PCSK9 and inflammatory biomarkers in the early post kidney transplantation period.

OBJECTIVE:   Various biomarkers have been studied in the early post-kidney transplantation (post-KTx) period in order to identify potential therapeutic targets for improving long-term graft survival. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a biomarker that has recently gained interest in cardiovascular disease but its role still remains to be defined post-KTx. PATIENTS AND METHODS: We prospectively evaluated the levels of PCSK9, interleukin (IL)-6, WBC and C-reactive protein in seventy-three hemodialysis patients undergoing KTx, at 3 time-points; pre-transplantation (day 0) and at 1 and 6-months post-KTx. All data were also analyzed according to donor-type (living or deceased) and compared with hemodialysis patients on transplant waiting list. RESULTS: At Day 0 there was no difference in WBC, CRP, IL-6 and PCSK9 levels between patients scheduled for transplantation and those who remained on hemodialysis. In transplanted patients WBC, CRP and IL-6 levels were significantly reduced early post-KTx [logIL-6 Day 0: 0.68 (0.33, 0.85) vs. 1-month: 0.57 (0.37, 0.75) vs. 6-months: 0.50 (0.32, 0.69) pg/ml, p=0.01], while PCSK9 levels were significantly increased (Day 0: 199.8±63.0 vs. 1-month: 276.2±79.4 vs. 6-months: 245.9±62.5 ng/ml, p<0.001). In contrast, no change of WBC, CRP, IL-6 and PCSK9 levels was observed in hemodialysis patients on follow-up (p=NS for all). Between living-donor and deceased-donor recipients, analysis showed reduced CRP and increased PCSK9 levels in both groups (p<0.05 for all), while IL-6 levels were reduced in living-donor and increased in deceased-donor recipients 1-month post-KTx. PCSK9 levels were not correlated with renal function, delayed graft function, rejection episodes or inflammatory biomarkers. CONCLUSIONS: PCSK9 levels were increased post-KTx independently from renal function and inflammatory biomarkers, in both living and deceased-donor recipients.

Colchicine in Renal Diseases: Present and Future.

Colchicine is a lipophilic alkaloid drug, which exhibits ant-inflammatory and anti-fibrotic properties. Cardinal mechanisms of action of colchicine are the disruption of the microtubule system and the inhibition of neutrophil adhesion and recruitment. Colchicine is indicated in the prevention and treatment of gouty arthritis and familial Mediterranean fever. In this review, we summarize current and potentially future pharmacologic activities of colchicine in various renal disease entities along with pharmacokinetic and pharmacodynamic properties. Additionally, we will refer to main interactions of colchicine with medications used in renal medicine, as well as dosing recommendations in patients with reduced glomerular filtration rate.

Syndrome of Inappropriate Antidiuretic Hormone Secretion Complicating Systemic Nocardiosis in a Renal Transplant Recipient: A Case Report.

BACKGROUND: Infection by Nocardia species is an uncommon cause of severe clinical syndromes, particularly in immunocompromised patients, and solid-organ transplantation is the most common underlying condition. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been described thus far in lung and stem cell transplants with systemic nocardiosis. CASE REPORT: We report the first case of SIADH in a female elderly renal transplant recipient diagnosed with systemic nocardiosis 2 years after transplantation. The SIADH was managed appropriately, and her immunosuppressive regimen remained unchanged but was adjusted at a lower level. The systemic Nocardia infection was successfully treated with intravenous administration of trimethoprim-sulfamethoxazole and imipenem for 2 weeks followed by oral trimethoprim-sulfamethoxazole for a total of 12 months. CONCLUSIONS: The SIADH syndrome is a recognizable complication of Nocardia infection in renal transplant recipients. Prompt identification along with proper management and prolonged antimicrobial treatment are essential to improve patients' outcome.

Glomerular Diseases and Renal Transplantation: Pathogenic Pathways and Evolution of Therapeutic Interventions.

Glomerular diseases and renal transplantation are the main fields of nephrology in which the immune system plays a prevalent role. Glomerular diseases have traditionally been attributed to auto-immune conditions, whereas allograft rejection has been considered an allo-immune response. However, common immunopathologic mechanisms that include Toll-like receptors, complement and B-cell activation, as well as genetic and infectious factors appear to be involved in the pathogenesis of both entities. Novel therapeutic regimens directed against specific targets of the immune system show promising results in glomerulopathies as well as in renal transplantation.

