Kidney Transplantation From Old Deceased Donors: Impact of Uric Acid Level-A Quarter-Century of Experience in One Transplant Center.

BACKGROUND: The long-term burden of higher donor age on graft function and survival after kidney transplantation remains uncertain. Because both recipient and donor characteristics have evolved and the general population age is on the increase, we looked at the causes of kidney graft outcome. AIM: The aim of this study was to evaluate the impact of different clinical parameters on long-term outcome of older-donor kidney transplantation. This retrospective study included 345 adult patients (58 patients received kidney from donors at least 55 years old) transplanted between January 1993 and December 2005 and were followed in one center throughout the post-transplant course (median, 9.4 years). Data included recipient and donor age, cold ischemia time, delayed graft function, panel reactive antibodies, HLA mismatch, time on dialysis, graft function at different time points, uric acid level, proteinuria, immunosuppression, and biopsy-proven rejection. RESULTS: Improvement of estimated glomerular filtration rate at 36 months after transplantation was a good prognostic factor for long-term kidney function. Higher donor age decreased the chance for improvement of kidney function by 2.8% per year of life (P = .0244). Hyperuricemia was found in 46% of the study population; estimated glomerular filtration rate less than 50 mL/min/1.72 m2 was associated with hyperuricaemia. A higher uric acid level was associated with inferior kidney function in recipient of older kidneys. Graft failure occurred late (median, 6.3 years post-transplantation) in 26 (44.8%) of older-donor recipients and in 87 (30.3%) of the remaining patients. CONCLUSIONS: Our results suggest an important association between older donor age and decreased allograft function in kidney recipients with elevated uric acid level. Recipients of older kidneys with normal uric acid level presented satisfactory outcomes.

Very Long-term Survival of the Transplanted Kidney-Characteristics of Recipients.

BACKGROUND: After kidney transplantation (KTx), donor- and recipient-dependent factors, as well as the immunosuppression protocol, may have an impact long-term graft function. The aim of this retrospective study was to identify and describe recipients from a single center who had their transplanted kidney survive for more than 20 years. METHODS: The database of KTx recipients was searched to find identify patients with a functioning kidney graft for >20 years. Clinical, demographic, and immunologic data were recorded and analyzed. Moreover, the Charlson Comorbidity Index was calculated. RESULTS: We identified 25 patients, with graft survival of 23.9 ± 3.2 years (maximum, 31.5 years), with following characteristics: age at time of transplantation 36.2 ± 11.9 years; median of 4 human leukocyte antigen (HLA) mismatches; low risk of rejection (panel-reactive antibodies [PRA] 0%); and 14 recipients had delayed graft function (DGF) and 9 had a single episode of acute rejection successfully treated with steroid pulses. In 24 cases there was a deceased donor. There was a predominance of males aged <54 years. At 1 year after KTx, serum creatinine was 1.36 ± 0.26 mg/dL. All recipients were given cyclosporine + azathioprine + prednisone as primary immunosuppression. The majority of recipients have continued to visit the clinic on an oupatient basis, with a most recent creatinine average of 1.5 ± 0.82 mg/dL. CONCLUSION: Very long-term kidney graft survival is most likely associated with a low risk of rejection (0% PRA pre-KTx), a relatively weak immunosuppression protocol, and optimal function at 12 months post-KTx.

B Cell Activating Factor (BAFF) in Long-term Kidney Transplant Recipients Is Not a Prognostic Marker for Allograft Dysfunction or Survival.

OBJECTIVE: B cell activating factor (BAFF) has been shown to play a role in B cell survival, maturation, and activation, and has been linked with renal transplant outcome. BAFF signaling has been associated with plasmablast survival, anti-HLA immunization, and loss of graft function. We aimed to analyze the interplay between BAFF, memory B cells, and plasmablasts in relation to allograft function in long-term kidney transplant (KTx) recipients and their anti-HLA sensitization. MATERIALS AND METHODS: This study included 70 long-term KTx recipients on standard immunosuppression 15 ± 6 years post transplantation (44 stable, 26 chronic allograft dysfunction, CAD) and 25 healthy volunteers. CD19+ B cells, memory B cells (CD19+CD27+), and plasmablasts (CD19+CD24-CD27++CD38++) were enumerated with flow cytometry. BAFF serum level and anti-HLA antibodies were assessed by Luminex bead arrays. RESULTS: We found no difference in BAFF levels between KTx recipients and controls (median, interquartile range: 1.67, 1.40-1.97 vs 1.78, 1.63-1.93 ng/mL, P = .478) and no correlation between BAFF level and cell counts. Recipients presented lower plasmablast count than controls (22.5, 8-57 vs 79, 48-166 cells/mL, P < .001). There was a positive correlation between estimated glomerular filtration rate and plasmablasts (rs = 0.30, P = .013) in recipients. Cell populations and BAFF were not related to the presence of anti-HLA antibodies. None of the parameters investigated was related to deterioration of allograft function during the 2-year follow-up. CONCLUSION: BAFF serum level is not related to anti-HLA sensitization, circulating memory B cells, plasmablast count, or allograft function. Circulating plasmablasts are associated with current allograft function but are not prognostic for future course.

