Reversal of stage 5 chronic kidney disease by aortic valve replacement in kidney transplant recipient: a case report.

BACKGROUND: Cardiorenal syndrome (CRS) is a group of pathophysiological disorders affecting heart and kidneys. CASE PRESENTATION: We present 44-year-old kidney transplant recipient with acute-on-chronic graft failure in the course of CRS due to acutely decompensated heart failure associated with severe aortic regurgitation successfully treated with aortic valve replacement. Because of graft failure progression and difficult to eradicate infections he was treated with dialysis and radical minimization of immunosuppression. After 74 days of renal replacement therapy the patient regained graft function after successful aortic valve replacement. The dialysis could be stopped and immunosuppressive therapy was reintroduced. Heart and renal function are stable and patient is doing well without dialysis for 3 years. CONCLUSIONS: The return of kidney graft function can occur even after a long period of dialysis therapy due to improved cardiovascular function. Therefore, distinguishing an acute-on-chronic CRS subtype is mandatory to enable specific patient approach.

Effect of Successful Treatment of Hepatitis C Virus Infection Recurrence With Direct-Acting Antiviral Agents on Physical Performance in Liver Transplant Recipients.

BACKGROUND: Hepatitis C virus (HCV) infection deregulates function of many organs and systems, affecting patient's daily functioning. The results of treatment of HCV infection recurrence after liver transplantation have improved significantly as a result of the introduction of direct-acting antiviral agents (DAA). This study was aimed at prospective assessment of the effect of HCV elimination with DAA on physical performance of liver transplant recipients. METHODS: Eight women and 21 men, median age 61.3 (range, 20.1-71.5) years, participated in the study. Assessment of serum total bilirubin, alanine and aspartate aminotransferase, muscle strength, body composition, and 6-minute walk test (6MWT) were performed before treatment and 12 weeks after the end of the treatment period. RESULTS: In the 6MWT test we observed significant subjective (dyspnea: 58.3% pretreatment vs 27.6% posttreatment, P = .018; fatigue: 96.6% pretreatment vs 51.7% posttreatment, P = .0001) and objective improvement (distance: 415.4 meters pretreatment vs 505.2 meters posttreatment, P < .0000001). We did not observe an increase in muscle mass nor improvement in blood biochemical parameters. CONCLUSION: A significant objective and subjective improvement in physical performance was seen in liver transplant recipients after successful treatment of HCV infection with DAA.

Evaluation of the Relationship Between Concentrations of Tacrolimus Metabolites, 13-O-Demethyl Tacrolimus and 15-O-Demethyl Tacrolimus, and Clinical and Biochemical Parameters in Kidney Transplant Recipients.

BACKGROUND: Tacrolimus (Tac), an essential component of immunosuppressive therapy after solid-organ transplantation, has a narrow therapeutic index and requires therapeutic drug monitoring. Monitoring of Tac predose blood concentrations seems to be not always sufficient to avoid adverse effects. The aim of the study was to evaluate the levels of main Tac metabolites, 13-O-demethyl tacrolimus (13-DMT), 31-O-demethyl tacrolimus (31-DMT), and 15-O-demethyl tacrolimus (15-DMT), in kidney transplant recipients and to link them to clinical and biochemical parameters. METHODS: In 63 kidney transplant patients, concentrations of 13-DMT, 31-DMT, and 15-DMT were quantified using liquid chromatography combined with tandem mass spectrometry (LC/MS/MS). RESULTS: None of the patients had detectable 31-DMT blood levels. There was a positive correlation between 13-DMT/Tac and alanine aminotransferase (ALAT) (r = 0.29, P = .046) and a negative correlation between 13-DMT/Tac and hemoglobin (r = -0.33, P = .008). Tac level did not correlate with ALAT nor with hemoglobin. There was no relationship between 13-DMT/Tac or 15-DMT/Tac and other biochemical or hematologic parameters or data, such as age, body mass index, arterial pressure, or time posttransplant. We observed significantly higher Tac concentrations in patients with hypercholesterolemia or hypertriglyceridemia compared with those without these comorbidities (6.45 ± 2.32 vs 5.16 ± 2.12 ng/mL, P = .043; 6.60 ± 2.30 vs 5.34 ± 2.20 ng/mL, P = .033, respectively). CONCLUSION: Our data may reflect 13-DMT accumulation in liver dysfunction and higher Tac clearance in anemia. However, these results may suggest that 13-DMT/Tac ratio is a marker of myelotoxicity and hepatotoxicity. Further studies should be carried out to determine whether monitoring of 13-DMT could be beneficial in minimizing the adverse effects.

