Influence of ATLG serum levels on CD3/CD19-depleted hematopoietic grafts and on immune recovery in pediatric haplo-HSCT.

ABSTRACT: Anti-T lymphocyte globulin (ATLG) significantly reduces the risk of engraftment failure in allogeneic hematopoietic stem cell transplant (HSCT) but hampers posttransplant immune reconstitution. We hypothesized that in patients receiving haploidentical CD3/CD19-depleted grafts, these double-edged effects could be better balanced by attaining high ATLG serum concentrations before transplant but as low as possible on the day of transplant. Therefore, we moved the start of ATLG application to day -12 and determined serum concentrations of T-cell-specific ATLG in pediatric patients treated with 3 established dosing regimens (15, 30, or 60 mg/kg). Corresponding mean T-cell-specific ATLG serum concentrations at day 0 were 1.14, 2.99, or 12.10 µg/mL, respectively. Higher ATLG doses correlated with higher peak levels at days -8 and -7 and reduced graft rejection, whereas lower ATLG doses correlated with significantly faster posttransplant recovery of T and natural killer cells. The rate of graft-versus-host disease remained low, independent of ATLG doses. Moreover, in vitro assays showed that ATLG concentrations of 2.0 µg/mL and lower only slightly reduced the activity of natural killer cells, and therefore, the function of such effector cells might be preserved in the grafts. Pharmacokinetic analysis, compatible with linear first-order kinetics, revealed similar half-life values, independent of ATLG doses. Hence, the day on which a desired ATLG serum level is reached can be calculated before HSCT. Our retrospective study demonstrates the relevance of dosing and time of administration of ATLG on engraftment and immune recovery in ex vivo CD3/CD19-depleted haploidentical HSCT.

Enemy or friend: the personal and the factual patient-physician relationship.

Physicians are expected to place the patient's interests above their own. Such prioritization has worldwide consent. It constitutes the difference between medicine and other professions. The present conceptual opinion paper summarizes the authors' clinical experience with patient care and student teaching during the last 45 years. The authors comment on their own conception by referring to present debates and prominent statements from the past. Fundamental changes in medicine have taken place over the last five decades. New diseases have emerged while diagnostic and therapeutic options for patients have grown steadily - along with healthcare costs. At the same time, economic and legal constraints for physicians have increased, as has moral pressure. The interaction of physicians with patients has gradually shifted from a personal to a factual relationship. In the factual, more formal relationship, the patient and physician represent equal partners of a legal contract, which jeopardizes the prioritization of the patient's interests. The formal relationship implies defensiveness. By contrast, in the personal relationship, the physician adopts an existentialist commitment while simultaneously enabling and respecting the patient's autonomous decision-making. The authors argue for the personal relationship. However, the patient and physician are no friends. Consequently, the physician in effect competes with the patient from a knowledge-based but opposite position. Both need to make efforts to consent and maintain the relationship even when they dissent. This implies that the physician does not simply comply with the patient's wishes.

Clinical Pharmacokinetics and Pharmacodynamics of Voclosporin.

Voclosporin is an approved option for the long-term treatment of lupus nephritis. We aimed to provide a narrative review of the pharmacokinetics and pharmacodynamics of voclosporin. In addition, we derived values for pharmacokinetic and pharmacodynamic parameters by graphical analysis of published diagrams. Compared with cyclosporin, low-dose voclosporin is associated with a lower nephrotoxicity risk and, compared to tacrolimus, with a lower diabetes risk. After repetitive dosing of 23.7 mg twice daily and at target trough concentrations of 10-20 ng/mL, the dominant or effect-indicative half-life is estimated at 7 hours. Compared with the pharmacodynamics of cyclosporin, the potency of voclosporin is stronger, with a lower concentration CE50 of 50 ng/mL already producing the half-maximum immunosuppressive effect. The Hill coefficient can be predicted to be low at H = 1.3, indicating a concentration-dependent effect on the immune system. The corresponding effect bisection time of 10 hours allows for dosing every 12 hours. Accordingly, the trough concentration will be above the threshold concentration that produces 5% of the maximum effect of 5.2 ng/mL for immunosuppression but below both the predicted threshold of 30 ng/mL for nephrotoxicity and the predicted threshold of 40 ng/mL for new-onset diabetes. The pharmacokinetic and pharmacodynamic properties suggest the use of low-dose voclosporin combined with mycophenolate and low-dose glucocorticoids for immunosuppressive maintenance therapy.

Graft function and pregnancy outcomes after kidney transplantation.