Lowering of Messenger Ribonucleic Acid Toll-Like Receptors 2-4,9 in Peripheral Blood Mononuclear Cells in Kidney Allograft Recipients, Relationships With Immunosuppressive Treatment, and Delayed Graft Function Occurrence.

BACKGROUND: Both tacrolimus (Tac) and cyclosporine (CsA) inhibit control peripheral blood mononuclear cells (PBMC) after stimulation of various Toll-like receptors (TLR) at supra-pharmacological concentrations. Earlier studies demonstrated that 24 hours after kidney transplantation (KT), the expression of the TLR4 messenger RNA (mRNA) in PBMC from patients with subsequent delayed graft function (DGF+) was lower than in patients without DGF (DGF-). An assessment was made of the interaction of immunosuppression with TLR mRNA in PBMC and to verify whether the reduced expression of TLR-2,3,4,9 mRNA in PBMC is permanent in DGF+. METHODS: We investigated mRNA expression of TLR in non-stimulated PBMC. All patients were transplanted more than 1 month before PBMC acquisition. Patients were divided into groups with respect to positive or negative history of delayed graft function (DGF+/-). RESULTS: The expression of TLR2, TLR3, and TLR9 in patients was lower than that in the control group. We found an association of Tac C0 with expression of TLR4 only and CsA dose per 1 kg body weight with TLR2 or up to 6 months after KT with TLR9. Mofetil mycophenolate (MMF)contributed to the change of TLR4 expression in the CsA group but not in the Tac group. TLR3 and TLR9 were nearly equally sensitive to both Tac and CsA, with a decrease of expression with respect to control. DGF+ was associated with variable degree of reduction of TLR2, TLR3, TLR4, and TLR 9 expression. CONCLUSIONS: We showed the importance of immunosuppression and delayed graft function as factors that modify the overall expression of mRNA-TLR PBMC for a period of time after KT. Patients with a history of DGF have chronically decreased expression of mRNA TLR2, TLR3, TLR4, and TLR9. This fact is associated with poorer graft function. Measuring the expression of the TLR in the upper range of therapeutic doses of calcineurin inhibitors and MMF gives the opportunity to assess the strength, effectiveness, and toxicity of immunosuppression.

Effect of Immunosuppressive Treatment on Carotid Atherosclerosis in Renal Transplant Recipients.

BACKGROUND: The aim of this study was to compare the effect of immunosuppressive regimens using either mammalian target of rapamycin inhibitors (mTORi) or calcineurin inhibitors (CNI) on the risk of atherosclerosis in renal transplant patients. MATERIALS AND METHODS: The study involved a group of 24 recipients treated with mTORi (mTORi group) and a group of 20 recipients treated with immunosuppressive regimen based on CNI (CNI group). Laboratory and clinical markers of cardiovascular risk in both groups were investigated. Carotid atherosclerosis was evaluated by measurement of the intima media thickness (IMT) of the common and internal carotid artery walls and detection of carotid plaques by a high-resolution ultrasonography. The study was performed 3-24 years after transplantation. RESULTS: The mTORi group showed higher level of total cholesterol (242 vs 201 mg/dL; P < .004), low-density lipoprotein cholesterol (140 vs 116 mg/dL; P < .05), and triglycerides (226 vs 168 mg/dL; P < .01). Posttransplant diabetes developed in 34% of mTORi group compared with 25% in the CNI group. The mean of IMT (left and right) of common and internal carotid arteries was similar in both groups. Carotid plaques were detected in 46% of patients from the mTORi group and 25% from CNI group (P < .02). The presence of carotid plaques combined with an IMT of >0.9 mm were associated with male gender, mTORi treatment (P = .03), and cardiovascular events. The incidence of coronary heart disease was higher in mTORi group than in CNI group (53% vs 20%; P = .03). CONCLUSIONS: There was not beneficial effect of immunosuppressive treatment with mTORi on carotid atherosclerosis in renal transplant patients.

Prevalence of Left Ventricular Hypertrophy and Left Ventricular Dysfunction in Older Renal Transplant Recipients.

