxide dismutase; and kidney function markers were measured. AOPP, TAC, and TBARS were significantly decreased, whereas GSH was significantly increased after KT. Antioxidant enzyme activities were not significantly changed during the monitored period after KT. Apropos specific kidney function markers and glomerular filtration significantly increased and creatinine level significantly decreased after transplantation. Changes in high-density lipoprotein cholesterol were also found. Our results show that successful KT results in normalization of the antioxidant status and lipid metabolism that is connected with both improved renal function and reduced cardiovascular complications.

Association of advanced vasculopathy and transforming growth factor-beta1 gene expression with immunoglobulin A nephropathy progression.

BACKGROUND: The mechanism of IgA nephropathy (IgAN) progression remains ill-defined. In this prospective study, the prognostic role of clinical, histological and molecular markers over a 2-year follow-up was evaluated. METHODS: Fifty-one patients with biopsy-proven IgAN were followed for 24 months. Besides routine histology, the intrarenal gene expressions of cytokines and chemokines were quantified by reverse transcription quantitative real-time polymerase chain reaction, and the presence of lymphocytes and macrophages were immunohistochemically examined. RESULTS: Higher transforming growth factor-ß1 and severe chronic vasculopathy (but not glomerulosclerosis, interstitial fibrosis or lymphocyte infiltrate) were associated with the IgAN progression 24 months after biopsy. The gene expression of chemokine (C-C motif) ligands 2 and 5, hepatocyte growth factor, bone morphogenic protein-7 and transforming growth factor-ß1 and the interstitial infiltrate of T and B lymphocytes and macrophages were significantly associated with serum creatinine and glomerular filtration rate at the time of biopsy. The intrarenal chemokine (C-C motif) ligand 2 and hepatocyte growth factor gene expression were associated with the proteinuria. CONCLUSIONS: Besides the known risk factors for chronic kidney disease, advanced vasculopathy and molecular signatures of fibrogenesis were associated with the IgAN progression.

Subclinical toxicity of calcineurin inhibitors in repeated protocol biopsies: an independent risk factor for chronic kidney allograft damage.

The purpose of the prospective study was to determine the prevalence of subclinical toxicity of calcineurin inhibitors (CI) in repeated protocol renal allograft biopsies and to assess its impact on the development of chronic graft changes. A total of 424 biopsies were conducted in a cohort of 158 patients; of these biopsies, 158 were in the third week, 142 were in the third month and 124 were in the first year after transplantation. Histological signs of toxicity occurred in the third week in 33 (20.1%) patients, with persistence after CI dose reduction in the third month in 27 (19.0%) and in the first year in 23 (18.5%) patients. Of the toxic changes, 52% were clinically silent. At the end of the one-year follow-up, both subclinical and clinically manifest toxicity resulted in a similar progression of chronic changes quantified by Banff chronicity score and they significantly differed from the control group (P < 0.05). Subclinical toxicity affects a significant percentage of grafts; it occurs independently of dosage, blood level and type of applied CI. It is associated with the progression of chronic changes as early as in the first year after transplantation and represents an independent risk factor for chronic allograft damage. We report here our clinical approach to toxicity.

Merkel cell carcinoma of the gluteal region with ipsilateral metastasis into the pancreatic graft of a patient after combined kidney-pancreas transplantation.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare tumour of the skin that predominantly affects elderly or immunocompromised patients. The malignant transformation of Merkel cells is currently considered to be related to an infection with Merkel cell polyomavirus. CASE REPORT: We present the case of a 62-year-old man who developed a Merkel cell polyomavirus-positive MCC in a non-UV-exposed part of the right gluteal region 8 years after combined kidney-pancreas transplantation. Following excision and radical re-excision of the tumour, no adjuvant radiotherapy was indicated because of the risk of adjacent pancreatic graft failure. Despite adjustment of the immunosuppressive therapy with conversion to sirolimus, the tumour generalised and metastasised into the pancreatic graft, leading to its failure. Subsequent chemotherapy did not affect the course of the disease, and the patient died 9 months after diagnosis. CONCLUSIONS: To our knowledge, we present the first case of MCC associated with metastatic involvement of the transplanted pancreas followed by its subsequent failure. Given the highly aggressive course of the disease in patients after organ transplantation, MCC therapy should be sufficiently aggressive from the time of diagnosis and should not be influenced by attempts to preserve graft function.