The Influence of Tacrolimus Exposure and Metabolism on the Outcomes of Kidney Transplants.

Tacrolimus (TAC) has a narrow therapeutic window and patient-specific pharmacokinetic variability. In our study, we analyzed the association between TAC exposure, metabolism, and kidney graft outcomes (function, rejection, and histological lesions). TAC trough (C0), coefficient of variation (TAC CV), concentration/dose ratio (C/D), and biomarkers related to kidney injury molecule-1 (KIM-1) and neutrophil gelatinase lipocalin (NGAL) were analyzed. We examined 174 patients who were subjected to a triple immunosuppressive regimen and underwent kidney transplantation between 2017 and 2022. Surveillance biopsies were performed at the time of kidney implantation and at three and twelve months after transplantation. We classified patients based on their Tac C/D ratios, classifying them as fast (C/D ratio < 1.05 ng/mL × 1/mg) or slow (C/D ratio ≥ 1.05 ng/mL × 1/mg) metabolizers. TAC exposure/metabolism did not significantly correlate with interstitial fibrosis/tubular atrophy (IF/TA) progression during the first year after kidney transplantation. TAC CV third tertile was associated with a higher chronicity score at one-year biopsy. TAC C/D ratio at three months and Tac C0 at six months were associated with rejection during the first year after transplantation. A fast TAC metabolism at six months was associated with reduced kidney graft function one year (OR: 2.141, 95% CI: 1.044-4.389, p = 0.038) and two years after transplantation (OR: 4.654, 95% CI: 1.197-18.097, p = 0.026), and TAC CV was associated with reduced eGFR at three years. uNGAL correlated with IF/TA and chronicity scores at three months and negatively correlated with TAC C0 and C/D at three months and one year. Conclusion: Calculating the C/D ratio at three and six months after transplantation may help to identify patients at risk of suffering acute rejection and deterioration of graft function.

Drugs with a negative impact on cognitive function (Part 1): chronic kidney disease as a risk factor.

People living with chronic kidney disease (CKD) frequently suffer from mild cognitive impairment and/or other neurocognitive disorders. This review in two parts will focus on adverse drug reactions resulting in cognitive impairment as a potentially modifiable risk factor in CKD patients. Many patients with CKD have a substantial burden of comorbidities leading to polypharmacy. A recent study found that patients seen by nephrologists were the most complex to treat because of their high number of comorbidities and medications. Due to polypharmacy, these patients may experience a wide range of adverse drug reactions. Along with CKD progression, the accumulation of uremic toxins may lead to blood-brain barrier (BBB) disruption and pharmacokinetic alterations, increasing the risk of adverse reactions affecting the central nervous system (CNS). In patients on dialysis, the excretion of drugs that depend on kidney function is severely reduced such that adverse and toxic levels of a drug or its metabolites may be reached at relatively low doses, unless dosing is adjusted. This first review will discuss how CKD represents a risk factor for adverse drug reactions affecting the CNS via (i) BBB disruption associated with CKD and (ii) the impact of reduced kidney function and dialysis itself on drug pharmacokinetics.

Factors influencing renal graft survival: 7-Year experience of a single center.

BACKGROUND AND OBJECTIVE: The demand for kidney transplants exceeds the existing supply. This leads to a recently growing interest of research in the area of factors that could prolong graft long-term outcomes and survival. In Lithuania, approximately 90% of kidney transplantations are from deceased donors. Donor organs are received and shared only inside the country territory in Lithuania; therefore, donor data is accurate and precise. This study was performed to present particularities of kidney transplantation data in Lithuania and to identify the effect of donor and recipient factors and histologic findings on renal graft outcomes. The aim of this study was to identify the effect of donor and recipient factors and histologic findings on renal graft outcomes. MATERIALS AND METHODS: We analyzed the influence of deceased donor and recipient factors and histological findings on the graft function in 186 renal transplant patients. Graft survival was estimated within the first year after transplantation. RESULTS: The donors and recipients were older in worse eGFR group 1 year after transplantation. Dissimilarity of degree of glomerulosclerosis (GS), interstitial fibrosis (IF) and arteriolar hyalinosis (AH) were significant in inferior and superior renal function groups (GS >20% 11.4 vs. 0%, P=0.017; IF 9.3 vs. 0%, P=0.034; AH 69 vs. 26.2%, P<0.001). Nine independent variables were significantly associated with a worse renal transplant function 1 year posttransplantation: AH (OR=6.287, P<0.001), an episode of urinary tract infection (OR=2.769, P=0.020), acute graft rejection (OR=3.605, P=0.037), expanded criteria (OR=4.987, P=0.001), female gender donors (OR=3.00, P=0.014), cerebrovascular disease caused donor brain death (OR=5.00, P=0.001), donor's age (OR=1.07, P<0.001), and recipient's age (OR=1.047, P=0.022). Worse renal graft survival 1 year posttransplantation was associated with a delayed graft function and a higher level of glomerulosclerosis in time-zero biopsy. CONCLUSIONS: Donor factors, such as age, female gender, brain death of cerebrovascular cause and expanded criteria donor status had a significant negative impact on the renal graft function 1 year after transplantation. Recipients' age, urinary tract infection and acute graft rejection episodes after transplantation were associated with a worse kidney function 1 year after transplantation. Lower 1-year graft survival was related to a delayed graft function (DGF) and a higher degree of glomerulosclerosis.