OBJECTIVE: Left ventricular hypertrophy (LVH) is a risk factor for premature cardiovascular morbidity and mortality in chronic kidney disease. The aim of the study was to determine echocardiographic evaluation morphology and function of the left ventricle in older renal transplantation patients. MATERIAL AND METHODS: We retrospectively analyzed clinical data of renal transplant recipients who underwent routine echocardiography. We compared the data from 38 patients who were older than 65 years with 49 patients who were a mean age of 47.8 ± 12 years (control group). RESULTS: At the time of cardiac evaluation, most patients were in stage 3 chronic kidney disease. In the older group of patients, the incidence of obesity and diabetes were significantly higher than in the control group. Also in the older patients, the serum level of albumin was lower (P < .001), and brain natriuretic peptide was higher (P = .046). The incidence of coronary heart disease, chronic heart failure, and atrial fibrillation were higher in the older patients (P = .011). LVH was common in older as well as younger patients (97.4% vs. 88.8%, P = .17). Left ventricle mass index ranged from 90.4 g/m(2) to 235.5 g/m(2) among examined kidney transplantation patients. In older patients, left ventricular mass index was 160.7 ± 34.5 g/m(2) compared to 141.8 ± 29.8 g/m(2) in younger patients (P = .008). Reduced ejection fraction was found only in 2 of 38 (5.3%) older patients. Diastolic dysfunction of left ventricle was present in 34 of 38 (89.5%) patients >65 years old and in 24 of 49 (49.9%) younger patients (P < .001). CONCLUSIONS: LVH and left ventricular dysfunction are more pronounced among older patients. Impaired renal function, proteinuria, diabetes, and severity of hypertension are the most important factors predisposing to LVH.

Renal Artery Denervation in Patient After Heart and Kidney Transplantation With Refractory Hypertension.

We describe the case of a 54-year-old patient after renal and heart transplantation in whom uncontrolled hypertension was diagnosed. Despite combined antihypertensive therapy, no significant therapeutic effect was achieved. Clinical assessment of ambulatory blood pressure monitoring (ABPM) revealed the ineffectiveness of a bisoprolol, nitrendypin, klonidyn, ramipryl, furosemide, and doxasosine combination used at high doses. High blood pressure levels with their effect on a hypertrophic transplanted heart (left ventricular mass 254 g) and poor renal graft function (39 mL/kg/min) posed an extremely high risk of future cardiovascular complications, and were the reason to perform a native renal arteries denervation. The procedure was carried out through the right femoral artery with the use of a 6F guiding catheter. During a 1-year observation, significant decreases in ABPM systolic and diastolic blood pressures were observed after the procedure (168/88 mm Hg vs 154/77 mm Hg, respectively). Moreover a significant regression of left ventricular mass (215 g/m(2)) and stable renal graft function were noted. The presented case shows that native renal arteries denervation may be successful and safe in kidney and heart transplant recipients. Moreover, during the 1-year follow-up, the reduction in blood pressure was followed by a reduction in transplanted heart hypertrophy, both leading to regression of cardiovascular risk for the patient.

Progressive outer retinal necrosis in immunocompromised kidney allograft recipient.

Ocular complications in patients who underwent renal transplantation are attributed to side effects of the immunosuppressive regimen. Progressive outer retinal necrosis (PORN) syndrome is a clinical variant of necrotizing herpetic retinopathy and it occurs almost exclusively in patients with acquired immunodeficiency syndrome. We present a case of a human immunodeficiency virus-negative patient who underwent renal transplant and, after a few years, developed bilateral PORN associated with viral infections. Varicella zoster virus (VZV) and BK virus were identified by polymerase chain reaction from the vitreous fluid. It is unclear which of the viruses identified had the dominant role in the pathogenesis of PORN and other organ damage, or whether their actions were synergistic. Adequate antiviral immune surveillance, as well as pre-transplant vaccination against VZV, may reduce the incidence of VZV infection and its complications.

A significant role for anti-human leukocyte antigen antibodies and antibody-mediated rejection in the biopsy-for-cause population.