BACKGROUND: After kidney transplantation, pregnancy and graft function may have a reciprocal interaction. We evaluated the influence of graft function on the course of pregnancy and vice versa. METHODS: We performed a retrospective observational study of 92 pregnancies beyond the first trimester in 67 women after renal transplantation from 1972 to 2019. Pre-pregnancy eGFR was correlated with outcome parameters; graft function was evaluated by Kaplan Meier analysis. The course of graft function in 28 women who became pregnant after kidney transplantation with an eGFR of < 50 mL/min/1.73m2 was compared to a control group of 79 non-pregnant women after kidney transplantation during a comparable time period and with a matched basal graft function. RESULTS: Live births were 90.5% (fetal death n = 9). Maternal complications of pregnancy were preeclampsia 24% (graft loss 1, fetal death 3), graft rejection 5.4% (graft loss 1), hemolytic uremic syndrome 2% (graft loss 1, fetal death 1), maternal hemorrhage 2% (fetal death 1), urinary obstruction 10%, and cesarian section. (76%). Fetal complications were low gestational age (34.44 ± 5.02 weeks) and low birth weight (2322.26 ± 781.98 g). Mean pre-pregnancy eGFR was 59.39 ± 17.62 mL/min/1.73m2 (15% of cases < 40 mL/min/1.73m2). Pre-pregnancy eGFR correlated with gestation week at delivery (R = 0.393, p = 0.01) and with percent eGFR decline during pregnancy (R = 0.243, p = 0.04). Pregnancy-related eGFR decline was inversely correlated with the time from end of pregnancy to chronic graft failure or maternal death (R = -0.47, p = 0.001). Kaplan Meier curves comparing women with pre-pregnancy eGFR of ≥ 50 to < 50 mL/min showed a significantly longer post-pregnancy graft survival in the higher eGFR group (p = 0.04). Women after kidney transplantation who became pregnant with a low eGFR of > 25 to < 50 mL/min/1.73m2 had a marked decline of renal function compared to a matched non-pregnant control group (eGFR decline in percent of basal eGFR 19.34 ± 22.10%, n = 28, versus 2.61 ± 10.95%, n = 79, p < 0.0001). CONCLUSIONS: After renal transplantation, pre-pregnancy graft function has a key role for pregnancy outcomes and graft function. In women with a low pre-pregnancy eGFR, pregnancy per se has a deleterious influence on graft function. TRIAL REGISTRATION: Since this was a retrospective observational case series and written consent of the patients was obtained for publication, according to our ethics' board the analysis was exempt from IRB approval. Clinical Trial Registration was not done. The study protocol was approved by the Ethics Committee of Hannover Medical School, Chairman Prof. Dr. H. D. Troeger, Hannover, December 12, 2015 (IRB No. 2995-2015).

Clinical Pharmacokinetics and Pharmacodynamics of Roxadustat.

The pharmacokinetics of roxadustat are well characterized, with an apparent volume of distribution after oral administration of 22-57 L, apparent clearance of 1.2-2.65 L/h, and renal clearance of 0.030-0.026 L/h in healthy volunteers; the elimination half-life is 9.6-16 h. Plasma binding is 99% and the fraction eliminated by hemodialysis is 2.34%. As an interpretation of the pharmacodynamics of roxadustat, we proposed a concept with a hypothetical cascade of two subsequent effects, first on erythropoetin (EPO) and second on hemoglobin (delta Hb). The primary effect on EPO is observed within a few hours after roxadustat administration and can be modeled using the sigmoidal Hill equation. The concentration at half-maximum effect can be inferred at 10-36 µg/mL, the Hill coefficient at 3.3, and the effect bisection time at 10-17 h, corresponding to EPO half-life. The subsequent effect on hemoglobin (delta Hb) is observed after several weeks and can be interpreted as an irreversible, dose proportional, unsaturable effect, continuing in agreement with the lifespan of red blood cells of 63-112 days.

[Analgesic Drug Therapy in Kidney Patients]. / Schmerzmedikamente bei Nierenpatienten.

Analgesic drug therapy in kidney patients needs special expertise. Patients with kidney disease frequently have pain and they have chronic pain more than others. Some analgesic drugs have a nephrotoxic potential and co-analgesics such as anticonvulsive, antidepressive and antipsychotic drugs need a dose adjustment to kindey function. When treating kidney patients with morphine, the accumulation kinetics of the M6 glucuronide must be observed. Otherwise, the risk increases for respiratory depression.