A Heartbreaking Renal Transplantation: Is Norepinephrine the Culprit to Blame?

INTRODUCTION: Takotsubo cardiomyopathy (TCM), also known as "broken heart syndrome," "apical ballooning syndrome," and "stress-induced cardiomyopathy," was first described in Japanese patients in 1990 by Sato et al. TCM is an increasingly recognized syndrome characterized by transient and reversible systolic dysfunction of the apical and middle segments of the left ventricle. This syndrome resembles acute myocardial infarction in the absence of evident coronary artery occlusion. Herein, we present a case of a 51-year-old male who underwent his second deceased-donor renal transplantation for end-stage-renal-disease due to a work-related accident. Perioperatively, initiation of continuous infusion of noradrenaline was decided to achieve adequate graft perfusion due to persistently low blood pressure. On the second postoperative day, the patient experienced tachycardia and atypical angina-like chest pain. Electrocardiogram (ECG) showed signs of myocardial infarction and elevated troponin levels were observed. Urgent coronary angiography was normal and transthoracic echocardiography (TEE) was indicative for Takotsubo cardiomyopathy. DISCUSSION: Although, the precise pathophysiology of Takotsubo cardiomyopathy is still unknown, it seems that it is associated with excessive sympathetic stimulation, microvascular dysfunction, coronary artery vasospasm, and abnormal myocardial tissue metabolism. The development of patient's symptoms after the initiation of norepinephrine along with their immediate resolution after the discontinuation of the drug might suggest a causal relationship. This is the first time that TCM after renal transplantation is thought to be linked with the administration of exogenous catecholamines.

Exploring associations between anthropometric indices and graft function in patients receiving renal transplant.

BACKGROUND: The aim of the present study was to identify indicators of malnutrition, as obtained by anthropometric measurements, that might be potential predictors of transplant outcomes. METHODS: One hundred and three patients receiving a graft from a living or a deceased donor were included in this prospective study. Body mass index (BMI) based on pretransplant dry body weight, triceps skinfold, mid-arm muscle circumference and corrected mid-arm muscle area were measured. Post-transplant data on delayed graft function (DGF) and glomerular filtration rate (GFR) at discharge were collected until patient discharge. RESULTS: Delayed graft function developed in 36.9% of the patients. BMI was the only anthropometric variable associated with a higher likelihood of DGF (odds ratio = 1.25, 95% confidence interval = 1.07-1.47) after adjusting for age, gender, donor group, donor age and years of dialysis before transplantation. Obesity was associated with a higher frequency of DGF (83.3% versus 31.1%, P = 0.001) compared to normal weight. GFR at discharge was negatively associated with BMI [ß = -0.014 (0.005), P = 0.004], being overweight [ß = -0.151 (0.041), P < 0.001] and obesity [ß = -0.188 (0.053), P = 0.001], after adjusting for age, gender, donor group, donor age and years of dialysis, but was not associated with indices of muscle reserves. CONCLUSIONS: The likelihood of DGF was higher among obese patients, whereas GFR at discharge was negatively associated with being overweight and obesity.

Patients After Kidney Allograft Failure: Immunologic and Nonimmunologic Considerations.

Patients returning to dialysis after kidney transplant failure represent approximately 5%-15% of the population starting hemodialysis. These patients exhibit a high risk of morbidity and mortality attributed mainly to the exposure to immunosuppressive medications and to a uremic environment. The purpose of this paper was to review data regarding survival after renal allograft failure and the optimal management of patients before returning to dialysis. Moreover, issues surrounding nephrectomy after renal allograft failure, the tapering of immunosuppression and the possibility of retransplantation are examined, because they seem to be crucial for patient survival and the quality of life.

Evolution of Renal Function in Renal Allograft Recipients Under Various Everolimus-Based Immunosuppressive Regimens.