The role of anti-human leukocyte antigen (HLA) antibodies and antibody-mediated rejection is well known, but our comprehension and the preventive measures we take seem to be insufficient. One of the major causes of premature renal transplant loss is recepients' immunologic hyperactivity to donors' antigens. Monitoring of humoral alloreactivity gives hope for early diagnosis and adequate therapy. The goal of our analysis was the assessment of the influence of anti-HLA antibodies on the function and survival of transplants. In our study we included 60 consecutive renal transplant recipients who had a renal transplant biopsy-for-cause performed due to insufficiency. Transplant biopsies were performed between the 7th day and 12th year (median, 2 years) after transplantation. Anti-HLA antibodies were present in 20 patients (33%). The patients were divided into 2 groups according the presence of anti-HLA antibodies. In a 12-month observation, 10/20 (50%) patients in the anti-HLA(+) group returned to dialysis in contrast with 7/40 (17.5%; P = .014) in the anti-HLA(-) group. Also, 8/10 (80%) of the anti-HLA(+) patients who lost the transplant had anti-HLA Abs class II and only 2/10 (20%) had anti-HLA Abs class I. Anti-HLA antibodies were specific to a donor (donor-specific antibodies [DSA]) in 8/10 (80%) of the patients who lost the transplant. Anti-HLA antibodies appeared de novo in 50% of patients who lost the transplant. Nonadherence was suspected in 50% of patients. Acute humoral rejection occurred in 1 patient. Also, 8/10 (90%) developed chronic active humoral rejection. Our study revealed that graft loss in the renal transplant biopsy-for-cause population with the presence of anti-HLA Abs during a 12-month observation reached 50%. Nonadherence in these patients was very high and amounted to 50%. Monitoring of renal transplant recipients and individualization of therapy considering humoral activity should prolong renal graft survival.

Non-HLA antibodies: angiotensin II type 1 receptor (anti-AT1R) and endothelin-1 type A receptor (anti-ETAR) are associated with renal allograft injury and graft loss.

INTRODUCTION: Non-HLA antibodies specific for angiotensin II type 1 receptor (anti-AT1R) and endothelin-1 type A receptor (anti-ETAR) of vascular cells activate signaling pathways leading to cell proliferation and vascular injury. The aim of this study was to evaluate the impact of non-HLA antibodies on kidney allograft morphology and function in patients who underwent a kidney biopsy due to renal function impairment. PATIENTS AND METHODS: The study included 65 consecutive renal transplant patients who were evaluated for the presence of non-HLA and anti-HLA antibodies at the time of transplant biopsy. Results of pre-transplant CDC cross-match were negative. A kidney allograft biopsy was performed between 6 days and 13 years (42 ± 49 months) after transplantation, and the diagnosis was made on the basis of the Banff criteria. The level >9 U/L of anti-AT1R and anti-ETAR antibodies was considered high. RESULTS: A high level of non-HLA antibodies (anti-AT1R and/or anti-ETAR) was found in 7 (10.7%) of 65 patients at the time of biopsy. Graft loss in the non-HLA-positive patients was significantly higher (71% in non-HLA-positive cases after 7.8 ± 2.6 months vs 11% after 6 months in non-HLA-negative cases [P = .00099]). In these non-HLA-positive patients, the mean anti-AT1R level was 15.3 ± 9.4 U/L and the mean anti-ETAR level was 13.8 ± 8.6 U/L. In only 2 of these patients were anti-HLA antibodies additionally detected: anti-class I in 1 and anti-class II in both patients. The mean serum creatinine level was 2.34 ± 0.6 mg/dL at the time of biopsy. Results of an early biopsy revealed acute vascular rejection (Banff grade IIB). Chronic allograft injury was found (grading cg1-3, cv1-2, ci1-2, ct1-2) in the remaining 6 patients. C4d was present in 3 of 7 patients. CONCLUSIONS: High levels of anti-AT1R and/or anti-ETAR antibodies were associated with morphological and functional allograft injury and graft loss in these study patients. Non-HLA antibodies can be helpful in assessing the risk of graft failure.

Increased plasma matrix metalloproteinase-2 (MMP-2), tissue inhibitor of proteinase-1 (TIMP-1), TIMP-2, and urine MMP-2 concentrations correlate with proteinuria in renal transplant recipients.