[Adverse Drug Effects - how to detect, how to avoid?] / Arzneimittelnebenwirkungen ­ wie erkennen, wie vermeiden?

There is no drug therapy without risk for toxicity. The patient must tolerate some toxic or idiosyncratic adverse events (e. g. hand foot syndrome). After life threatening adverse effects, one needs to screen (hyperkalemia). The sick-day-rule should be communicated with the informed patient as for example stopping SGLT2-inhibitors (loss of appetite, hypotension). The list of prescriptions should regularly criticized for dangerous or superfluous medicines (deprescribing).

[Moment of Shock - What Does This Gap Mean?] / Schrecksekunde ­ was bedeutet diese Lücke?

Ludwig van Beethoven's Opus 119 represents a series of "bagatelles" for piano. On closer inspection, or better listening, one can get to the thought: How should one interpret the pause that the Maestro has woven into bar 65 of the first piece?

Immunological Alterations due to Hemodialysis Might Interfere with Early Complications in Renal Transplantation.

BACKGROUND: Chronic or intercurrent alterations of the immune system in patients with end-stage renal disease (CKD) and intermittent hemodialysis (CKD5D, HD) have been attributed to an acute rejection of renal allograft. METHODS: Leukocyte subsets in flow cytometry, complement activation, and concentrations of TGFß, sCD30 (ELISA), and interleukins (CBA) of fifteen patients eligible for renal transplantation were analyzed before, during, and after a regular HD. RESULTS: Before HD, the median proportion of CD8+ effector cells, CD8+ CCR5+ effector cells, and HLA-DR+ regulatory T cells as well as the median concentration of soluble CD30 increased and naive CD8+ T cells decreased. During HD, there was a significant decrease in CD4- CD8- T cells (p < 0.001) and an increase in CD25+ T cells (p = 0.026), sCD30 (p < 0.001), HLA-DR+ regulatory T cells (p = 0.005), and regulatory T cells (p = 0.003). TGFß and sCD30 increased significantly over time. The activity of the classical complement pathway started to slightly increase after the first hour of HD and lasted until fifteen minutes after finishing dialysis. The decrease in the functional activity of the alternative pathway was only transient and was followed by a significant increase within 15 minutes after finishing the treatment. CONCLUSION: HD might interact with the allograft outcome by influencing T cell subsets and activation of the complement system in a biphasic course.

Clinical Pharmacodynamics: Principles of Drug Response and Alterations in Kidney Disease.

Pharmacokinetics and pharmacodynamics follow the logic of cause and consequence. Receptor-mediated and reversible effects can be distinguished from direct and irreversible effects. Reversible effects are capacity-limited and saturable whereas irreversible effects are limited only by the number of viable targets. In the case of receptor-mediated and reversible effects a threshold and a ceiling concentration can be defined. Antimicrobial drugs with concentration-dependent action are distinguished from drugs with time-dependent action. Concentration-dependent effects are associated with a high ceiling concentration and the target is the high peak. Time-dependent effects are associated with a high threshold concentration and the target is the high trough. During kidney dysfunction, alterations of drug response are usually attributed to pharmacokinetic but rarely to pharmacodynamic changes. Dose adjustment calculations, therefore, tacitly presume that pharmacodynamic parameters remain unchanged while only pharmacokinetic parameters are altered in kidney failure. Kidney dysfunction influences the pharmacokinetic parameters of at least 50% of all essential drugs. Clinicians usually consider pharmacokinetics when kidney disease is found, but pharmacodynamics is as important. Alterations of pharmacodynamic parameters are conceivable but only rarely reported in kidney failure. Sometimes surprising dosing adjustments are needed when pharmacodynamic concepts are brought into the decision process of which dose to choose. Pharmacokinetics and pharmacodynamics should both be considered when any dosing regimen is determined.

Early Flow Disturbances of Tunnelled Haemodialysis Catheters and Topographic Landmarks in Chest X-Ray.

BACKGROUND/AIMS: The position of the tip of tunnelled haemodialysis (HD) catheters (THC) might influence flow characteristics during HD. In chest X-ray (CXR), carina-related landmarks may be practicable to verify the THC position, and tip-carina distance (TCD) might be useful to predict early-flow dysfunctions. METHODS: In this single-centre, retrospective study, the TCD and the angle between the distal catheter and the body vertical axis (tip-body vertical-angle [TVA]) was measured in 115 THC by post-procedure CXR with 2 investigators. The parameters were proved to be feasible by interrater-reliability and correlated with the incidence of flow-dysfunction within 10 days after insertion. RESULTS: Steep-aligned (TVA <40°, p < 0.01) and deep-ending catheters (TCD: right-sighted >1.5 cm or left-sighted >4.5 cm below the carina; p < 0.01) showed a significantly less dysfunction with a good interrater-reliability (R[TVA] = 0.8, R[TCD] = 0.9). CONCLUSIONS: Carina-related landmarks in CXR might be helpful to predict early-flow dysfunctions. However, randomized studies will be necessary to confirm this in fluoroscopic-guided placement during the insertion of THC.