Outcomes of Prolonged Treatment With Intravenous Immunoglobulin Infusions for Acute Antibody-mediated Rejection in Kidney Transplant Recipients.

BACKGROUND: Treatment of antibody-mediated rejection (AMR) is one of the main problems after kidney transplantation (KTx). The results of intensive AMR treatment with plasmapheresis (PF) and repeated infusions of intravenous immunoglobulin (IVIg) are presented. METHODS: Diagnosis of AMR was based on graft biopsy and the presence of donor-specific antibodies (DSAs). AMR therapy consisted of 5 PF and IVIg infusions given after the last PF. Subsequent IVIg doses were given every 4 weeks for 6 months. Graft biopsy and DSA assessment were repeated at the end of the treatment (ET). RESULTS: Four women and 10 men were included in our study; mean time from KTx to AMR was 79 (range, 3-193) months. During the treatment, 4 patients had graft failure. Graft function at baseline was significantly worse (P = .02) in this group compared with patients who completed the therapy. At baseline, mean flourescence intensity (MFI) was 6574 (range, 852-15,917) in the whole group, 7088 (range, 1054-15,917) in patients who completed treatment, and 4828 (range, 852-11,797) in patients who restarted hemodialysis. At ET, DSA MFI decreased in 8 of 10 patients (80%) who completed the therapy. The MFI decrease was 3946 (range, 959-11,203). Control graft biopsies revealed decreased intensity of C4d deposits in peritubular capillaries in 7 patients (78%) and decreased peritubular capillaritis in 2 patients (22%). CONCLUSION: Intensive, prolonged AMR therapy with PF and IVIg resulted in a decrease in DSA titer and intensity of C4d deposits, but was not associated with reduction of microcirculation inflammation. Treatment was ineffective in patients with baseline advanced graft insufficiency.

Kidney Transplant Recipients With Rheumatic Diseases: Epidemiological Data From the Polish Transplant Registries 1998-2015.

Chronic kidney disease (CKD) is a common complication of rheumatic disorders. We analyzed the incidence of different rheumatic conditions as a primary diagnosis of end-stage renal disease (ESRD) in kidney transplant recipients in Poland. Data were received from the national waiting list for organ transplantation (Poltransplant) registries. Primary diagnosis leading to ESRD were analyzed in 15,984 patients who received kidney transplants between 1998 and 2015. There was no information about primary diagnosis in 4981 cases (31%) and in 1482 cases (9%) the diagnosis was described as unknown. Rheumatic diseases were specified in 566 (5.14%) kidney transplant recipients: lupus erythematosus, (systemic lupus erythematous nephritis) in 211 (1.92%), vasculitis in 176 (1.60%), amyloidosis AA in 82 (0.75%), hemolytic uremic syndrome in 59 (0.54%), secondary glomerulonephritis in 24 (0.22%), scleroderma in 9 (0.08%), rheumatoid arthritis in 4 (0.04%) and Sjögren syndrome in 1 (0.01%). Graft survival at 1 and 5 years were significantly better in the nonrheumatic versus rheumatic group (90 vs 87% and 76 vs 72% respectively, P = .04). Recipient survival at 5 years was significantly better in the nonrheumatic versus the rheumatic group (88 vs 84%, P = .02). Our study showed that systemic lupus erythematosus and systemic vasculitides are the major rheumatic causes of ESRD in the Polish population. Long-term graft and recipient survival were significantly better in the nonrheumatic versus the rheumatic group in the Poltransplant cohort.