BACKGROUND: The most frequent cause of kidney allograft loss is chronic allograft injury, often with proteinuria as the clinical feature. Occurrence of proteinuria late after kidney transplantation is associated with worse graft function and patient survival. AIM: The aim of the study was to assess plasma and urine matrix metalloproteinases (MMP-2 and MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in proteinuric renal transplant recipients (RTRs). The factors were determined by enzyme-linked immunosorbent assay in 150 RTRs (51 women and 99 men), aged 49.2 ± 11.5 years, at mean 73.4 ± 41.2 months after kidney transplantation (range: 12 to 240 months). RESULTS: Proteinuric RTRs compared with non-proteinuric RTRs had higher median plasma MMP-2 (P = .012), TIMP-1 (P = .0003), and TIMP-2 (P = .0021) concentrations, as well as higher urine MMP-2 (P < .0001) excretion. The presence of proteinuria had no impact on plasma MMP-9 and urine MMP-9, TIMP-1, and TIMP-2. Proteinuria and estimated daily proteinuria (uPr:uCr) correlated positively with plasma MMP-2 (rs = 0.226, P = .0054 and rs = 0.241, P = .003), TIMP-1 (rs = 0.305, P = .00015 and rs = 0.323, P = .000055), TIMP-2 (rs = 0.273, P = .0007 and rs = 0.269, P = .001) and urine MMP-2 (rs = 0.464, P < .0001 and rs = 0.487, P < .0001), respectively. Proteinuric RTRs had impaired graft function with higher median serum creatinine concentrations (1.91 [1.60-2.43] mg/dL versus 1.41 [1.20-1.65] mg/dL, P < .00001) and lower estimated glomerular filtration rate (36 [28-45] mL/min/1.73 m(2) versus 53 [43-61] mL/min/1.73 m(2), P < .00001) than RTRs without proteinuria. CONCLUSIONS: Our research revealed that in RTRs, proteinuria was significantly associated with increased concentrations of enzymes involved in extracellular matrix (ECM) degradation: plasma MMP-2, TIMP-1, TIMP-2, and urine MMP-2. Findings strongly emphasize increased plasma TIMPs in proteinuric RTRs that inhibit degradation of ECM by MMPs and favor excessive deposition of ECM proteins.

Advanced age of renal transplant recipients correlates with increased plasma concentrations of interleukin-6, chemokine ligand 2 (CCL2), and matrix metalloproteinase 2, and urine concentrations of CCL2 and tissue inhibitor of metalloproteinase 1.

BACKGROUND: Advanced age of renal transplant recipients (RTRs) has a negative impact on kidney allograft survival through impaired extracellular matrix degradation by the matrix metalloproteinases/tissue inhibitors of metalloproteinases (MMPs/TIMPs) system. Moreover, older RTRs are at risk of smoldering inflammation, known as inflammaging. AIM: The aim of the study was to assess the impact of a RTR's age on plasma and urine concentrations of interleukin 6 (IL-6), chemokine ligand 2 (CCL2), and the MMPs/TIMPs system. MATERIAL AND METHODS: One hundred fifty adult RTRs (8.7% ≥ 65 years) and 37 adult healthy volunteers (10.8% ≥ 65 years) were enrolled in the study. The studied factors (IL-6, CCL2, MMP-2, MMP-9, TIMP-1 and TIMP-2) were quantified in plasma and urine with enzyme-linked immunosorbent assay. The Mann-Whitney U test and Spearman's (rs) rank correlation were applied, and differences with a P < .05 were considered statistically significant. RESULTS: There was a weak but significant positive correlation between increasing RTR's age and plasma IL-6 (rs = 0.18, P = .028), CCL2 (rs = 0.27, P = .001), and MMP-2 (rs = 0.20, P = .017), as well as urine CCL2 (rs = 0.16, P = 0.050) and TIMP-1 (rs = 0.20, P = .014) concentrations. CONCLUSIONS: Advancing age of RTRs correlates with increasing plasma IL-6 and CCL2 concentrations, reflecting smoldering inflammation (known as inflammaging) and alterations in MMPs/TIMPs profiles, especially with increased plasma MMP-2 and urine TIMP-1 concentrations.

Chronic allograft dysfunction in kidney transplant recipients: long-term single-center study.

OBJECTIVE: The aim of this study was to determine the prevalence and risk factors responsible for the occurrence and progression of chronic allograft dysfunction (CAD) among patients treated in our transplant center. MATERIAL AND METHODS: Retrospective analysis included 637 kidney allograft recipients transplanted between 1990 and 2003 with functioning graft for at least 1 year. CAD was diagnosed based on increased creatinine concentration ≥ 2 mg/dL, occurrence of proteinuria, and worsening of arterial hypertension. In immunosuppressive treatment, 50% of patients received cyclosporine A (CsA), azathioprine, and prednisone; 25% received CsA, mycophenolate mofetil (MMF), and prednisone; whereas 20% received tacrolimus, MMF, and prednisone. The influence of immune and non-immune factors before and after transplantation on the occurrence and progression of CAD was analyzed. RESULTS: CAD was diagnosed in 43.1% of patients within 10 years after kidney transplantation. CAD development considerably worsened the actual 10-year survival rate of patients (80% versus 92%) and the graft (42% versus 92%). The following factors had the greatest influence (as confirmed with multivariate regression analysis) on CAD progression: proteinuria (odds ratio [OR]: 11.3; P < .0001), serum creatinine concentration > 1.5 mg/dL at 12th month (OR: 3.5; P < .0001) and 24th month (OR: 6.69; P < .0001), cytomegalovirus (CMV) infections (OR: 3.15; P < .0001), and male gender of recipients (OR: 1.48; P < .04). In the CAD patients, acute rejection episodes, delayed graft function, urinary tract infections, and hepatitis C virus (HCV) infections were statistically significantly more often observed compared with the group of patients with stable renal function (reference group). Moreover, in the CAD group, donors were older and recipients younger. The CAD patients had higher arterial pressure and uric acid concentration. CONCLUSIONS: During the 10-year follow-up, chronic renal allograft dysfunction developed in 43.1% of patients. Proteinuria, serum creatinine level >1.5 mg/dL at 12th and 24th month, and CMV infections were identified as the most significant CAD progression factors. CAD had detrimental effects both on graft and patient survival rates.

