Vitamin D Concentration in Patients After Heart and Kidney Transplantation

Background

One of the main actions of vitamin D is bone mineralization regulation. Vitamin D is linked also to hypertension, diabetes, and cardiovascular disease. Vitamin D deficiency may result in osteomalacia, but its excess may result in bone calcium mobilization. Kidney transplant recipients are also at risk of hypovitaminosis D because of impaired graft function. The aim of the study was to assess vitamin D concentration in patients after heart and kidney transplantation.

Serum Concentration of Vitamin D and Parathyroid Hormone After Living Kidney Donation

Background

Metabolic consequences resulting from loss of renal mass in living kidney donors remain uncertain. There is recent focus on the changes in the active form of vitamin D because it is an agent for cancer regulation. The objective of the study was to measure serum concentrations of 1,25-dihydroxycholecalciferol, parathyroid hormone and insulin-like growth factor-1 (IGF-1) in living donors after kidney donation.

Patients and Methods

Forty living kidney donors reported for follow-up visits. Their mean age was 46.14 years. They were women in 52.5% of cases. The mean observation period was 65.6 months. Serum 1,25(OH)₂D₃ and IGF-1 concentrations were measured by radioimmunoassay after extraction. Serum intact parathyroid hormone (PTH) was quantified using an enhanced chemiluminescence immunoassay system.

Results

1,25-dihydroxycholecalciferol deficiency in 57.5% patients after nephrectomy was the most important change we noted. No correlation was observed between 1,25(OH)₂D₃ and PTH. A decreased serum IGF-1 concentration was observed in 17.5% of donors. However, decreases in both serum IGF-1 and 1,25(OH)₂D₃ concentrations were observed in 12.5% of donors.

Conclusion

Prospective studies may be essential to determine metabolic changes after nephrectomy among living kidney donors.     

Chlamydia Pneumoniae Infection in Patients After Kidney Transplantation Treated With Spiramycin

Introduction

Previous research has pointed to a role of Chlamydia pneumoniae infection in the development of chronic renal allograft dysfunction, chronic liver rejection, and vasculopathy in the transplanted heart. The aim of this study was to evaluate the presence of C. pneumoniae prior to and after kidney transplantation as well as to determine the role of spiramycin therapy among kidney transplant recipients.

Materials and Methods

The study group consisted of 50 patients (25 pairs) who received kidney transplants from cadaveric donors. One of the 2 kidneys from a donor was transplanted to a patient randomized to spiramycin (2 × 3 million U/d orally for 3 months; group S) and the other to a patient assigned as control (group C). Markers of infection were assessed on day 1 posttransplantation and 3 months later (average, 94 days). All 50 patients were examined for the presence of bacterial DNA in peripheral blood leukocytes using real-time polymerase chain reaction (PCR) and for titers of serum anti C. pneumoniae immunoglobulin (IgG) and IgA antibodies using microimmunofluorescence (MIF). C. pneumoniae infection was diagnosed by the presence of C. pneumoniae DNA in peripheral blood leukocytes or positive antibodies of both classes.

Results

C. pneumoniae infection was initially diagnosed in 14 patients among group S and 8 patients among group C (P = not significant [ns]) and after 3 months in 12 and 9 patients, respectively (P = ns). Conversion from positive to negative C. pneumoniae status occured in 7 patients among group S and 1 patient among group C (P = .04). Conversion from negative to positive C. pneumoniae status occured in 5 patients from group S and 2 patients from group C (P = ns).

Conclusions

These results suggest a possible role for spiramycin treatment of C pneumoniae infection in kidney allograft recipients. C. pneumoniae infection diagnosis and treatment should be considered to be routine for every patient awaiting transplantation.     

Surgical Site Infections in the Early Posttransplant Period After Simultaneous Pancreas–Kidney Transplantation

Objective

This study evaluated the frequency of microbial isolates and their susceptibility profiles among cultures from the “surgical site” of 26 simultaneous pancreas-kidney (SPKT) recipients in the early posttransplant period.

