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.

BACKGROUND:Modern treatment strategies have markedly improved the chances of survival for patients with cancer. As the population ages, cancer is becoming more common, as is chronic kidney disease (CKD). CKD increases the risk of cancer; conversely, cancer treatments can cause CKD. METHODS:This review is based on publications retrieved by a selective literature search concerning the epidemiology and comorbidities of cancer and kidney diseases, the renal side effects of new anticancer drugs, and the need to consider renal function in cancer treatment. RESULTS:The prevalence of severe CKD in Germany is 2.3%. Persons who have CKD, are on dialysis, or have undergone kidney transplantation are 1.2 to 3.5 times more likely to develop cancer than the general population. For patients who have CKD or are dialysis-dependent, the doses of approximately 67% of anticancer drugs need to be adjusted on the basis of their glomerular filtration rate and the renally excreted fraction of the drug. The optimal efficacy of therapeutic drugs, as well as of those used for diagnostic purposes, and the minimization of side effects, depend critically on adapted dosing and on proper timing of administration before or after dialysis. Modern anticancer drugs can also cause acute kidney damage (incidence with checkpoint inhibitors: 2-16%). CONCLUSION:Patients who have CKD, are on dialysis, or have undergone kidney transplantation make up a considerable fraction of persons being treated for cancer, and they need interdisciplinary treatment.

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.

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 CE 50 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.

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/1.73m 2 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/1.73m 2 (15% of cases < 40 mL/min/1.73m 2 ). 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/1.73m 2 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).

Zur Nierenersatztherapie auf der Intensivstation werden die intermittierende Hämodialyse, die kontinuierliche Hämofiltration und die prolongierte Tankdialyse eingesetzt. Unabhängig vom Nierenersatzverfahren beginnt die Antibiotikatherapie mit einer hohen Startdosis. Die Dosisanpassung an die Niere wird erst nach 48 h erforderlich, wenn toxische Spiegel akkumulieren könnten. Empfehlungen zur Dosisanpassung in den Fachinformationen sind häufig unterdosiert. Bei kontinuierlicher Hämofiltration geben viele Intensivmediziner inzwischen eine normale Standarddosis, da die Filtrationsrate oft schon einer halbnormalen glomerulären Filtrationsrate entspricht. Die Dosis nach intermittierender Hämodialyse orientiert sich an der Startdosis. Am Nichtdialysetag muss die Erhaltungsdosis der Nierenfunktion angepasst werden. Unmittelbar nach prolongierter Tankdialyse wird jeweils wieder eine Startdosis gegeben; die Erhaltungsdosis bei 12-stündigem Dosierungsintervall muss ebenfalls der Nierenfunktion angepasst werden. Ein therapeutisches Drugmonitoring empfiehlt sich bei Gentamicin, Vancomycin, Piperacillin, Meropenem und Voriconazol. Aus pharmakodynamischen Gründen sollte als Zielspiegel die Konzentration des halbmaximalen Effekts gewählt werden. Der Zielspiegel entspricht so den normalen Spitzenspiegeln bei konzentrationsabhängiger Wirkung mit Bolusdosierung. Die Zielspiegel bei zeitabhängiger Wirkung und kontinuierlicher Infusion entsprechen dann der mittleren Gleichgewichtskonzentration.

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 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.

In der Arzneimitteltherapie gilt: keine Wirkung ohne Nebenwirkung. Manche Nebenwirkungen mussen die Patienten hinnehmen (z.B. Hand-Fu ss -Syndrom). Nach gefahrlichen Nebenwirkungen muss man suchen (Hyperkaliamie). uber die Sick-Day-Rule sollte mit den Patienten gesprochen und z.B. SGLT2-Inhibitoren sollten bei ubelkeit oder Schwindel pausiert werden. Notwendig ist auch die regelma ss ige Medikationskritik mit dem Ziel, uberflussige oder riskante Medikamente abzusetzen (Deprescribing). Abstract 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).

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.