Impaired kidney allograft: how long can it function? A single-center study of the transplantation population.

Impaired renal graft function is a matter of particular concern during post-transplantation care because low estimated glomerular filtration rate (eGFR) is a risk factor for graft loss. The aim of the study was to assess risk factors for inferior outcomes of kidney transplantations with low eGFRs. We identified 72 patients who underwent transplantation between 1999 and 2005 who had chronic renal graft dysfunction after 6 months post-transplantation (eGFR < 40 mL/min/1.73 m(2)), received a kidney transplant between 1999 and 2005, and were treated in one center through the entire post-transplantation course. Three patients who were lost for follow up after 6.4, 6.7, and 8.5 years are not included in this analysis. A group of 23 patients (33%) had chronic kidney disease stage 4 (eGFR < 30 mL/min/1.73 m(2)) at 6 months. In 39 patients (56%), delayed graft function was diagnosed. Forty-eight patients (70%) had at least one episode of acute graft rejection. Results were confirmed using biopsy in 39 patients. Eight patients (12%) died and 35 patients (51%) lost their grafts between 1.6 and 14 years (median, 6.3 years). The remaining 26 (38%) patients have still functioning allografts 11 years after transplantation (median). The initial immunosuppression included calcineurin inhibitor (CNI) in all cases. At the end of study, 6 (8.3%) patients received mammalian target of rapamycin inhibitor plus steroids, whereas the remaining were treated with CNIs. Improvement of kidney function by 15% was observed in 23% of the studied population between 6 and 24 months. This satisfactory outcome was a result of the careful follow-up examinations and comprehensive medical care provided by our dedicated staff of nurses and physicians. Improvement of kidney function may reflect a state of immune quiescence in some patients which allows them to sustain a functioning kidney despite injury.

Significant infections after hand transplantation in a Polish population.

The study was conducted to assess serious infectious complications in five hand allograft recipients (four males, one female, age 40 ± 10 years), transplanted between 2006 and 2010. All donors and recipients were positive but one for cytomegalovirus (CMV) immunoglobulin G. All recipients received immunosuppressive therapy basiliximab, tacrolimus, mycophenolate mofetil and methylprednisolone. Until May 2013, there were four cases of severe infections requiring hospitalization. One patient developed CMV infection on the 28th postoperative day. Despite therapy with ganciclovir and prophylaxis with valganciclovir, reinfection episodes occurred both 4 weeks and 7 months later. The female recipient developed CMV infection 8 months after hand transplantation. After 3 weeks of ganciclovir treatment, the polymerase chain reaction results remained negative. We found that the CD4/CD8 T lymphocytes ratio differs in those two patients who had developed CMV disease in the past in comparison to the three remaining hand transplant recipients (mean 0.46 versus 1.7, respectively). Moreover, the ratio of patients who were CD4-8 negative to total T lymphocytes in CMV recovered patients was two-fold higher compared to the remaining recipients (10.0 versus 4.4, respectively). The female recipient was also hospitalized because of acute tonsillitis 25 months after hand transplantation, and successfully treated with amoxicillin clavulanate. The third recipient was hospitalized because of severe acute pain involving right lower limb, especially foot, 74 months after hand transplantation. After 48 hours, a painful vesicular rash occurred on the plantar as well as dorsal surface of right foot and herpes zoster was diagnosed. Immunosuppressive therapy after hand transplantation may be complicated by serious infections. CMV disease was associated with persistent alterations in T lymphocyte subsets.

Impact of immunosuppressive treatment on the cardiovascular system in patients after hand transplantation.