Patients and Methods

Data on microbiologic cultures of 26 adult patients undergoing SPKT were collected prospectively from 2001 to the end of 2006. The isolation and identification of cultured micro-organisms was performed according to standard microbiological procedures and commercially available tests. Susceptibility of the strains to antibacterial agents was made by the Clinical and Laboratory Standards Institute (CLSI) guidelines.

Results

All patients were followed prospectively for the first 4 weeks after surgery yielding 168 microbial isolates from the surgical site. The most commonly isolated organisms were Gram-positive bacteria (65.5%) with domination of staphylococci (52.7%) as methicillin-resistant S aureus and methicillin-resistant coagulase-negative staphylococci. The second most common were enterococci (33.6%) with the presence of an high level aminoglycoside-resistant strains (64.9%) and vancomycin-resistant strains (2.7%). Gram-negative bacteria comprised 19% of positive cultures; among them were isolated extended spectrum beta-lactamase producers and carbapenem-resistant strains. Yeast-like fungi comprised 15.5% of positive cultures. In conclusion, we observed predominantly Gram-positive bacteria, comprising 65.5% of isolates. The increased proportion of multi-drug-resistant bacterial isolates may be due to the frequent prophylaxis of bacterial infections in patients.     

Urinary Tract Infections in the Early Posttransplant Period After Simultaneous Pancreas–Kidney Transplantation

Objective

Urinary tract infection (UTI) is among the common infection in simultaneous pancreas-kidney transplantation (SPKT).

Patients and Methods

The study included 26 adult patients undergoing SPKT between September 2001 and December 2006. All the patients were followed prospectively for UTI during the first 4 weeks after surgery. Urine samples were investigated for bacteriologic cultures. The micro-organisms were identified in accordance with standard bacteriologic procedures. Susceptibility testing was carried out using Clinical and Laboratory Standards Institute (CLSI) procedures.

Results

Among 77 urine specimens obtained from all recipients during the first month, there were 30 isolated bacterial strains. The most common were Gram-positive bacteria (53.3%) with predominance of enterococci (75%) associated with high levels of aminoglycoside resistant strains (HLAR; 58.3%) and vancomycin-resistant strains (VRE; 25%). Gram-negative bacteria were detected in 46.7% of positive cultures.

Conclusions

In our study, enterococci predominated as 75% of Gram-positive isolates. The increased proportion of multi-drug-resistant bacteria, which can caused severe UTI in patients after SPKT, may be due to the frequent use of prophylaxis of bacterial infections in patients.     

Etiologic Agents of Bacteremia in the Early Period After Simultaneous Pancreas–Kidney Transplantation

Background

Bacteremia is among the known complications in simultaneous pancreas-kidney transplantation (SPKT). This study evaluated the frequency of microbial isolates and their susceptibility profiles among cultures of clinical samples obtained from blood and from the tips of blood vessel catheters of 26 SPKT recipients suspected of bacteremia in the early posttransplant period.

Patients and Methods

Data on microbiologic blood cultures of 26 adult patients undergoing SPKT were collected prospectively from 2001 to the end of 2006. The isolation and identification of cultured microorganisms were performed according to standard microbiological procedures and commercially available tests. The susceptibility of the strains to antibacterial agents was established by the Clinical and Laboratory Standards Institute guidelines.

Results

All patients were followed prospectively for the first 4 weeks after surgery. Among 66 clinical samples, there were 23 microbial isolates from blood samples of 17 recipients and catheter tips of 12 recipients. The most common isolates were Gram-positive bacteria (73.9%) with domination of staphylococci (64.7%) and MRCNS strains (81.8%). Gram-negative bacteria comprised 17.4% of positive cultures, whereas yeast-like fungi, 8.7% with a predominance of Candida glabrata.

