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.

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.

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.

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.

Kidney transplantation in lupus patients: a case-control study from a single centre.

This study was conducted to determine kidney transplantation (KTx) outcomes for Greek patients with renal failure caused by lupus nephritis (LN) compared with matched controls, kidney recipients with other causes of end-stage renal disease (ESRD). Twenty-six patients with systemic lupus erythematosus (SLE) subjected to 26 kidney transplants were studied. For comparative purposes a case-control group was selected, matched for gender, source of donor, age and time of KTx. Patient and graft survival estimates were calculated with the Kaplan-Meier product limit estimator and survival estimates were compared with the log-rank test. All patients received cyclosporine or tacrolimus in combination with azathioprine or mycophenolate mofetil for chronic immunosuppression in addition to steroids. Fourteen transplants were from living-related donors and 12 were from deceased donors. The graft survival rates for lupus patients were 88% at 1 year, 67% at 5 years, 38% at 10 years, poorer than the control survival rates of 92%, 92% and 84% (P=0.004). Patient survival in the lupus group did not differ from that of the controls. Survival in the lupus group was 92% at 1 year, 77% at 5 years and 77% at 10 years vs. 96%, 92% and 92% (P=0.26). Chronic allograft nephropathy was the major cause of graft loss. Recurrent LN was detected in two patients, but only one lead to graft failure. SLE patients compared with controls had significantly higher rates of hypertension, cardiovascular disease, infections and malignancies. Compared with matched controls, SLE patients had inferior but still satisfactory graft survival rates, whereas patient survival rates were similar.

Increased expression of the FoxP3 functional marker of regulatory T cells following B cell depletion with rituximab in patients with lupus nephritis.

B cell depletion may affect T cell activation and costimulation status in rituximab-treated patients with SLE. We examined whether rituximab administration in patients with active lupus nephritis is related to changes in mRNA expression of genes that define regulatory T cells (Tregs) in peripheral blood lymphocytes, measured by real-time PCR. At the early phase of B cell depletion mRNA levels of CD25, CTLA-4, GITR and the bona fide Treg functional marker FOXP3 increased significantly in all 7 patients examined. In contrast, mRNA levels of the costimulatory/activation T cell molecule CD40L were profoundly reduced, while mRNA levels of TGF-beta, a cytokine contributing to Treg induction, increased significantly in all. During follow-up, increased FOXP3 mRNA persisted in those patients in clinical remission, while in those patients with active disease subsequent decreases were noted. Further studies should examine whether modulation of Tregs by therapeutic B cell depletion contributes and/or predicts lupus disease remission.

Diabetic muscle infarction after kidney and pancreas transplantation: case report and literature review.

Diabetic muscle infarction (DMI) is a rare, long-term complication of poorly controlled diabetes (typically of type I). DMI was first described in 1965 and more than 100 cases have been reported thereafter in the English literature. Usually, there is a coexistence with concomitant nephropathy, neuropathy, and retinopathy. The etiology remains uncertain, but appears to be attributable to diabetic microangiopathy and hypercoagulability and is believed that hypoxia-reperfusion injury is involved. DMI presents with sudden onset of pain associated with a tender mass in the thigh in most instances. The diagnosis is based on magnetic resonance imaging, which is not specific but highly indicative. Treatment is conservative with relapses occurring in 50% of the patients, but not necessarily in the same muscle group. We describe a case of DMI that occurred 4 months after simultaneous kidney and pancreas transplantation in one patient with type I diabetes mellitus and end-stage renal disease.

A comparative randomised study of valacyclovir vs. oral ganciclovir for cytomegalovirus prophylaxis in renal transplant recipients.