BACKGROUND: Cardiovascular disease is a major cause of mortality in solid organ allograft recipients. Hand transplantation is not a lifesaving procedure, thus the effect of long-term immunosuppression on the cardiovascular system in these patients should be monitored. The aim of this study was to evaluate the morphology and function of heart and blood vessels in patients after hand transplantation. METHODS: The study included 5 patients at ages 32 to 58 years, mean 39 years, who underwent hand transplantation between 2006 and 2010. Immunosuppressive treatment included basiliximab in induction and tacrolimus, mycophenolate mofetil, and prednisone. Cardiac status was assessed by echocardiography (according to the American Society of Echocardiography) and cardiac biomarkers. Blood vessels were estimated by carotid intima-media thickness, pulse wave velocity, and brachial artery flow-mediated dilatation (FMD). The examinations were performed at 28 to 79 (mean 43) months after transplantation. RESULTS: Cardiovascular risk factors were observed in all patients after transplantation: 2 had insulin-dependent diabetes, 3 developed dyslipidemia and hypertension, 2 had chronic kidney disease stage 3. Concentric left ventricular hypertrophy was found in 1 and ventricular concentric remodeling in 4 patients. Impaired diastolic function (E/e' > 8) was observed in 2 patients. The index volume of the left atrium was higher in all patients. The cardiac biomarkers N-terminal pro-brain natriuretic peptide, C-reactive protein, and troponins were within normal range. Carotid intima-media thickness was higher in 1 patient and normal in 4 patients. Arterial stiffness measured by pulse wave velocity was not increased in all patients. Native brachial artery FMD response, an index of endothelium-dependent function, was abnormal in 2 patients, but in the transplanted extremity FMD was abnormal in 4 patients. CONCLUSIONS: Pathologic changes in cardiac structures were found in all patients, but the arterial wall changes and endothelial dysfunction were observed in some patients. Patients after hand transplantation are at higher risk for cardiovascular disease.

The impact of de novo donor-specific anti-human leukocyte antigen antibodies on 5-year renal transplant outcome.

Numerous studies have shown that circulating donor-specific antibodies targeting human leukocyte antigen (HLA) are associated with accelerated renal transplant failure, but many patients with these antibodies have good graft function. The aim of our study was to investigate the long-term graft function and survival in patients with de novo post-transplant donor-specific anti-HLA antibodies (DSA). Our prospective study included 78 consecutive recipients with a negative crossmatch before transplantation. Recipient serum samples were assayed for DSA in week 2 and 1, 3, 6, 9, 12 months after transplantation using a complement-dependent lymphocytotoxic technique with donor lymphocytes. Additionally, patients with DSA and stable renal function in the first year were tested with a more sensitive flow-panel-reactive antibody. DSA were present in 34 (44%) of our patients during the first 12 months after transplantation. Biopsy-proved acute rejection occurred in 11 DSA-positive and 10 DSA-negative patients. Seven DSA-positive patients had antibody-mediated rejection and no DSA-negative ones developed humoral rejection. The serum creatinine level in DSA-positive patients was significantly higher (2.48 vs 1.43 mg/dL) in year 5. The 13 (38%) DSA-positive patients with good graft function in month 12 were stable during a 5-year follow-up: their serum creatinine was 1.46 ± 0.4 in year 1 and 1.56 ± 0.4 mg/dL in year 5 and nobody lost their allograft. One- and 5- year graft survivals were appropriately 85% and 59% in DSA-positive patients compared to 93% and 93% in DSA-negative patients. To sum up, post-transplant DSA had a significant influence on kidney function and graft survival but in 38% of patients the presence of DSA did not decrease a 5-year renal function. A good renal allograft function in the presence of DSA in the first year after transplantation and cessation of their production in the subsequent years may be a good prognostic marker for a long-term allograft function and survival.

Increased plasma tissue inhibitors of metalloproteinase concentrations as negative predictors associated with deterioration of kidney allograft function upon long-term observation.

Chronic allograft injury (CAI) is the most frequent cause of progressive kidney allograft impairment and eventual loss, which is due to interstitial fibrosis and tubular atrophy (IF/TA). Mechanisms of CAI are not fully understood. Chemokines, cytokines, metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) play roles in fibrosis development. The aims of this study were to evaluate plasma and urine TIMPs (TIMP-1 and TIMP-2), MMPs (MMP-2 and MMP-9), proinflammatory interleukin-6 (IL-6), chemokine (C-C motif) ligand 2 (CCL2 chemokines previously known as monocyte chemoattractant protein-1 [MCP-1]) among 150 recipients beyond 1 year post-renal transplantations and to explore the usefulness of these potential biomarkers of ongoing allograft injury. Renal transplant recipients compared with healthy volunteers (control group) showed significantly increased plasma and urine IL-6, MMP-9, TIMP-1, and TIMP-2, as well as lower plasma MMP-2 and urine CCL2 concentrations. Compared with recipients showing good function those with impairments displayed higher plasma TIMP-1 (P < .001) and TIMP-2 (P = .003) concentrations. The recipient estimated glomerular filtration rate (eGFR) values negatively correlated with plasma TIMP-1 and TIMP-2 levels (r = -0.43; P < .0001 and rs = -0.42; P < .0001, respectively) and with urine IL-6 excretion (rs = -0.33; P < .0001). Multivariate and receiver operating characteristic (ROC) analyses showed TIMP-1 plasma level assessments to be useful estimates of allograft injury.