Conclusion

Our study showed predominately Gram-positive bacteria in 73.9% of isolates. The increased proportion of multi-drug-resistant bacteria and fungi to antimicrobial agents may be due to the frequent use of these agents for prophylaxis of bacterial infections in patients.     

Vitamin D in Renal Transplantation – from Biological Mechanisms to Clinical Benefits

Recent developments in our understanding of vitamin D show that it plays a significant role in immunological health, uniquely occupying both an anti‐microbial and immunoregulatory niche. Vitamin D deficiency is widespread amongst renal transplant recipients (RTRs), thus providing one patho‐mechanism that may influence the achievement of a successful degree of immunosuppression. It may also influence the development of the infectious, cardiovascular and neoplastic complications seen in RTRs. This review examines the biological roles of vitamin D in the immune system of relevance to renal transplantation (RTx) and evaluates whether vitamin D repletion may be relevant in determining immunologically‐related clinical outcomes in RTRs, (including graft survival, cardiovascular disease and cancer). While there are plausible biological and epidemiological reasons to undertake vitamin D repletion in RTRs, there are few randomized‐controlled trials in this area. Based on the available literature, we cannot at present categorically make the case for routine measurement and repletion of vitamin D in clinical practice but we do suggest that this is an area in urgent need of further randomized controlled level evidence.     

Donor‐Specific HLA Antibodies in a Cohort Comparing Everolimus With Cyclosporine After Kidney Transplantation

Donor‐specific HLA antibodies (DSA) have a negative impact on kidney graft survival. Therefore, we analyzed the occurrence of DSA and antibody‐mediated rejection (AMR) in patients from two prospective randomized trials in our center. At 3–4.5 months posttransplant 127 patients were randomized to continue cyclosporine or converted to everolimus therapy. The presence of DSA was prospectively assessed using Luminex assays. AMR was defined according to the Banff 2009 classification. Antibody screening was available in 126 patients with a median follow‐up of 1059 days. Seven out of 65 (10.8%) patients on cyclosporine developed DSA after a median of 991 days. In comparison, 14/61 patients (23.0%) randomized to everolimus developed DSA after 551 days (log‐rank: p = 0.048). Eight patients on everolimus compared to two patients on cyclosporine developed AMR (log‐rank: p = 0.036). Four of 10 patients with AMR—all in the everolimus group—lost their graft. A multivariate regression model revealed everolimus, >3 mismatches and living donor as significant risk factors for DSA. Acute rejection within the first year, >3 mismatches, everolimus and living donor were independent risk factors for AMR. This single center analysis demonstrates for the first time that everolimus‐based immunosuppression is associated with an increased risk for the development of DSA and AMR.     

Renal Recovery After Liver Transplantation Alone in Patients With Liver Cirrhosis and Severe Chronic Kidney Disease With Normal Kidney Size

BackgroundMost guidelines recommend simultaneous liver-kidney transplantation (SLKT) in patients with liver cirrhosis (LC) and severe chronic kidney disease (CKD) over liver transplantation alone (LTA). CKD, however, is not irreversible. This study evaluates the reversibility of kidney disease after LTA based on kidney size.Materials and methodsIn this single-center retrospective study, we classified 90 patients with LC and severe CKD into 3 groups: the normal kidney (NK)-LTA group (n=39), small kidney (SK)-LTA group (both kidneys <9 cm at the time of LTA, n=40), and SK-SLKT group (n=11).ResultsThe NK-LTA group had a lower percentage of hepatocellular carcinoma and a higher pre-liver transplantation (LT) estimated glomerular filtration rate. This group, however, was older, received livers from a higher percentage of deceased donors, and had a higher Child-Pugh score. Renal recovery, defined as the return of creatinine to their baseline, or a persistent change from baseline but not persistent (≥3 months) need for renal replacement therapy after LT, was found in 79% in the NK-LTA group, which was higher than 7.5% in the SK-LTA group. Renal and patient survival was found in 56% of the NK-LTA group, which was higher than 2.5% of the SK-LTA group.ConclusionsThere is a high percentage of renal recovery in the NK-LTA group, and accordingly, this does not justify SLKT, since this would result in a "waste" of kidneys. Therefore, KT after LT is recommended over SLKT for the LC patients with NK size.     