BACKGROUND: Long-term allograft survival is a major challenge in kidney transplantation. This study sought to estimate the evolution of renal function in patients receiving different immunosuppressive regimens based on everolimus (EVR). METHODS: Ninety-nine renal allograft recipients were included in a 12-month open-label, noninterventional, prospective, single-center study. Patients were divided into 2 groups, de novo and late conversion to EVR. RESULTS: Group A included 40 patients under calcineurin inhibitor (CNI) plus EVR. Median time posttransplantation was 33.06 months (interquartile range 18.25 to 42.85). Mean estimated glomerular filtration rate (eGFR) the first month posttransplantation (using Modification of Diet in Renal Disease formula) was 54.89 ± 19.08 mL/min, and mean proteinuria was 0.54 ± 0.38 g/24 h. At the end of follow up, mean eGFR and mean proteinuria significantly improved (65.49 ± 20.79 mL/min; P = .011 and 0.157 ± 0.089 g/24 h; P = .002, respectively). Group B consisted of 59 patients; 49 of them initially received mycophenolic acid (MPA) plus CNI, and 10 had been on azathioprine plus CNI. Initial immunosuppression was switched to MPA plus EVR in 49 patients, CNI plus EVR in 4 patients, and EVR in 6 patients, in a median time of 37 months (interquartile range 14.75 to 112.5) posttransplantation. Main indications for conversion were malignancies and biopsy-proven chronic allograft injury. Mean eGFR 1 month posttransplantation and at the time of conversion were 50.79 ± 17.83 mL/min and 57.39 ± 19.17 mL/min, respectively (P = .014). After conversion, mean eGFR increased (66 ± 24.89 mL/min; P = .006). Mean proteinuria was 0.509 ± 0.530 g/24 h the first posttransplantation month, and it remained stable at 0.415 ± 0.431 g/24 h until study completion. Two acute rejection episodes occurred. At the end of follow-up, patient and death-censored graft survival were 97% and 100%, respectively. CONCLUSIONS: In kidney transplant recipients, EVR either de novo or after conversion with or without CNI is a safe and effective treatment that preserves renal function.

The Importance of Novel Inflammatory Biomarkers in Renal Disease.

Kidney disease, whether acute or chronic, represents a major health hazard. Acute kidney injury (AKI) detection is based mainly on serum creatinine, which is considered to delay prompt diagnosis and management, thus increasing substantially patient morbidity and mortality and prolonged hospitalization. Several biomarkers have been evaluated as early prognostic markers of AKI. However, the vast majority of them are still far from being implicated into clinical practice. On the other hand, routine eGFR estimation and proteinuria monitoring have contributed to previous identification of chronic kidney disease (CKD). Hence, more sensitive and specific biomarkers are needed to enable us recognize individuals at increased risk for progression of CKD to end-stage renal disease (ESRD) and occurrence of cardiovascular complications. This review focuses on the most important novel inflammatory biomarkers that have emerged for early prediction, monitoring and management of kidney disease.

Adenosine triphosphate production by peripheral blood CD4⁺T cells in clinically stable renal transplant recipients.

Previous studies have shown that intracellular adenosine triphosphate (iATP) in activated CD4 T cells in vitro may identify patients at risk of infection or rejection post-transplantation. In this study, we evaluated whether this test could identify the level of risk in 656 renal transplant recipients (RTRs) with good and stable graft function. Therefore, 1095 blood samples from RTRs and 200 from healthy blood donors (normal controls [NCs]) were collected in 2 years and analyzed using the Cylex(®) ImmuKnow™ assay (Cylex, Inc., Columbia, MD, USA). The classification of T cell responses into strong, moderate, and low revealed significant differences between patients and NCs in low and strong responses (P < .001 and P = .021, respectively). The majority of patient samples exhibited moderate immune response (72.2%) in comparison with NC (75%). One hundred twenty-eight patients had fluctuated T cell responses between the three response zones. All patients were clinically stable for at least 1 month after the test. T cell response was increased after time post-transplantation (P < .001) and was found higher in protocols using azathioprine versus other immunosuppression (P < .001) and cyclosporine instead of tacrolimus (P = .012). According to the results of this study, we are not able to support this assay as an immune monitoring test post-transplantation in clinically stable RTRs. In contrast, measuring of iATP in CD4 T cells is a valuable tool for estimating T cell activation capacity. Because T cell activation is mainly affected by immunosuppression, this test may give information regarding the strength of different immunosuppressive protocols or the strength of immunosuppression as it is associated with longer follow-up periods.