An open, prospective, randomised study was conducted to compare the safety and efficacy of valacyclovir vs. oral ganciclovir for cytomegalovirus (CMV) prophylaxis in renal transplant recipients. Eighty-three renal transplant recipients were assigned randomly to receive valacyclovir (n=43) or oral ganciclovir (n=40) for the first 3 months after transplantation. Both groups were similar in terms of demographics, primary renal disease, graft source, HLA matching, immunosuppressive therapy and donor-recipient CMV antibody status. CMV infection was diagnosed by detection of virus DNA in plasma with the Amplicor CMV Test. CMV disease was observed in only one patient belonging to the ganciclovir group, who developed enterocolitis 6 months post-transplantation. No difference was observed between the two treatment groups with respect to detection of CMV DNA, virus infections other than CMV, acute rejection episodes, and serum creatinine levels at 3 and 6 months following transplantation. An increased number of bacterial infections was noted in the ganciclovir group (p 0.003). No adverse reactions with either treatment were reported. The estimated cost of valacyclovir treatment was 20% higher than that of ganciclovir treatment. Overall, both valacyclovir and oral ganciclovir were found to be effective and safe for CMV prophylaxis in renal transplant recipients. Decisions regarding prophylactic regimens should include additional criteria, such as cost or possible development of resistance.

Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial.

OBJECTIVE: Autoreactive B cells play a key role in tissue injury in systemic autoimmune disease, and therefore a treatment resulting in B cell depletion could have benefit. This open-label study was undertaken to evaluate the efficacy of the anti-CD20 monoclonal antibody rituximab in the treatment of lupus nephritis. METHODS: Lupus patients with active proliferative nephritis (4 with focal disease and 6 with diffuse disease) received rituximab (4 weekly infusions of 375 mg/m(2)) combined with oral prednisolone. Clinical, laboratory, and immunologic responses, including peripheral lymphocyte subsets measured by flow cytometry, were prospectively assessed at monthly intervals for 12 months. Complete remission of nephritis was defined as normal serum creatinine and albumin levels, inactive urine sediment, and 24-hour urinary protein <500 mg. Partial remission was defined as >50% improvement in all renal parameters that were abnormal at baseline. RESULTS: B cell depletion lasted from 1 month to 7 months and was well tolerated. Partial remission was achieved in 8 of 10 patients within a median of 2 months (range 1-4 months); in 5 of them, complete remission was subsequently established (at a median of 3 months from baseline), and it was sustained at 12 months in 4. As early as 1 month from baseline, the expression of the costimulatory molecule CD40 ligand on CD4+ T cells was decreased by 4-fold, and it was almost blocked when partial remission was clinically evident. The expression of T cell activation markers CD69 and HLA-DR was significantly decreased at time points when partial remission was observed, and was further decreased during complete remission. In contrast, in patients who did not exhibit a response or when relapse was detected in patients in whom an initial remission had been achieved, such decreases were not prominent. Serum concentrations of double-stranded DNA autoantibodies were decreased in all patients, regardless of clinical outcome. CONCLUSION: Following B cell depletion, clinical remission of lupus nephritis is associated with a decrease in T helper cell activation, suggesting an additional role for B cells, independent of autoantibody production, in promoting disease. A controlled trial to confirm these promising clinical results is warranted.

Cyclosporine levels at 2 hours after dose and body mass index in relation to graft function in renal transplant patients treated with azathioprine or mycophenolate mofetil.

The aim of this study was to evaluate the effect of C(2) levels on renal graft function in relation to body mass index (BMI). This retrospective study of 95 renal transplant patients included 53 on AZA and 42 on MMF at 3.1 years after transplantation. The cohort was divided into groups according to their C(2) levels, namely <600 ng/mL, 600 to 900 ng/mL, or >900 ng/mL, and according to BMI (>26 kg/m(2)). In every group, we evaluated the percentage of patients with an increase in creatinine by 1 mg/dL or >/=50% from the first year posttransplant. There was no difference in age, gender, graft source, and dose of corticosteroids or CsA between the groups. Patients on AZA with C(2) 600 to 900 ng/mL showed a lower prevalence of renal dysfunction (3.4%) than those with C(2) levels <600 ng/mL (14.3%) or >900 ng/mL (20%). Seventeen percent of the patients on AZA and 11.9% on MMF had BMI >26 kg/m(2) (P = NS). An increased serum creatinine was present in 22.2% of patients with BMI >26 kg/m(2) in the AZA group vs 20% in the cohort MMF (P = NS). These findings suggest that long-standing renal recipients on AZA with C(2) levels of between 600 and 900 ng/mL show better preservation of renal function. We did not identify differences on the basis of C(2) levels in MMF-treated recipients. The influence of BMI on long-term graft function seemed to be independent of AZA or MMF therapy.