Cardiovascular Disease in Kidney Transplantation and Its Association With Blood Concentrations of Cyclosporine and Cyclosporine Metabolites.

Cyclosporine A (CsA) is the first calcineurin inhibitor used as immunosuppressive agent. Its administration is associated with multiple adverse effects including cardiovascular diseases (CVDs), but their mechanisms have not been fully elucidated. Cyclosporine metabolites are not well studied in this context. This study was aimed at analysis of the incidence of CVDs and their association with concentrations of cyclosporine and its metabolites. Sixty patients after kidney transplantation (KTX) taking an immunosuppressive regimen including CsA participated in the study. There were 22 women (36.67%) and 38 men (63.33%), mean age 51.73 years, mean 109.38 months after KTX. We observed a correlation between mean diastolic blood pressure and concentrations of metabolite to parent drug ratios of AM1-CsA/CsA (r = 0.35, P = .006), dihydroxy-CsA/CsA (r = 0.42, P = .001), trihydroxy-CsA/CsA (r = 0.42; P = .003) and desmethyl-carboxy-CsA/CsA (r = 0.65, P = .003). There were no significant associations of other CsA metabolites' parameters with CVDs (coronary disease, hypertension, stroke, arrhythmia, diabetes mellitus, obesity). Study results suggest that blood pressure increases associated with CsA therapy could be caused by CsA metabolites that influence mainly diastolic blood pressure levels. A lack of such differences in relation with other CVDs may suggest that more complex mechanisms are involved in the development of cardiovascular injury and disease after kidney transplantation.

Clinical Significance of Gastrointestinal Carriage of Klebsiella Pneumoniae-Producing Extended-Spectrum Beta-Lactamases in Kidney Graft Recipients.

The burden of Klebsiella pneumoniae (KP) producing extended-spectrum beta-lactamases (ESBL+) urinary tract infections (UTIs) is a growing problem after kidney transplantation (KTX). The study was aimed at evaluating the incidence of KP ESBL+ gut colonization in KTX recipients and its correlation with clinical outcomes with special regard to UTIs. The study included all KTX patients hospitalized in our department between January 2014 and December 2016. During this period 2018 KTX patients were admitted: 605 in 2014, 750 in 2015, and 663 in 2016, respectively. Screening for drug-multiresistant Enterobacteriaceae gut carriage was performed in 104 patients (2014), 122 (2015), and 166 (2016). In 2014, 2015, and 2016, 18 (17.3%), 26 (21.3%), and 30 (18.1%) patients had positive test results, and 44 (42.3%), 36 (29.5%), and 45 (27.4%) KTX patients were diagnosed with KP ESBL+ UTI. In 2014, KP ESBL+ UTI was diagnosed in 30 (34.9%) cases with negative anal swab and in 14 patients (77.8%) with positive test result (P = .0008). In 2015, KP ESBL+ UTI was diagnosed in 21 patients (21.9%) with negative anal swab and in 15 (57.7%) with positive test result (P = .0004). In 2016, KP ESBL+ UTI was diagnosed in 24 patients (17.8%) with negative anal swab and in 21 (72.4%) with positive test result (P = .000001). In conclusion, we have revealed a strong association between gut K. pneumoniae colonization, female sex, and MPA intake and KP ESBL+ urinary tract infections in kidney transplant recipients. Our results indicate the very important role of KP ESBL+ screening, while strategies of identified carriers require further research.

Tacrolimus Metabolite M-III May Have Nephrotoxic and Myelotoxic Effects and Increase the Incidence of Infections in Kidney Transplant Recipients.