Infectious complications in the first year post renal transplantation.

BACKGROUND: The aim of this study was a prospective assessment and determination of risk factors for infections among renal transplant recipients (Rtr) during the 1st year after renal transplantation (Rtx). METHODS: From June 2004 to October 2005, we performed 133 Rtx in 88 men and 45 women of overall mean age of 46 ± 14 years (range; 13-75). RESULTS: During the first year post-Rtx, 88 (58 men and 30 women) infectious episodes were observed in 60 patients (45%). Thirty-nine (65%) required ≥1 hospitalization. Most common was urinary tract infections (UTI; 54 episodes; 61%). The causative organism was identified in 61 of the 88 (69%) episodes: In 51 it was bacterial, in 8 cytomegalovirus (CMV), and in 2 fungi. Forty-three episodes (49%) were observed during the first 3 months; 22 (25%) between 3 and 6 months and 23 (26%) between 6 and 12 months post-Rtx. There were no significant differences between patients with versus without hospitalization owing to infections with regard to recipient gender and age, duration of dialysis pre-Rtx, donor kidney source, acute rejection episodes, donor age, or arterial hypertension. Diabetes was a significant risk factor for infections (odds ratio [OR], 1.154; 95% confidence interval [CI], 1.045-1.274; P = .001], as well as an immunosuppressive regimen that included tacrolimus, mammalian target of rapamycin inhibitor, corticosteroids, and anti-interleukin-2 monoclonal antibody as initial treatment (OR, 3.053; 95% CI, 1.007-9.349; P = .043). There was an increased prevalence of CMV infections after the chemoprophylaxis period (OR, 0.456; 95% CI, 0.358-0.580; P = .002). Mean duration of hospitalization was 11.5 days (range, 2-109). In 3 of 133 (5%) Rtr, the outcome was fatal. CONCLUSION: The frequency of infections during the 1 st year post-Rtx is influenced by the primary disease of the Rtr as well by the choice of immunosuppressive regimen. UTI remains the commonest infection, accounting for half of all infections in the first 3 months post-Rtx. There was an increased risk for CMV infection after the chemoprophylaxis period.

Glomerular disease recurrence in the renal allograft: a hurdle but not a barrier for successful kidney transplantation.

Almost all forms of primary as well as secondary glomerulonephritides may recur after renal transplantation. Recurrence of the original disease is now the third most common cause of late allograft loss. Nevertheless, in most cases it is difficult to assess the true impact of primary disease recurrence in the allograft; histological recurrence with mild features does not necessarily implicate clinically severe disease. Moreover it is often difficult to distinguish recurrent from de novo disease as in membranous glomerulopathy. Because recurrence occurs late, histological lesions of recurrent glomerulonephritis may be unmasked by chronic damage from other causes such as chronic rejection. Beside the difficulties to interpret renal histology due to the variety of allograft lesions, there are no well-established options to prevent clinically severe disease recurrence nor the therapeutic approaches to the problem. The purpose of this review was mainly to underline that almost all primary and secondary glomerulonephritides represent a contraindication to transplantation. For the majority of patients with end-stage renal disease due to glomerulonephritis, transplantation still represents the treatment of choice.

B cell depletion: rituximab in glomerular disease and transplantation.

B cells play a central role in the pathogenesis of many autoimmune diseases. Selective targeting can be achieved with the use of the monoclonal antibody rituximab. In addition to being a drug for non-Hodgkin's lymphoma, rituximab is also an FDA-approved treatment for refractory rheumatoid arthritis and, since recently, ANCA vasculitis. It has shown efficacy in many autoimmune diseases. This review will discuss current evidence and the rationale of the use of rituximab in glomerular diseases, including randomized controlled trials. The focus will be on the use of rituximab in idiopathic membranous nephropathy, systemic lupus erythematosus and ANCA-associated vasculitis. The emerging role of rituximab in renal transplantation, where it seems to be important for the desensitization protocols for highly sensitized patients as well as for the preconditioning of ABO-incompatible recipients and the treatment of antibody-mediated rejection, will also be addressed.