Mortality prediction in patients with acute kidney injury requiring renal replacement therapy after cardiac surgery.

BACKGROUND AND OBJECTIVE: Acute kidney injury (AKI) is a common and potentially serious postoperative complication after cardiac surgery, and it remains a cause of major morbidity and mortality. The aim of our study was to assess the prognostic illness severity score and to estimate the significant risk factors for poor outcome of patients with AKI requiring renal replacement therapy (RRT) after cardiac surgery. MATERIALS AND METHODS: We retrospectively analyzed data of adult (>18 years) patients (n=111) who underwent open heart surgery and had developed AKI with need for RRT. Prognostic illness severity scores were calculated and perioperative risk factors of lethal outcome were assessed at the RRT initiation time. We defined three illness severity scores: Acute Physiology and Chronic Health Evaluation (APACHE II) as a general score, Sequential Organ Failure Assessment (SOFA) as an organ failure score, and Liano score as a kidney-specific disease severity score. Logistic regression was also used for the multivariate analysis of mortality risk factors. RESULTS: Hospital mortality was 76.5%. More than 7% of patients remained dialysis-dependent after their discharge from the hospital. The prognostic abilities of the scores were assessed for their discriminatory power. The area under the receiver-operating characteristic (ROC) curve of SOFA score was 0.719 (95% CI, 0.598-0.841), of Liano was 0.661 (95% CI, 0.535-0.787) and 0.668 (95% CI, 0.550-0.785) of APACHE II scores. From 16 variables analyzed for model selection, we reached a final logistic regression model, which demonstrated four variables significantly associated with patients' mortality. Glasgow coma score<14 points (OR=3.304; 95% CI, 1.130-9.662; P=0.003), mean arterial blood pressure (MAP)<63.5mmHg (OR=3.872; 95% CI, 1.011-13.616; P=0.035), serum creatinine>108.5µmol/L (OR=0.347; 95% CI, 0.123-0.998; P=0.046) and platelet count<115×109/L (OR=3.731; 95% CI, 1.259-11.054; P=0.018) were independent risk factors for poor patient outcome. CONCLUSIONS: Our study demonstrated that SOFA score estimation is the most accurate to predict the fatal outcome in patients with AKI requiring RRT after cardiac surgery. Lethal patient outcome is related to Glasgow coma score, mean arterial blood pressure, preoperative serum creatinine and postoperative platelet count.

Hepcidin serum levels and resistance to recombinant human erythropoietin therapy in hemodialysis patients.