BACKGROUND: Tacrolimus (Tac) is one of the most commonly used immunosuppressive drugs after solid organ transplantation. Eight Tac metabolites have been described, but their clinical importance remains unclear. The aim of this study was quantification of the 2 major Tac metabolites, 13-O-demethyl (M-I) and 15-O-demethyl (M-III), in kidney transplant recipients and to link them with parameters of kidney and liver function, peripheral blood cell counts, and infection incidence. METHODS: In 81 kidney transplant recipients, concentrations of Tac, M-I, and M-III were measured with the use of liquid chromatography combined with tandem mass spectrometry (LC-MS-MS). RESULTS: There was a negative correlation between M-III levels and estimated glomerular filtration rate (eGFR; r = -0.244; P < .05). Also, a negative correlation between M-III concentrations and red blood cell count (RBC) was found (r = -0.349; P < .05). Neither concentrations of Tac nor of M-I correlated with eGFR or RBC. M-I, M-III, and Tac were not related to alanine aminotransferase activity. Significantly higher Tac and M-III concentrations in the group with all types of infections in comparison with the group without infections were observed (6.95 ± 2.09 ng/mL vs 5.73 ± 2.43 ng/mL [P = .03] and 0.27 ± 0.17 ng/mL vs 0.20 ± 0.11 ng/mL [P = .04], respectively). CONCLUSIONS: The results suggest that higher concentrations of M-III may have a nephrotoxic or myelotoxic effect and result in higher incidence of infections. Further studies are needed to confirm if monitoring of M-III could minimalize adverse effects such as nephrotoxicity or infections.

Hydroxylated, Hydroxymethylated, Dihydroxylated, and Trihydroxylated Cyclosporine Metabolites Can Be Nephrotoxic in Kidney Transplant Recipients.

BACKGROUND: Cyclosporine (CsA) is an immunosuppressive agent whose use is associated with adverse effects, including nephrotoxicity. There are reports indicating that some CsA metabolites may contribute to these effects. This study was aimed at evaluation of CsA metabolites and correlating them with kidney function. METHODS: In 62 kidney transplant recipients (41.9% women; overall mean age, 48.44 ± 11.75 years), concentrations of CsA and 4 groups of metabolites were assessed: hydroxylated (HCsA), hydroxymethylated (HMCsA), dihydroxylated (DHCsA), and trihydroxylated (THCsA). The results were normalized with the use of the metabolite-to-parent drug ratio, and results were linked with estimated glomerular filtration rate (eGFR) at 3 months before (-3M), point zero (0M), and after 3 (+3M) and 12 (+12M) months. RESULTS: Multivariate analysis demonstrated the negative influence of eGFR -3M on HMCsA/CsA (ß = -0.266; P < .05) and the negative influence of HCsA/CsA, HMCsA/CsA, DHCsA/CsA, and THCsA/CsA on eGFR +3M (ß = -0.339, ß = 0.396, ß = -0.314, and ß = -0.321, respectively; P < .005) and eGFR +12M (ß = -0.363, ß = -0.316, ß = -0.267, and ß = -0.312, respectively; P < .05). We did not detect such influence of CsA concentrations on eGFR +3M and +12M. The THCsA/CsA receiver operating characteristic cutoff value for prediction of improvement of kidney function at +12M was 0.143. CONCLUSIONS: Our results suggest that impaired function of the transplanted kidney affects the accumulation of HMCsA. It is possible that the increased metabolite (HCsA, HMCsA, DHCsA, and THCsA) to cyclosporine ratio could influence or could be a marker of cyclosporine nephrotoxicity. In this context, the most promising marker seems to be THCsA/CsA ratio, but its real significance requires further studies to determine.

Determination of Concentrations of Azathioprine Metabolites 6-Thioguanine and 6-Methylmercaptopurine in Whole Blood With the Use of Liquid Chromatography Combined With Mass Spectrometry.