Experience with conversion from Sandimmun to Neoral cyclosporine and the correlation of C2 levels with renal function.

Pharmacologic monitoring of the cyclosporine microemulsion Neoral is an important tool to improve the efficacy and to avoid toxicity of the drug. Recent trials have shown that the absorption profiling tools represented by the area under the time-concentration curve from 0 to 4 hours postdose and concentration 2 hours postdose (C2) levels are the best predictors of acute rejection in the early posttransplant period. Since similar data regarding maintenance immunosuppression are scarce, we report our experience on Neoral C2 monitoring in renal transplant recipients during the late posttransplant period. However, available data on optimal Neoral C2 levels in the late posttransplantation period are scant and have not been correlated with well-defined endpoints such as chronic allograft nephropathy.

Lupus nephritis: treatment with mycophenolate mofetil.

OBJECTIVE: To evaluate the safety and efficacy of mycophenolate mofetil (MMF) treatment in patients with lupus nephritis. METHODS: Eighteen patients with biopsy-proven lupus nephritis (17 females, one male; mean age 31.6 yr; mean lupus duration 92 months; mean duration of nephritis 57 months; nine with focal proliferative glomerulonephritis, three with diffuse proliferative glomerulonephritis, six with membranous nephropathy) were included. With five exceptions, all patients had been treated previously with cyclophosphamide and were selected because of either toxicity or inadequate clinical response to treatment. MMF was given at 2 g daily in combination with steroids for up to 31 months (mean 15.3 months). The side-effects of MMF were recorded and efficacy was assessed as the renal function profile. RESULTS: Complete remission was observed in 10/18 patients and another 4/18 went into partial remission. Both creatinine clearance and proteinuria were significantly improved during MMF treatment in patients with the proliferative forms of nephritis. MMF demonstrated a steroid-sparing effect in the whole population. Treatment failure was recorded in 4/18 patients, all with membranous nephropathy. Two patients developed gastrointestinal complaints and infectious meningitis occurred in one patient. CONCLUSION: MMF appears to be an efficacious and safe treatment in patients with proliferative forms of lupus nephritis who do not respond to or cannot tolerate conventional treatment. The efficacy of MMF in lupus membranous nephropathy remains unclear.

Beneficial effects of fluvastatin on progressive renal allograft dysfunction.

To assess the time-dependent changes in renal function in relation to antioxidant and lipid-lowering effects of fluvastatin in hyperlipidemic renal transplant recipients, 20 patients were treated with fluvastatin 40 mg/d for 12 months, after failure of a dietary program. Plasma malondialdehyde (MDA) levels and lipid profiles were evaluated in relation to serum creatinine and calculated creatinine clearances 18 months before and during the fluvastatin treatment. Mean baseline lipid values were: total cholesterol 318 mg/dL, triglycerides 212 mg/dL, LDL cholesterol 219 mg/dL, HDL cholesterol 58 mg/dL, apolipoprotein A 176 mg/dL, and apolipoprotein B 145 mg/dL. During 12 months of treatment, fluvastatin produced consistent and significant reductions in total and LDL cholesterol (-18.4% and -24.1%), triglycerides (-17.7%), and apolipoprotein B (-22.7%) as well as an increase in HDL cholesterol (12.3%) and apolipoprotein A (9.2%). Plasma MDA levels decreased by 41.8% (from 3.5 +/- 0.3 to 1.8 +/- 0.1 nmol/mL, P =.00002). Creatinine clearance, which had been declining at a rate of 0.32 mL/min/month during the previous 18 months before treatment, progressively improved during treatment, giving a positive slope of the creatinine clearance, which increased by 0.35 mL/min/month, (P =.016; 53.3 +/- 4.2 mL/min vs 49.8 +/- 4.1 mL/min pretreatment). Multiple linear regression analysis revealed that MDA was the parameter most closely associated with the variability in creatinine clearance. In conclusion, renal transplant patients with lipid abnormalities display renoprotective activity of fluvastatin, possibly due to its lipid-lowering and antioxidant effects.