OBJECTIVE: The aim of this study was to analyze the factors that are associated with the response to erythropoiesis-stimulating agents (ESAs) and its association with hospitalization and mortality rates; to evaluate the serum hepcidin level and its associations with iron profile, inflammatory markers, ESA responsiveness, and mortality; and to determine independent factors affecting ERI and hepcidin. MATERIALS AND METHODS: To evaluate a dose-response effect of ESAs we used the erythropoietin resistance index (ERI). Patients were stratified in two groups: nonresponders and responders (ERI>15, n=20, and ERI ≤15U/kg/week/g per 100mL, n=153, respectively). Hematological data, hepcidin levels, iron parameters, inflammatory markers, hospitalization and mortality rates were compared between the groups. Multiple regression analysis was used to determine independent factors affecting ERI and hepcidin. RESULTS: C-reactive protein (CRP) (ß=0.078, P=0.007), albumin (ß=-0.436, P=0.004), body mass index (ß=-0.374, P<0.001), and hospitalization rate per year (ß=3.017, P<0.001) were found to be significant determinants of ERI in maintenance hemodialysis (MHD) patients. Inadequate dialysis was associated with higher ERI. Patients with concomitant oncological diseases had higher ERI (31.2±12.4 vs 9.7±8.1U/kg/week/g per 100mL, P=0.002). The hepcidin level was 158.51±162.57 and 120.65±67.28ng/mL in nonresponders and responders, respectively (P=0.33). Hepcidin correlated directly with ERI, dose of ESAs, ferritin and inversely with Hb, transferrin saturation, and albumin. ERI (ß=4.869, P=0.002) and ferritin (ß=0.242, P=0.003) were found to be significant determinants of hepcidin in MHD patients. The hospitalization rate per year was 2.35±1.8 and 1.04±1.04 in nonresponders and responders, respectively (P=0.011). The mean length of one hospitalization was 25.12±21.26 and 10.82±17.25 days, respectively (P=0.012). Death occurred in 30% of the patients from the responders' group and in 50% from the nonresponders' group (P=0.289). The mean hepcidin concentration of patients who died was 141.9±129.62ng/mL and who survived, 132.98±109.27ng/mL (P=0.797). CONCLUSIONS: CRP, albumin, BMI, and hospitalization rate per year were found to be significant determinants of ERI in MHD patients. Inadequate dialysis was associated with higher epoetin requirements. There were no difference in patient mortality by ERI, but a significant difference in hospitalization rates and mean length of one hospitalization was revealed. A significant positive relation between hepcidin and ERI was revealed. ERI and ferritin were found to be significant determinants of hepcidin in MHD patients. Hepcidin was not related to mortality.

Nationwide renal biopsy data in Lithuania 1994-2012.

BACKGROUND: Our aim was to evaluate the incidence of biopsy-proven kidney diseases in Lithuania and to compare their changes in three different time intervals. All Lithuanian kidney biopsies were performed in the National Center of Pathology, enabling analysis at the national level. METHODS: The native kidney biopsy data were reviewed, and incidence of renal disorders and patient demographics were compared during three time intervals: 1994-1999, 2000-2006, and 2007-2012. RESULTS: A total of 5,368 kidney biopsies were performed, including 3,640 native kidney and 1,728 kidney transplant biopsies; 59.5% (2,165) of the native kidney biopsies were classified as primary glomerulopathies. The most common entity was IgA nephropathy (737; 34.0%), followed by focal segmental glomerulosclerosis (285; 13.2%) and membranoproliferative glomerulonephritis (256; 11.8%). Prominent decrease in incidence of membranoproliferative glomerulonephritis (16.8 to 8.7% from the first to third time interval) and increase in (mainly, pauci-immune) crescentic glomerulonephritis (6.2 to 15.3%) were noted over the study period. In a subgroup of 427 pediatric native kidney biopsies, IgAN accounted for 24.9% of biopsies. The incidence of MCNS increased dramatically from the first to third time interval (6.3 to 25.4%), while the number of MPGN increased in the second time interval (from 7.2 to 8.9%) but decreased in the third one (to 4.4%). CONCLUSIONS: Decrease in relative incidence of membranoproliferative glomerulonephritis, most likely, reflects improvement in socioeconomic conditions, while relative increase in crescentic glomerulonephritis is interpreted as improved diagnostics of the disease.

[The prevalence of Fabry's disease among male patients on hemodialysis in Lithuania (a screening study)]. / Fabry ligos paplitimas tarp hemodializuojamu ligoniu (vyru) Lietuvoje (atrankinis tyrimas).