Lupus nephritis and non-Hodgkin lymphoma simultaneously diagnosed in a patient on methimazole.

A 78 year old white male on methimazole due to Grave's thyroiditis presented with acute renal failure after a short term history of progressive shortness of breath, malaise, myalgias, arthralgias, and bilateral lower limb swelling. The abdomen was remarkable for splenomegaly and lower extremities for erythema nodosum. No peripheral lymphadenopathy was detected. Serum albumin was 1.7 g/dl and very high erythrocyte sedimentation rate. Urine sediment was very active with dysmorphic red blood cells and casts and significant proteinuria (6.6 grams/day). Serum complements were abnormally low and antinuclear and anti-DNA antibodies were positive. Renal histopathology revealed membranoproliferative glomerulonephritis, along with a full house pattern on IFF consistent with lupus nephritis. Bone marrow aspiration revealed a 40% infiltration by a lymphocyte population of small cells consistent with a B cell non-Hodgkin lymphoma. The patient was treated with methylprednisolone, cyclophosphamide and rituximab and acute dialysis. Over the following weeks the patient became dialysis independent and returned to his baseline GFR.

Advanced donor age alone is not a risk factor for graft survival in kidney transplantation.

BACKGROUND: The use of kidneys from elderly deceased donors has substantially increased organ supply, although it is associated with worse graft function and survival rates. The risk of kidneys from elderly donors as well as expanded criteria donors (ECDs) on kidney transplant outcome was investigated. PATIENTS AND METHODS: Seventy-five kidney transplants from ECDs over a 5-year period were reviewed retrospectively. Old age and increased donor risk variables were analyzed separately in relation to graft function and survival. RESULTS: Sixty-four of 75 (85.3%) recipients had functioning grafts 5 years posttransplant. The overall actuarial graft survivals from 1 to 5 years were 87.5%, 68.1%, 57.3%, 55.4%, and 47.3%, respectively. Early graft function gave 47 (62.7%) kidneys remarkable actuarial survivals of 100.0%, 88.3%, 75.8%, 75.8%, and 68.4% at 1 to 5 years posttransplant, and 28 (37.3%) kidneys had delayed graft function with substantially decreased actuarial survival rates, ranging from 66.7% to 23.2%. Kidneys from elderly donors had considerable actuarial graft survival rates of 100.0%, 83.3%, 76.9%, 76.9%, and 67.0% from 1 to 5 years, respectively; these were the best graft survival rates compared with kidneys from the other donor categories. The other donor risk variables when associated with advanced age of any had an adverse effect on recipient graft function and survival, but no single risk variable alone, or a combination of any two, showed any statistically significant variability. CONCLUSION: Elderly kidney donors provided a substantial organ pool expansion without affecting patient and graft survival in many patients. ECDs can be utilized safely if adequate measures are taken.

Long-term post transplant alloantibody monitoring: a single center experience.

Between 2000 and 2010, 4241 sera from 597 renal transplant (RTx) recipients were monitored for DSA development. The patients were selected in the absence of immunological memory to donor HLA before RTx and were divided into two groups: the historic group, consisting of patients transplanted before December 1996 and the study group, consisting of those transplanted after December 1996. Ninety-two out of 597 (15.4%) patients developed de novo DSA post-RTx, while 196 had third party anti-HLA antibodies. DSA were more frequent in the historic group compared with the study group (P < 0.001). Anti-HLA class-III DSA predominated in both groups (84.6% vs. 69.7%) and were directed preferentially against donor HLA-DQ (65/92,70.6%). Recipients of class II-incompatible grafts developed DSA more frequently than those receiving class II-compatible grafts (P = 0.003). DSA production was not different between pre-sensitized and non-sensitized patients (P = 0.842). DSA class I (HR = 31.78), DSA class II (HR = 20.92), and non-DSA (HR = 5.94) were the only independent predictors for graft failure. In conclusion, this study shows the results of long-term post-transplant alloantibody monitoring, and confirm the strong association of DSA and graft loss. Protocols that remove anti-HLA antibodies from RTx recipients may benefit allograft survival.