Development of Autoimmune‐Mediated β Cell Failure After Total Pancreatectomy With Autologous Islet Transplantation

Total pancreatectomy with islet autotransplantation (TPIAT) is performed for definitive treatment of chronic pancreatitis; patients are not diabetic before surgery, or have C‐peptide positive pancreatogenous diabetes. Thus, TPIAT recipients are not traditionally considered at risk for autoimmune loss of the islet graft. We describe a 43‐year‐old female who underwent TPIAT with high mass islet graft of 6031 IEQ/kg, with no evidence of presurgical β cell autoimmunity who developed type 1 diabetes within the first year after TPIAT, resulting in complete loss of beta cell function. The patient had positive GAD and insulin autoantibodies at 1 year and 18 months after TPIAT, not present prior, and undetectable C‐peptide after mixed meal and intravenous glucose tolerance testing at 18 months. Glucagon secretion was preserved, suggesting the transplanted alpha cell mass was intact. HLA typing revealed a DR3/DR4 class II haplotype. This case highlights the need to consider de novo type 1 diabetes in patients with unexpected islet graft failure after TPIAT.     

Pretransplantation Donor–Recipient Pair Seroreactivity Against BK Polyomavirus Predicts Viremia and Nephropathy After Kidney Transplantation

Kidney transplant donors are not currently implicated in predicting BK polyomavirus (BKPyV) infection in kidney transplant recipients. It has been postulated, however, that BKPyV infection originates from the kidney allograft. Because BKPyV seroreactivity correlates with BKPyV replication and thus might mirror the infectious load, we investigated whether BKPyV seroreactivity of the donor predicts viremia and BKPyV‐associated nephropathy (BKPyVAN) in the recipient. In a retrospective cohort of 407 living kidney donor–recipient pairs, pretransplantation donor and recipient sera were tested for BKPyV IgG levels and correlated with the occurrence of recipient BKPyV viremia and BKPyVAN within 1 year after transplantation. Donor BKPyV IgG level was strongly associated with BKPyV viremia and BKPyVAN (p < 0.001), whereas recipient BKPyV seroreactivity showed a nonsignificant inverse trend. Pairing of high–BKPyV‐seroreactive donors with low‐seroreactive recipients resulted in a 10‐fold increased risk of BKPyV viremia (hazard ratio 10.1, 95% CI 3.5–29.0, p < 0.001). In multivariate analysis, donor BKPyV seroreactivity was the strongest pretransplantation factor associated with viremia (p < 0.001) and BKPyVAN (p = 0.007). The proportional relationship between donor BKPyV seroreactivity and recipient infection suggests that donor BKPyV seroreactivity reflects the infectious load of the kidney allograft and calls for the use of pretransplantation BKPyV serological testing of (potential) donors and recipients.     

Aggressive Pulmonary Calcification Developed After Living Donor Kidney Transplantation in a Patient With Primary Hyperparathyroidism

Metastatic pulmonary calcification, defined as calcium deposition in the intact lung, is commonly seen in patients with chronic renal failure, and it is known to be a benign clinical condition when detected by chance in an asymptomatic patient. Here we report the case of a 33-year-old woman who developed rapid and aggressive metastatic pulmonary calcification shortly after a living donor kidney transplantation, which induced acute antibody-mediated rejection. The patient's metastatic pulmonary calcification was successfully improved by extensive treatment for graft rejection, the correction of her accompanying primary hyperparathyroidism, and medical treatment with a bisphosphonate and sodium thiosulfate. Aggressive pulmonary calcification is reported as a rare complication seen in patients who have undergone a failed renal transplantation. A failed renal graft and accompanying secondary hyperparathyroidism seem to accelerate metastatic calcification. Most of the patients who develop aggressive pulmonary calcification suffer from the rapid progression of dyspnea and occasionally fever, and they die of respiratory failure. Pulmonary calcification should be considered in a patient developing dyspnea and unexplained pulmonary infiltrate, especially in the context of renal graft rejection; otherwise the prognosis of the patient will be very poor.     

