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Despite (repeated) boosting, kidney transplant recipients (KTRs) may remain at increased risk of severe COVID-19 since a substantial number of individuals remain seronegative or with low antibody titers. In particular, mycophenolic acid use has been shown to affect antibody formation negatively and may be an important modifiable risk factor. We investigated the exposure–response relationship between mycophenolic acid 12-hour area under the curve (AUC 0–12h) exposure and seroconversion including antibody titers after vaccination using mRNA-1273 SARS-CoV-2 vaccine (Moderna) in 316 KTRs from our center that participated in the national Dutch renal patients COVID-19 vaccination – long term efficacy and safety of SARS-CoV-2 vaccination in kidney disease patients vaccination study. After two vaccination doses, 162 (51%) KTRs seroconverted. KTRs treated with mycophenolic acid showed less seroconversion and lower antibody titers compared with KTRs without mycophenolic acid (44% vs. 77%, and 36 binding antibody units (BAU)/mL vs. 340 BAU/mL; P < 0.001). The mean mycophenolic acid AUC 0–12h exposure was significantly lower in KTRs who seroconverted compared with KTRs who did not (39 vs. 29 mg⋅h/L; P < 0.001). High mycophenolic acid exposure (±90 mg⋅h/L) and no exposure to mycophenolic acid resulted in a seroconversion rate ranging from 10% to 80%. Every 10 mg⋅h/L increase in mycophenolic acid AUC 0–12h gave an adjusted odds ratio for seroconversion of 0.87 (95% confidence interval (CI), 0.79–0.97; P = 0.010) and 0.89 (95% CI, 0.85–0.93; P < 0.001) for KTRs on dual and triple maintenance immunosuppressive therapy, respectively. Higher mycophenolic acid AUC 0–12h correlated with lower antibody titers (R = 0.44, P < 0.001). This study demonstrates the exposure–response relationship between gold standard mycophenolic acid exposure and antibody formation to support interventional studies investigating mycophenolic acid adjustment to improve antibody formation after further boosting.

Introduction: In autosomal dominant polycystic kidney disease (ADPKD) patients, predicting renal disease progression is important to make a prognosis and to support the clinical decision whether to initiate renoprotective therapy. Conventional markers all have their limitations. Metabolic profiling is a promising strategy for risk stratification. We determined the prognostic performance to identify patients with a fast progressive disease course and evaluated time-dependent changes in urinary metabolites. Methods: Targeted, quantitative metabolomics analysis (1H NMR-spectroscopy) was performed on spot urinary samples at two time points, baseline (n = 324, 61% female; mean age 45 years, SD 11; median eGFR 61 mL/min/1.73 m2, IQR 42–88; mean years of creatinine follow-up 3.7, SD 1.3) and a sample obtained after 3 years of follow-up (n = 112). Patients were stratified by their eGFR slope into fast and slow progressors based on an annualized change of > −3.0 or ≤ −3.0 mL/min/1.73 m2/year, respectively. Fifty-five urinary metabolites and ratios were quantified, and the significant ones were selected. Logistic regression was used to determine prognostic performance in identifying those with a fast progressive course using baseline urine samples. Repeated-measures ANOVA was used to analyze whether changes in urinary metabolites over a 3-year follow-up period differed between fast and slow progressors. Results: In a single urinary sample, the prognostic performance of urinary metabolites was comparable to that of a model including height-adjusted total kidney volume (htTKV, AUC = 0.67). Combined with htTKV, the predictive value of the metabolite model increased (AUC = 0.75). Longitudinal analyses showed an increase in the myoinositol/citrate ratio (p < 0.001) in fast progressors, while no significant change was found in those with slow progression, which is in-line with an overall increase in the myoinositol/citrate ratio as GFR declines. Conclusion: A metabolic profile, measured at a single time point, showed at least equivalent prognostic performance to an imaging-based risk marker in ADPKD. Changes in urinary metabolites over a 3-year follow-up period were associated with a fast progressive disease course.

Aims Immunosuppressant and kidney function monitoring are crucial for kidney transplant recipient follow-up. Microsamples enable remote sampling and minimise patient burden as compared to conventional venous sampling at the clinic. We developed a liquid chromatography-tandem mass spectrometry assay to quantify tacrolimus, mycophenolic acid (MPA), creatinine and iohexol in dried blood spot (DBS), and volumetric absorptive microsample (VAMS) samples. Methods The assay was successfully validated analytically for all analytes. Clinical validation was conducted by direct comparison of paired DBS, VAMS and venous reference samples from 25 kidney transplant recipients. Patients received iohexol 5-15 minutes before immunosuppressant intake and were sampled 0, 1, 2 and 3 hours thereafter, enabling tacrolimus and MPA area under the concentration-time curve (AUC) and creatinine-based and iohexol-based glomerular filtration rate (GFR) estimation. Method agreement was evaluated using Passing-Bablok regression, Bland-Altman analysis and the percentages of values within 15-30% of the reference (P-15-P-30) with a P-20 acceptance threshold of 80%. Results For DBS samples, method agreement was excellent for tacrolimus trough concentrations (n = 25, P-15 = 92.0%) and AUCs (n = 25; P-20 = 95.8%) and adequate for creatinine-based GFR trend monitoring (n = 25; P-20 = 80%). DBS-based MPA AUC assessment showed suboptimal agreement (n = 16; P-20 = 68.8%), but was considered acceptable given its P-30 of 100%. The assay performed inadequately for DBS-based iohexol GFR determination (n = 24; P-20 = 75%). The VAMS technique generally showed inferior performance, but can be considered for certain situations. Conclusion The assay was successfully validated for tacrolimus, MPA and creatinine quantification in DBS samples, enabling simultaneous remote kidney function trend monitoring and immunosuppressant therapeutic drug monitoring in kidney transplant recipients.