The value of transcranial Doppler sonography with a transorbital approach in the confirmation of cerebral circulatory arrest.

OBJECTIVE: Transcranial Doppler sonography (TCD) provides accurate confirmation of cerebral circulatory arrest (CCA) in brain death (BD), but is not feasible in patients with absent temporal bone windows. We added the transorbital approach in the TCD protocol for the diagnosis of CCA and compared findings with angiography. Furthermore, we evaluated whether reporting the angiographic and sonographic confirmation of CCA to relatives of brain-dead patients improves their comprehension and satisfaction with the medical information. PATIENTS AND METHODS: Eighty-two clinically brain-dead patients underwent 4-vessel angiography, TCD of the basilar and middle cerebral arteries, and transorbital Doppler sonography (TOD) of the internal carotid arteries. Relatives were randomly allocated to 41 in whom BD was presented as a clinical diagnosis (group A) and to 41 in whom BD was presented as a clinical diagnosis confirmed by TCD and angiography (group B). Comprehension and satisfaction of the relatives were assessed using an interview and a questionnaire. RESULTS: Both angiography and TCD verified CCA in all cases (k = 1). In 11 patients with failure of the transtemporal approach, CCA was confirmed by the transorbital recordings. The addition of TOD enabled 15.5% more cases of CCA to be diagnosed by TCD. Group B exhibited improved comprehension and satisfaction rates (P < .05). CONCLUSIONS: The addition of TOD increases the efficacy of TCD in confirming CCA in BD. Reporting confirmation of CCA to families of brain-dead patients may improve their comprehension and satisfaction with the provided medical information.

Evolution of Fabry disease in male patients: the Greek experience.

Fabry disease is a progressive metabolic disorder with a clinical course characterized by different phases and a variety of disease manifestations. The first symptoms generally appear in childhood or early adolescence and are followed by late life-threatening complications involving vascular, renal, cardiac, and cerebral systems. We report the clinical and biochemical characteristics of 16 male patients from 10 unrelated families who represent almost the entire cohort of known Fabry patients in Greece. Despite the presence of early symptoms in almost every patient (mean age at onset of symptoms 15.6 years), the diagnosis was delayed for a mean of about 18 years (mean age of diagnosis 36 years). Patients are currently monitored and the majority (15 out 16 patients) treated with Enzyme Replacement Therapy.

Mycophenolate mofetil as maintenance therapy in patients with vasculitis and renal involvement.

AIM: Cytotoxic drugs have reduced the mortality in patients with ANCA-associated vasculitis (AASV) but their use carries a substantial risk of toxicity. Efforts are made to switch from cytotoxic drugs to less toxic maintenance regimens. In this study we aimed to assess the efficacy of mycophenolate mofetil (MMF) as maintenance therapy in patients with AASV and renal involvement. METHODS: 22 patients with newly diagnosed AASV, microscopic polyangiitis (MPA) (n = 16), Wegener's granulomatosis (WG, n = 4), renal limited vasculitis (RLV, n = 1) and Churg-Strauss syndrome (CSS, n = 1) and renal involvement were followed for a median of 42 months (range 24 - 101). After 6 months of standard induction therapy, patients were switched to MMF monotherapy for 18 months. Renal parameters i.e. serum creatinine, proteinuria and urine sediment, BVAS scores and ANCA titers were assessed at baseline, after induction and after 18 months with MMF. RESULTS: After the end of induction, 3 of the 4 patients who were initially hemodialysis (HD) dependent, remained on HD and were withdrawn from further analysis. In the remaining 19 patients, the improvement in renal function (p < 0.001), hematuria (p = 0.011), proteinuria (p = 0.007) and BVAS scores (p < 0.001) after induction was sustained after 18 months maintenance with MMF and no patient relapsing during this period. Until the end of the follow up, 31.58% of patients relapsed, at a median of 21.5 months (range: 18 - 60). Side effects were transient and infrequent. CONCLUSION: In patients with AASV and renal involvement, MMF seems to be an effective and well tolerated option in sustaining short- and medium-term remission.