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

Abstract Background and Aims When anuria suddenly occurs, the rise in creatinine and consequently the decrease in the estimated glomerular filtration rate (eGFR) will always be delayed. Thus, the drug dose could be selected too high in the progressive phase whereas it could be adjusted too low in the restitution phase of acute kidney disease (AKD). Sheldon Chen proposed a solution for changing kidney function with the kinetic GFR (KeGFR). A simplified but also more general solution (kinetGFR) might even facilitate the automatic implementation into lab systems. Method Deterioration of kidney function is diagnosed when the creatinine increases within a definite time interval (Δ t) and the estimated eGFR declines (Δ eGFR). The new 2-point estimate of the kinetGFR can be derived when the prospective eGFRt+24 predicted for the next day (t+24) will be set equal to the present true GFR at critical day (t2). kinetGFR=eGFR2−eGFR1−eGFR2t2−t1⋅t+24 h The 24 h delay follows from anuria, the most extreme and most relevant case (GFR = 0). A zero GFR will be associated with a linear rise in creatinine according to the constant production rate by roughly 100 µmol/l every day. This rise leads to the corresponding bisection of the estimated eGFR nearly every day (100 => 50 => 25 => 13 => … ml/min). The curvilinear eGFR decline will never become zero even after > 2 weeks. The new kinetGFR can identify a complete anuria already after one day (24 h). kinetGFR=50−100−5024−0⋅24=0.0 ml/min This is already at the critical day (t2). Results The retrospective look at the anonymized data from 20 patients with AKD allowed for comparing the former KeGFR with the new two-point kinetGFR estimate. For worsening kidney function, the average eGFR2 was 18 ml/min (+ 12) and the KeGFR estimate was not different with 19 ml/min (+ 17). The new 2-point kinetGFR, however, was 13 ml/min (+ 11) and 28 % less than eGFR2 at the critical day (t2). For improving kidney function, the eGFR2 was 15 ml/min (+ 4) and the KeGFR was already much higher at 27 ml/min (+ 3). The new 2-point estimate of the kinetGFR was in between at 21 ml/min (+ 7). Conclusion In AKD, the difference between eGFR and presumably true GFR was the higher the more rapidly kidney function declined. The new kinetGFR estimate appears clinically more plausible than the former KeGFR estimates.

IntroductionNeuroleptic malignant syndrome (NMS) is a rare, potentially life‐threatening antipsychotic‐associated disorder that requires an efficient and timely therapy. The aim of the study was to compare the effectiveness of different NMS therapies and to analyze its outcome depending on NMS severity.MethodSystematic search for NMS cases in biomedical databases. The focus of the analysis was on therapy with dantrolene, bromocriptine, and electroconvulsive therapy (ECT) when each was compared with symptomatic therapy. Primary outcomes were the survival rate and the duration of treatment.Result405 case reports were included. Overall, no statistically significant differences regarding mortality rate or duration of treatment were found between dantrolene, bromocriptine, or ECT compared to supportive care. A subgroup analysis regarding NMS severity showed that the mortality under specific NMS pharmacotherapy (dantrolene, bromocriptine) and under ECT was significantly lower than under purely symptomatic therapy in severe NMS (P = 0.018). The difference was not significant in mild and moderate cases.DiscussionAn overall superiority of the specific NMS therapy (dantrolene, bromocriptine, and ECT) was not found in this study. When regarding severity classification, specific therapies were superior but only in severe cases, and ECT showed the lowest mortality rate. In previous case series, an effect on survival or the duration of the disease could only be observed in part for specific therapies, but the evidence available is inconsistent. The results of this study support our hypothesis that NMS treatment with dantrolene, bromocriptine, and ECT is advantageous over purely symptomatic therapy in severe NMS cases.

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?

Maßgeblich für die Arzneimitteldosierung ist die glomeruläre Filtrationsrate (GFR) nicht der Kreatininwert. Bei lebensbedrohlichen Erkrankungen darf man die Startdosis nicht vergessen, die zumeist der Normaldosis entspricht. Die Halbwertszeit gibt Auskunft über die Dauer des Dosierungsintervalls. Für konzentrationsabhängig wirkende Antibiotika, wie Daptomycin, Linezolid oder Colistin, ist ein hoher Spitzenspiegel der Zielspiegel. Für zeitabhängig wirkende Antibiotika ist ein hoher Talspiegel der Zielspiegel. Bei Piperacillin, Meropenem und Vancomycin wird deshalb die Dauerinfusion bevorzugt. Mit kontinuierlichen Nierenersatzverfahren entspricht die Gesamtfiltration oft einer GFR von 30–50 ml/min: Viele Antibiotika kann man dann in voller Normaldosis verabreichen. Nach intermittierender Hämodialyse empfiehlt es sich, eine erneute Startdosis zu geben um danach ausreichende Spiegel zu garantieren.