BACKGROUND: 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are used in many autoimmune diseases and after solid-organ transplantation. Their properties are mediated by active metabolites, 6-thioguanine nucleotides (6-TGN), and 6-methylmercaptopurine (6-MMP). The most common adverse effects are myelo- and hepato-toxicity. The aim of the study was quantification of 6-TG and 6-MMP, with the use of liquid chromatography combined with tandem mass spectrometry (LC/MS/MS) in solid-organ transplant recipients. METHODS: In 33 patients, kidney transplant recipient (n = 25) and liver transplant recipient (n = 8) intra-erythrocyte concentrations of 6-TG and 6-MMP were measured with the use of LC/MS/MS. RESULTS: The mean concentration of 6-TG was 205.35 ± 157.62 pmol/8 × 10(8) red blood cells (RBC); median concentration of 6-MMP was 1064.1 (35.78-11,552.9) pmol/8 × 10(8) RBC. There were no correlations between 6-TG levels and peripheral blood parameters (white blood cell count, WBC; hemoglobin, Hb concentration; PLT, blood platelet count) or alanine aminotransferase activity (AlAT) activity. Relationships between 6-MMP concentrations and peripheral blood parameters (WBC, Hb, PLT) or AlAT activity have not been found. Subgroups with leukopenia, anemia, thrombocytopenia, and liver dysfunction did not differ in concentrations of 6-TG or 6-MMP. We have observed a negative correlation between daily azathioprine dose and WBC count (r = -0.37, P = .04). CONCLUSIONS: Relationships between concentrations of azathioprine metabolites and myelotoxicity or hepatotoxicity have not been confirmed. Further studies on larger groups of patients would be helpful in a more accurate understanding of the impact of azathioprine metabolites on parameters of bone marrow and liver function.

Cytomegaloviral infection in solid organ transplant recipients: preliminary report of one transplant center experience.

BACKGROUND: Despite advances in immunosuppressive therapy and post-transplantation care, antiviral prevention, and therapy, cytomegalovirus (CMV) infection remains the most common viral infection after solid organ transplantation (SOT). METHODS: This study included 2,375 patients under the care of our transplant center during the 1-year period from June 2012 to June 2013. There were 351 patients (14.78%) suspected and tested for CMV infection with the use of viral DNA amplification test. RESULTS: Symptoms that triggered diagnostics were graft dysfunction in 24 (55.8%), diarrhea in 18 (41.9%), fever in 15 (34.9%), leukopenia in 14 (32.6%), abdominal pain in 13 (30.2%), nausea in 7 (16.3%), cough in 6 (14%), and shivers in 2 (4.7%). Positive test results were obtained in 43 patients (12.3% of patients tested and 1.8% of the entire cohort). The group consisted of 17 women (39.5%) and 26 men (60.5%), 26 kidney (60.5%) and 17 liver (39.5%) transplant recipients, aged 49.3 years (SD 14.9). The initial viral load was median 8,093 (range: 4,232-219,180) copies/mL. The mean ganciclovir (GCV) treatment duration was 19.05 (SD 8.1) days. GCV doses ranged from 100 to 1,000 mg/d, mean 370.6 (SD 254.2) mg/d. Clinical resistance to treatment was diagnosed in 5 patients (11.6%). We found a positive correlation of GCV treatment duration with natural logarithm of initial CMV viremia (r = 0.56; P = .0002) and of time in months to CMV infection with mean cyclosporine level (r = -0.74; P = .04) and GCV dose (r = -0.34; P = .03). The duration of GCV therapy was positively influenced by CMV load and tacrolimus administration and negatively by patient's age and male sex. CONCLUSIONS: Appearance of any symptoms occurring after transplantation, even nonspecific, should lead to diagnostics for CMV infection. The duration of treatment depends on the severity of the infection expressed by CMV viremia. Clinical resistance to GCV is not frequent, but it is an important transplantologic problem.

Is neutrophil gelatinase-associated lipocalin an optimal marker of renal function and injury in liver transplant recipients?