Immunosuppression With CD40 Costimulatory Blockade Plus Rapamycin for Simultaneous Islet–Kidney Transplantation in Nonhuman Primates

The lack of a reliable immunosuppressive regimen that effectively suppresses both renal and islet allograft rejection without islet toxicity hampers a wider clinical application of simultaneous islet–kidney transplantation (SIK). Seven MHC‐mismatched SIKs were performed in diabetic cynomolgus monkeys. Two recipients received rabbit antithymocyte globulin (ATG) induction followed by daily tacrolimus and rapamycin (ATG/Tac/Rapa), and five recipients were treated with anti‐CD40 monoclonal antibody (mAb) and rapamycin (aCD40/Rapa). Anti‐inflammatory therapy, including anti–interleukin‐6 receptor mAb and anti–tumor necrosis factor‐α mAb, was given in both groups. The ATG/Tac/Rapa recipients failed to achieve long‐term islet allograft survival (19 and 26 days) due to poor islet engraftment and cytomegalovirus pneumonia. In contrast, the aCD40/Rapa regimen provided long‐term islet and kidney allograft survival (90, 94, >120, >120, and >120 days), with only one recipient developing evidence of allograft rejection. The aCD40/Rapa regimen was also tested in four kidney‐alone transplant recipients. All four recipients achieved long‐term renal allograft survival (100% at day 120), which was superior to renal allograft survival (62.9% at day 120) with triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and steroids). The combination of anti‐CD40 mAb and rapamycin is an effective and nontoxic immunosuppressive regimen that uses only clinically available agents for kidney and islet recipients.     

Association of Serum Uric Acid With Graft Survival After Kidney Transplantation: A Time‐Varying Analysis

The association of serum uric acid (UA) with kidney transplant outcomes is uncertain. We examined the predictive value of UA during the first year posttransplant as a time‐varying factor for graft survival after adjustment for time‐dependent and independent confounding factors. Four hundred and eighty‐eight renal allograft recipients transplanted from January 2004 to June 2006 and followed for 41.1 ± 17.7 months were included. Data on UA, estimated glomerular filtration rate (eGFR), tacrolimus level, mycophenolate mofetil (MMF) and prednisone doses, use of allopurinol, angiotensin‐converting enzyme‐inhibitor/angiotensin‐receptor‐blocker (ACEi/ARB) and diuretics at 1, 3, 6, 9 and 12 months were collected. Primary endpoint of the study was graft loss, defined as graft failure and death. Cox proportional hazard models and generalized estimating equations were used for analysis. UA level was associated with eGFR, gender, retransplantation, decease‐donor organ, delayed graft function, diuretics, ACEi/ARB and MMF dose. After adjustment for these confounders, UA was independently associated with increased risk of graft loss (HR: 1.15, p = 0.003; 95% CI: 1.05–1.27). Interestingly, UA interacted with eGFR (HR: 0.996, p < 0.05; 95% CI: 0.993–0.999 for interaction term). Here, we report a significant association between serum UA during first year posttransplant and graft loss, after adjustment for corresponding values of time‐varying variables including eGFR, immunosuppressive drug regimen and other confounding factors. Its negative impact seems to be worse with lower eGFR.     