UNLABELLED: Fabry's disease is an X-linked inborn error of glycosphingolipid metabolism caused by a deficiency of the lysosomal hydrolase alpha-galactosidase A. Due to deficiency of this enzyme activity, a progressive lysosomal accumulation of glycosphingolipids, in particular globotriaosylceramide, takes place within endothelial cells and cells of the vascular and nervous systems, myocardial cells, endothelial, and mesangial and epithelial cells of the kidney, eventually leading to organ dysfunction. The degree of renal involvement generally correlates with the progression of glycosphingolipid accumulation and may lead to renal insufficiency and failure. Renal dysfunction can progress to end-stage renal failure, which usually occurs in the third to fifth decade of life. The prevalence of this disease among males on chronic hemodialysis is different in various countries. Screening for alpha-galactosidase A deficiency by blood spot tests was performed among 536 male dialysis patients in all 42 hemodialysis centers in Lithuania in the period of April-June, 2005. All tests, showed normal galactosidase A enzymatic activity. CONCLUSION: No patient with suspicion of Fabry's disease was found by this screening method.

[Changes of control of disorders of calcium and phosphorus metabolism in Lithuanian hemodialysis centers 1996-2003]. / Kalcio ir fosforo apykaitos sutrikimu kontroles pokyciai Lietuvos hemodializes centruose 1996-2003 m.

The aim of the study was to evaluate the changes of the rate of disorders of calcium and phosphorus metabolism and their control in patients on hemodialysis (HD) in Lithuania in 1996-2003. Every December during this period we visited all HD centers of Lithuania and collected data on calcium-phosphorus metabolism in HD patients. 51.8% of HD patients in 1999 and 44.6% in 2003 had hyperphosphatemia (>1.8 mmol/l) (p<0.05). The mean phosphate concentration was 1.82+/-0.56 mmol/l in 2003 (p<0.05, comparing with 1.95+/-0.72 mmol/l in 1999 and 1.9+/-0.72 mmol/l in 2001). 7.1% of HD patients had hypocalcemia in 2003 and 7.8% hypercalcemia. Serum parathyroid hormone level was investigated only in 27.3% of HD patients in 1999 and 84.8% in 2003 (p<0.05). Use of alfacalcidol significantly decreased from 77.5% in 1998 to 29.4% in 2003, when the evaluation of serum parathyroid hormone increased (r=-0.911, p=0.03). Serum parathyroid hormone level was not analyzed for 59.8% of patients who used alfacalcidol and 59.4% of them had hyperphosphatemia in 1999 (6.3% and 32.9% in 2003, respectively; p<0.05). 10.7% of these patients had hypercalcemia in 2003. In summary, the correction of disorders of calcium and phosphorus metabolism in HD patients was insufficient but ameliorative. Monitoring of serum parathyroid hormone increased significantly during 1997-2003. The percentage of the precarious use of alfacalcidol decreased significantly when the evaluation of serum parathyroid hormone level became regular.

[The indications of renal biopsies and spectrum of renal diseases in five nephrological centers of Lithuania (a five-year study)]. / Inkstu biopsijos indikacijos, inkstu biopsijos budu nustatytu inkstu ligu struktura penkiuose Lietuvos nefrologijos centruose (5 metu trukmes tyrimas).

A retrospective study of 316 patients, who underwent renal biopsy, during the period of 1995-1999 in five nephrological centers of Lithuania. All renal biopsy materials were investigated in the State Center of Pathology. Male:female ratio was 204:112, the mean age 41.4 (SD 16.7) yrs., range 15-80. The main indications for renal biopsy were nephrotic syndrome (29.1%), hematuria and nonnephrotic proteinuria (27.8%). The leading type of kidney damage was primary glomerulonephritis--194 (69.3%), which was 2.4 times more frequent in males than in females. The dominant types of primary glomerulonephritis were IgA nephropathy--30.4%, membranoproliferative glomerulonephritis--26.8%, membranous nephropathy--10.3% and focal segmental glomerulosclerosis--9.8%. Renal amyloidosis was found even in 8.6% of all renal biopsies.

[Prognosis of chronic renal failure in patients with membranous nephropathy]. / Letinio inkstu nepakankamumo prognoze ligoniams, sergantiems membranine nefropatija.

Two hundred eighty patients underwent renal biopsy during the period of 1995-1999 in five nephrological centers of Lithuania. All renal biopsies materials were examined in the State Center of Pathology. In 20 patients (7.1%) membranous nephropathy was found. The main clinical presentation at the moment of renal biopsy were nephrotic syndrome (55%) and arterial hypertension (55%). Glomerulosclerosis was found in 30% of patients, interstitial fibrosis--in 40% of patients. The results of analysis showed multiple risk factors for renal failure progression: initial renal failure (p=0.000), systolic and diastolic hypertension (p=0.009 and p=0.009), proteinuria (=1 g/l, =3 g/l) (p=0.026). Membranous nephropathy was found to have a relatively good long-term prognosis - the renal survival rate in 5 years was 84.2%. Kaplan-Meier survival analysis showed that initial renal failure was risk factor (logrank p=0.018, Breslov p=0.032) associated with development of end-stage renal disease in 5 years.