Long-term follow-up of non-HLA and anti-HLA antibodies: incidence and importance in renal transplantation.

BACKGROUND: Detection of antibody-mediated injury is becoming increasingly important in post-transplant patient care. The role of donor-specific anti-human leukocyte antigen (HLA) antibodies in kidney transplant damage is known, whereas the significance of non-HLA antibodies remains an unresolved concern. The aim of the study was to determine the presence and influence on renal function of non-HLA and anti-HLA antibodies in stable patients at 5 years after kidney transplantation. METHODS: We evaluated the antibodies in 35 consecutive patients with stable renal function at 5 years after transplantation. RESULTS: Pretransplant screening for donor-specific antibodies by CDC cross-matches was negative in all patients. Anti-endothelial cell antibodies (AECA), anti-angiotensin II type 1 receptor antibodies (anti-AT1R), and anti-endothelin receptor antibodies (anti-ETAR) were assayed as non-HLA antibodies. Non-HLA antibodies were observed in 12 (34%) patients, including AECA (n = 5; 14%), anti- AT1R (n = 6; 17%), anti-ETAR (n = 4; 11%), and both anti-AT1R and anti-ETAR (n = 3). Among 13 (37%) patients with anti-HLA antibodies, 7 also had both non-HLA antibodies: AECA (n = 1), anti-AT1R (n = 3), and anti-ETAR (n = 3). The antibody-negative group (n = 13) showed significantly better renal function than the antibody-positive group (non-HLA and/or anti-HLA; n = 22). Biopsy-proven acute rejection had occurred in 2 of 13 (15%) antibody-negative versus 8 of 22 (36%) antibody-positive patients. These preliminary data revealed an high prevalence of autoantibody and alloantibody production among stable patients at 5 years after kidney transplantation. CONCLUSION: Simultaneous production of these antibodies and their association with reduced renal function suggests that active humoral immune responses are poorly controlled by immunosuppression.

Effect of reduced sympathetic hyperactivity on cardiovascular risk factors in kidney transplantation patients.

BACKGROUND: Hyperactivity of the sympathetic nervous system caused by chronic kidney disease has detrimental effects on hypertension and cardiovascular morbidity. Kidney transplantation does not ameliorate sympathetic nerve overactivity; however, bilateral nephrectomy eliminates it. The aim of the study was to evaluate the effect of bilateral nephrectomy on risk factors for cardiovascular morbidity and mortality in long-term follow-up. MATERIAL AND METHODS: We studied 24 kidney recipients aged 44 ± 13 years who had undergone native bilateral nephrectomy. The control group included 17 recipients with preserved native kidneys who were matched for age, gender, cause of end-stage renal disease, immunosuppressive treatment, and time after transplantation. The mean follow-up after transplantation was 103 months. We evaluated arterial blood pressure, pulse pressure, metabolic markers, allograft function, echocardiography, and cardiac morbidity in all patients throughout follow-up. RESULTS: Systolic and diastolic blood pressures, number of antihypertensive drugs, and pulse pressure (a marker of arterial stiffness), were significantly lower among the study versus the control group (P < .05). The left ventricular mass, left ventricular mass index, left ventricular posterior wall thickness, and interventricular septum thickness were also lower in the study than in the control group (P < .05). Cardiac morbidity, including ischemic heart disease, atrial fibrillation, heart failure and stroke, occurred in 4 (16%) study group and 6 (35%) control subjects. Metabolic disorders, namely, new onset diabetes after transplantation, hyperuricemia, and dyslipidemia, occurred with similar frequencies in both groups. Serum levels of creatinine and estimated glomerular filtration rates were comparable in both groups, remaining stable throughout the observation time. CONCLUSIONS: Reduction of sympathetic hyperactivity by nephrectomy improved blood pressure control as well as decreased arterial stiffness and left ventricular hypertrophy over long-term follow-up. These results support native renal denervation to prevent the harmful effects of sympathetic hyperactivity on the cardiovascular system of renal transplant recipients.