Microvascular Damage in Type 1 Diabetic Patients Is Reversed in the First Year After Simultaneous Pancreas–Kidney Transplantation

Simultaneous pancreas–kidney transplantation (SPK) is an advanced treatment option for type 1 diabetes mellitus (DM) patients with microvascular disease including nephropathy. Sidestreamdarkfield (SDF) imaging has emerged as a noninvasive tool to visualize the human microcirculation. This study assessed the effect of SPK in diabetic nephropathy (DN) patients on microvascular alterations using SDF and correlated this with markers for endothelial dysfunction. Microvascular morphology was visualized using SDF of the oral mucosa in DN (n = 26) and SPK patients (n = 38), healthy controls (n = 20), DM1 patients (n = 15, DM ≥ 40 mL/min) and DN patients with a kidney transplant (KTx, n = 15). Furthermore, 21 DN patients were studied longitudinally up to 12 months after SPK. Circulating levels of angiopoietin‐1 (Ang‐1), angiopoietin‐2 (Ang‐2) and soluble thrombomodulin (sTM) were measured using ELISA. Capillary tortuosity in the DN (1.83 ± 0.42) and DM ≥ 40 mL/min (1.55 ± 0.1) group was increased and showed reversal after SPK (1.31 ± 0.3, p < 0.001), but not after KTx (1.64 ± 0.1). sTM levels were increased in DN patients and reduced in SPK and KTx recipients (p < 0.05), while the Ang‐2/Ang‐1 ratio was normalized after SPK and not after KTx alone (from 0.16 ± 0.04 to 0.08 ± 0.02, p < 0.05). Interestingly, in the longitudinal study, reversal of capillary tortuosity and decrease in Ang‐2/Ang‐1 ratio and sTM was observed within 12 months after SPK. SPK is effective in reversing the systemic microvascular structural abnormalities in DN patients in the first year after transplantation.     

Acute Anti-A/B Antibody-Mediated Rejection After ABO-Incompatible Kidney Transplantation Treated With Bortezomib and Plasmapheresis: A Case Report

BackgroundABO-incompatible kidney transplantation (KTP) is effective for avoiding transplantation-related issues. It is a viable alternative to ABO-compatible KTP, as both techniques have similar patient and graft survival rates. However, anti-A/B antibody-mediated rejection (AMR) can occur, resulting in poor long-term graft survival.CaseA 45-year-old man with end-stage renal disease presented with a serum creatinine level of 10.2 mg/dL. We decided to perform KTP with spousal donation. He had panel-reactive antibody class I and II and cross matching test negativity, a 3/6 mismatch on human leukocyte antigen typing, an ABO antibody titer of 1:256, and no donor-specific antibodies. The patient and donor blood types were O+ and A+, respectively. The anti-A/B antibody titer was reduced preoperatively with rituximab (200 mg/body), plasmapheresis, and intravenous immunoglobulin (0.2 mg/kg). Basiliximab and methylprednisolone were used for induction immunosuppression, and tacrolimus, mycophenolate mofetil, and prednisolone were used for maintenance immunosuppression. KTP was successful, and graft function was initially normal. On postoperative day (POD) 5, the serum creatinine level and anti-A/B antibody titer increased from 0.9 mg/dL to 1.9 mg/dL and 1:16 to 1:64, respectively. Graft biopsy revealed acute AMR and tubular injury. We started steroid pulse therapy, plasmapheresis, and subcutaneous bortezomib (2.6 mg, twice a day, every 3 days) with no side effects. The serum creatinine level decreased from 5.7 mg/dL to 1.5 mg/dL on POD 28. Graft biopsy showed no rejection, and normal function was maintained for 40 months.ConclusionsAcute, early anti-A/B AMR was successfully treated with plasmapheresis and bortezomib.     

Assessment of the Learning Process After Introducing a New Liver Transplantation Procedure in a Center With Extensive Experience in Kidney Transplantation

Background

Liver transplantation (LTx) is one of the most complex transplant procedures. The aim of the present study was to determine whether the learning process can be observed after the introduction of LTx in a center with extensive previous experience in renal transplantation.