BACKGROUND: Recently, research has focused on the association of neutrophil gelatinase-associated lipocalin (NGAL) with acute and/or active kidney injury. However, it should be remembered that NGAL is involved in iron metabolism and antimicrobial defense mechanisms. METHODS: One hundred seven consecutive liver transplant recipients were included in this study. Plasma and urine NGAL levels were measured with the use of enzyme-linked immunosorbent assay. NGAL levels were studied as plasma concentrations (pNGAL), urine concentrations (uNGAL), urinary NGAL to creatinine ratio (uNGAL/Cr), and fractional NGAL secretion (fNGAL). RESULTS: pNGAL was found to be inversely correlated with estimated glomerular filtration rate (eGFR) and plasma cystatine C (pCysC) (r = -0.26 and P = .007, r = -0.38 and P = .00006, respectively). uNGAL was positively correlated with urinary cystatine C to creatinine ratio (uCysC/Cr) and fractional cystatine C excretion (fCysC) (r = 0.43 and P = .000004; r = 0.4 and P = .1; respectively). uNGAL/Cr was inversely correlated with hematocrit (Htc) and hemoglobin (Hb) (r = -0.35 and P = .0002; r = -0.39 and P = .00004; respectively), and positively correlated with uCysC/Cr (r = 0.5 and P < .0000001). fNGAL was directly correlated with uCysC/Cr and fCysC (r = 0.53 and P < .0000001; r = 0.39 and P = .00005; respectively) and inversely correlated with red blood cell count (RBC; r = -0.31 and P = .001). We observed significant differences of pNGAL, uNGAL/Cr, and fNGAL between sexes, with highest values of uNGAL, uNGAL/Cr, and fNGAL in women and pNGAL in men. In multivariate regression analysis, pNGAL was positively correlated with time elapsed from liver transplantation, neutrophil count, pCysC, and sex (ß = 0.36 and P = .00001; ß = 0.32 and P = .0001; ß = 0.58 and P < .0000001; ß = 0.17 and P = .025; respectively) and inversely correlated with patient's age (ß = -0.18 and P = .02) with R = 0.67 and R(2) = 0.45, independently from blood glucose, eGFR, RBC, white blood cell count, Hb, uCysC, uCysC/Cr, and fCysC. CONCLUSIONS: Plasma and urine NGAL levels are strongly correlated not only with kidney function parameters, but also with red and white blood cell parameters and patient's age and sex.

Arterial hypertension in liver transplant recipients.

Hypertension is an important cardiovascular risk factor that influences patient survival. This study sought to evaluate hypertension incidence and circadian rhythms of blood pressure (BP) among liver transplant recipients during the first posttransplant month. We also compared hypertension incidence according to clinical and automated blood pressure monitoring methods. BP was determined by clinical blood pressure monitoring (CBPM) methods and by automated blood pressure monitoring (ABPM) using the SpaceLabs device. We also assessed blood biochemistry, particularly kidney function parameters and immunosuppressive drug blood trough levels, among 32 white subjects (10 women and 22 men) of average age 47.58±14.19 years. The leading cause for transplantation was liver insufficiency due to viral hepatitis B and/or C infection (43.75%). The majority (93.75%) of patients was prescribed immunosuppressive treatment with tacrolimus. Although we observed hypertension in 28 patients (87.5%) by ABPM measurements and in 25 (78.12%) using CBPM method, the difference did not reach statistical significance. However, BP control was inadequate in 28 patients (87.5%) by ABPM assessment versus 3 (9.38%) according to CBPM readings (P=.025). The BP circadian rhythm was altered in 30 patients (93.75%) including 15 with higher nighttime BP readings. There was no correlation between tacrolimus blood levels and BP values or with kidney function as assessed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. We concluded that prevalence of arterial hypertension among liver transplant recipients within 1 month after transplantation is high. The majority of the patients show disturbed circadian rhythms in the early period after liver transplantation with loss or even reversal of the normal nocturnal decrease in BP. Owing to the fact that ABPM enables more adequate daily assessment of BP values, it is an optimal method to adjust antihypertensive therapy to optimal levels.