[Focal segmental glomerulosclerosis: prognosis of chronic renal failure]. / Zidinine segmentine glomeruloskleroze. Letinio inkstu nepakankamumo raidos prognozavimas.

We analyzed 19 patients with focal segmental glomerulosclerosis (FSGS): 11 males and 8 females (mean age 38.3 yrs. (SD 16.4), who were under observation for 39.4 months (SD 17.2). At the moment of renal biopsy 73.7% of patients had arterial hypertension, 52.6%--nephrotic proteinuria, 36.9%--chronic renal failure. Global glomerulosclerosis was present in 14 biopsies (73.7%), and intersticial fibrosis--in 13 biopsies (68.4%). The results of analysis showed multiple risk factors for progression of renal failure: initial renal failure (p=0.005), proteinuria (> or =3 g/l) (p=0.005), expressed glomerulosclerosis (p=0.005) and expressed interstitial fibrosis (p=0.034). Focal segmental glomerulosclerosis were found to have a relatively bad long-term prognosis--the renal survival rate in 5 years was 77.8%. Kaplan-Meier survival analysis showed that expressed glomerulosclerosis was risk factor (logrank p=0.016, Breslov p=0.043) associated with end-stage renal disease in 5 years.

[Clinical and laboratory features and prognostic implications in myeloma with and without renal impairment]. / Mielomine liga ir jos sukelto inkstu pazeidimo klinikiniai ir laboratoriniai duomenys bei prognoze nulemiantys faktoriai.

Presenting clinical and laboratory features, prognostic implications and survival in 124 multiple myeloma patients were reviewed in a retrospective study based on hospital records. The median age was 65 years. Out of all patients, 2.42% were younger than 40 years and 62.9% were 60 years and older. The main presenting clinical features were bone pain (70.16%), fatigue (31.45%), recurrent infections (9.68%) and weight loss (0.3%). Renal failure was present in 35.48% of patients. The higher means of ionised calcium, uric acid, erythrocyte sedimentation rate, M protein were correlated with the higher mean of serum creatinine. The acturial survival of myeloma patients without renal failure at 1 and 2 years was 95.08% and 89.23% respectively, while acturial survival of myeloma patients with renal failure at 1 and 2 years was 82.5% and 73.35% respectively (p<0.01). One-year survival in myeloma patients maintained on chronic hemodialysis was 68.75% while it is reported as 90.91% for myeloma patients not on dialysis (p<0.006).

[Relationship between lethality of hemodialysis patients, erythropoietin dosage for renal anemia treatment and hemodialysis quality]. / Hemodializes kokybes rysys su hemodializuojamu ligoniu mirstamumu ir eritropoetino doze, skiriama inkstu anemijai gydyti.

In December of 1999 and 2000 we visited all hemodialysis centers of Lithuania and collected data about all hemodialysis patients, using special questionnaires. The aim of the study was to evaluate the relationship between lethality of hemodialysis patients, erythropoietin dosage for renal anemia treatment and hemodialysis quality. The patients with higher Kt/V, higher levels of iron and albumin, normal levels of phosphorus and parathyroid hormone (PTH) requested lower doses of erythropoietin (analysis of the patients who were on hemodialysis in 2000 more than 6 months). So, we can conclude that adequate hemodialysis procedure and good management of hemodialysis patient are leading to the decrease request of erythropoietin doses for anemia treatment. We compared two groups of patients in order to examine relationship between hemodialysis quality and lethality of hemodialysis patients. We selected incident patients registered in December of 1999 and we divided these patients in December of 2000 in two groups: a) 175 patients, who continued hemodialysis treatment and b) 41 patients, who died in 2000. The results revealed, that dead patients were elder, their duration of weekly hemodialysis was shorter, Hb concentration lower, they had worse nutritional status (blood albumin level was lower). Lethality was associated with underlying diseases such as diabetes, hypertensive nephropathy and renal amyloidosis.