Chemotherapeutic agents eligible for prior dosing in pancreatic cancer patients requiring hemodialysis: a systematic review
.

AIMS: New chemotherapeutic agents prolong survival of patients with pancreatic ductal adenocarcinoma (PDAC). Although their incidence is rising, patients with end-stage renal disease (ESRD) requiring hemodialysis (HD) are not included in the phase III trials evaluating the effects of these chemotherapies. Many experts recommend applying chemotherapy after HD using a reduced dose. Alternatively, the concept of prior dosing allows for the application of dialyzable chemotherapeutic drugs using a normal dose, with an HD followed shortly after to mimic normal renal function. In this work, we provide guidance for clinicians on how to use chemotherapy in patients with PDAC on HD and how to identify substances suitable for prior dosing. MATERIALS AND METHODS: We systematically searched PubMed, from inception to September 2016, for published studies describing patients with ESRD on HD who received chemotherapies commonly applied in PDAC, including gemcitabine, fluorouracil (5-FU), capecitabine, oxaliplatin, irinotecan, docetaxel, erlotinib, sunitinib, S-1, and afatinib. Applied dosages, described toxicities, application time relative to HD, and pharmacokinetic measurements of the drug and its metabolites were assessed. Quantitative analysis of the drug plasma concentrations, including half-life during and in between HD and fraction of the drug eliminated during HD, were assessed. RESULTS: We identified 56 studies describing 128 patients with ESRD undergoing HD during chemotherapeutic treatment. Quantitative pharmacokinetic analysis revealed that the following substances are dialyzable and thus suitable for application using the prior-dosing method: gemcitabine, 5-FU, oxaliplatin, irinotecan, and S-1. CONCLUSION: This work supports the application of dialyzable chemotherapeutic agents in patients with PDAC in standard dose when HD is performed shortly after the infusion.
.

The Pituitary-Thyroid Axis and Prolactin Secretion in Hemodialysis Patients in Two Endemic Regions of Eastern Germany.

INTRODUCTION: Endocrine disorders of the pituitary axes are frequent in patients with hemodialysis (CKD5D). The aim of this multicenter study (Leipzig (L), Quedlinburg and Blankenburg in the Harz region (Hz)) in CKD5D patients was to evaluate influences of CKD5D related factors, morphological and biochemical parameters, and serum iodine and prolactin concentrations on the pituitary-thyroid axis. PATIENTS AND METHODS: 170 patients (L n=58; Hz n=112) were included in this prospective, non-interventional, cross-sectional study. Mann-Whitney-U-test and bivariate correlation analyses with Spearman-Rho test (r correlation coefficient) were used in statistical analysis. RESULTS: TSH was higher in patients with prolactin concentrations>370 mIU/l (p=0.013), in patients with high flux membranes (p=0.0013) and in patients with longer dialysis vintage (p=0.04). Median iodine serum concentrations were slightly elevated in the Leipzig cohort (p=0.001) and correlated with fT4 (p<0.001, r=0.43) and albumin (p=0.001, r=0.245) but not with morphological signs. Albumin was correlated with fT3 (p<0.001, r=0.339) and fT4 (p<0.001, r=0.421). Prolactin was correlated with residual excretion rate (p=0.001, r=- 0.303) and thyroid volume (p=0.027, r=0.217). CONCLUSIONS: In the assessment of the thyroid status in CKD5D patients, the synopsis of the clinical and nutritional status, comorbidities, ultrasound of the thyroid gland and laboratory results is necessary for further intervention with hormone replacement. Standardized reference values of the pituitary-thyroid axis should be critically evaluated and are still lacking in CKD5D.

Survey among nephrologists in Germany: current practice and management of pregnant women on dialysis
.

BACKGROUND: To assess the experience and practice patterns of nephrologists in Germany with regard to the care of pregnant women on dialysis. METHODS: The 26-item internet survey sent by email asked for demographic information, subjective proficiency, maternal and fetal complications, treatment approaches and goals. RESULTS: Of the 2,015 surveys sent out, 200 (10%) were available for evaluation. 38% of respondents never provided care, whereas 62% treated at least one pregnant patient on dialysis. In 306 total reported cases of pregnant women on dialysis, 58% became pregnant while on maintenance dialysis, and 42% developed dialysis-dependent renal failure in the course of pregnancy. For women on peritoneal dialysis (PD), only 22% of the nephrologists would continue PD until delivery, while 78% would convert to hemodialysis either immediately or shortly before delivery. 40% of the respondents reported complications in either mother or child. 45% of the respondents routinely provided prenatal counseling, and 2/3 of the nephrologists did not routinely perform fetal monitoring. While we found a significant difference in self-reported proficiency between nephrologists having and those not having treated pregnant women on dialysis, only 40% of all physicians felt confident in treating pregnant women on dialysis. CONCLUSIONS: Our survey demonstrates that the practice of nephrologists in treating pregnant women on dialysis differs significantly. These findings highlight the need for European guidelines to standardize the care of pregnant dialysis patients.
.

Correlation between pharmacokinetics of tacrolimus and pharmacodynamics on NFAT-regulated gene expression in stable kidney transplant recipients
.

Gene expression regulated by the transcription factor NFAT (nuclear factor of activated T-cells) has been proposed for monitoring the pharmacodynamic effect of calcineurin inhibitors. We aimed to correlate the pharmacokinetics of tacrolimus with the suppression of NFAT-regulated gene expression. Tacrolimus trough (Ctrough) and peak concentrations (Cpeak) were measured by LC-MS. The effect on NFAT-regulated gene expression at trough (Etrough) and at peak levels (Epeak) were determined by qRT-PCR. The pharmacodynamic concentration producing the half-maximum effect (CE50) and the Hill coefficient (H) were estimated from Etrough and from Epeak. Ten stable kidney transplant recipients on triple immunosuppression with prednisolone, mycophenolate, and tacrolimus were analyzed. Median age was 58 years, median time since transplant was 84 months, and median serum creatinine was 249 µmol/L. The immunosuppressive effect on NFAT-regulated genes at trough concentrations was 38% (Etrough), and the effect at peak concentrations was 59% (Epeak) of maximum immunosuppression (Emax). The pharmacodynamic parameters of the action of tacrolimus were estimated with the Hill coefficient H at 1.5 and the CE50 at 6.7 ng/mL. Accordingly, the pharmacodynamic threshold concentration was estimated at 0.9 ng/mL and the ceiling concentration at 48 ng/mL, indicating a wide span between target trough and peak levels. The low Hill coefficient indicates concentration-dependent pharmacodynamics of tacrolimus on NFAT transcripts. Therefore, the extension of the administration interval to 24 hours is not likely to jeopardize the immunosuppressive effect of the prolonged-release tacrolimus preparations. 
.

Renal Effects and Carcinogenicity of Occupational Exposure to Uranium: A Meta-Analysis.

PURPOSE: Uranium is a heavy metal with alpha radioactivity. We state the hypothesis that uranium exposure is harmful to human kidneys and carcinogenic to body tissues. Therefore, we review epidemiological studies from people with known long-lasting uranium exposure. MATERIALS AND METHODS: Three meta-analyses are performed using clinical studies published in the PubMed database and applying RevMan 5.3 from the Cochrane Collaboration to calculate the outcome. The first two meta-analyses examine the standardized mortality ratio (SMR) and the standardized incidence ratio for any cancers of uranium workers who were operating in areas ranging from uranium processing to the assembly of final uranium products. The third meta-analysis evaluates the nephrotoxic risk in uranium workers as well as soldiers and of individuals with exposure to drinking water containing uranium. RESULTS: Overall and contrasting to our hypothesis, the tumor risk is significantly lower for uranium workers than for control groups (SMR = 0.90 with a 95% confidence interval of 0.84 to 0.96). In addition and also contrasting to our hypothesis, the risk of nephrotoxicity is not increased either. This holds for both the incidence and the mortality due to renal cell carcinoma or due to acute kidney injury or chronic kidney disease. In contrast, a significantly better creatinine clearance is found for the uranium cohort as compared to the control groups (mean difference = 7.66 with a 95% confidence interval of 0.12 to 15.2). CONCLUSION: Our hypothesis that a chronic uranium exposure is associated with an increased risk of cancer mortality or of kidney failure is refuted by clinical data. The decreased risk may result from better medical surveillance of uranium workers.