Acute kidney injury (AKI) is a frequent complication in patients with Staphylococcus aureus bacteremia (SAB), with a significant impact on patient management and outcome. This study aimed to provide insight in the proportion of patients with SAB that develop AKI, the risk factors for developing AKI in this population, and its reversibility. In this retrospective, multicenter cohort study, adult patients with SAB were eligible for inclusion. Patient characteristics, clinical variables, and laboratory results were retrieved from the electronic patient files. Primary outcome was development of AKI, defined as 1.5 times baseline creatinine. Secondary outcomes were reversibility of AKI and risk factors for AKI. A total of 315 patients with SAB were included, of whom 115/315 (37%) developed acute kidney injury. In 68/115 (59%), the AKI was reversible. If kidney function recovered, this occurred within 7 days in 56/68 (82%) of patients. In multivariable logistic regression analyses, independent risk factors for AKI were as follows: complicated SAB, use of diuretics, and hemodynamic instability. Development of AKI was associated with 30-day mortality (OR 3.9; CI 2.2-6.9; p < 0.01). Acute kidney injury is a frequent complication in patients with Staphylococcus aureus bacteremia. Considering the irreversibility in a relevant proportion of patients, future research into the underlying pathophysiology and potential interventions is warranted.

Background and objectives In older people with kidney failure, improving health-related quality of life is often more important than solely prolonging life. However, little is known about the effect of dialysis initiation on health-related quality of life in older patients. Therefore, we investigated the evolution of health-related quality of life before and after starting dialysis in older patients with kidney failure. Design, setting, participants, & measurements The European Quality study is an ongoing prospective, multicenter study in patients aged >_65 years with an incident eGFR

Acute cellular rejection (ACR) occurs in 10% of renal allograft recipients and is characterized by leukocyte infiltration as observed in needle biopsies. ACR onset is subject to several risk factors, including delayed graft function (DGF). As the impact of DGF on the etiology of ACR remains unclear, this study analyzed the association between presence of leukocyte subsets and ACR onset, in DCD kidney biopsies with extensive DGF following transplantation. Immunohistochemical analysis of protocol biopsies taken 10 days after kidney transplantation revealed that patients with high levels of renal CD163+ macrophages have a decreased risk (OR = 0.021, P = 0.008) for ACR in the first 6 months after transplantation. In pre-transplant biopsies of a comparable DCD cohort, with >80% DGF, presence of donor CD163+ macrophages showed no effect on ACR risk. Therefore, leukocyte infiltrate present during the inflammatory response at the time of DGF may contain anti-inflammatory macrophages that exert a protective effect against ACR development.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation, leading to growth in kidney volume and renal function decline. Although therapies have emerged, there is still an important unmet need for slowing the rate of disease progression in ADPKD. High intracellular levels of adenosine 3′,5′-cyclic monophosphate (cAMP) are involved in cell proliferation and fluid secretion, resulting in cyst formation. Somatostatin (SST), a hormone that is involved in many cell processes, has the ability to inhibit intracellular cAMP production. However, SST itself has limited therapeutic potential since it is rapidly eliminated in vivo. Therefore analogues have been synthesized, which have a longer half-life and may be promising agents in the treatment of ADPKD. This review provides an overview of the complex physiological effects of SST, in particular renal, and the potential therapeutic role of SST analogues in ADPKD.

Background The variable course of autosomal dominant polycystic kidney disease (ADPKD), and the advent of renoprotective treatment require early risk stratification. We applied urinary metabolomics to explore differences associated with estimated glomerular filtration rate (eGFR; CKD-EPI equation) and future eGFR decline. Methods Targeted, quantitative metabolic profiling (1H NMR-spectroscopy) was performed on baseline spot urine samples obtained from 501 patients with ADPKD. The discovery cohort consisted of 338 patients (56% female, median values for age 46 [IQR 38 to 52] years, eGFR 62 [IQR 45 to 85] ml/min/1.73m2, follow-up time 2.5 [range 1 to 3] years, and annual eGFR slope -3.3 [IQR -5.3 to -1.3] ml/min/1.73m2/year). An independent cohort (n = 163) was used for validation. Multivariate modelling and linear regression were used to analyze the associations between urinary metabolites and eGFR, and eGFR decline over time. Results Twenty-nine known urinary metabolites were quantified from the spectra using a semi-automatic quantification routine. The model optimization routine resulted in four metabolites that most strongly associated with actual eGFR in the discovery cohort (F = 128.9, P = 7×10-54, R2 = 0.724). A model using the ratio of two other metabolites, urinary alanine/citrate, showed the best association with future annual change in eGFR (F = 51.07, P = 7.26×10-12, R2 = 0.150). This association remained significant after adjustment for clinical risk markers including height-adjusted total kidney volume (htTKV). Results were confirmed in the validation cohort. Conclusions Quantitative NMR profiling identified urinary metabolic markers that associated with actual eGFR and future rate of eGFR decline. The urinary alanine/citrate ratio showed additional value beyond conventional risk markers.

OBJECTIVE In patients with type 1 diabetes and end-stage renal disease, it is controversial whether a simultaneous pancreas-kidney (SPK) transplantation improves survival compared with kidney transplantation alone. We compared long-term survival in SPK and living- or deceased-donor kidney transplant recipients. RESEARCH DESIGN AND METHODS We included all 2,796 patients with type 1 diabetes in the Netherlands who started renal replacement therapy between 1986 and 2016. We used multivariable Cox regression analyses adjusted for recipient age and sex, dialysis modality and vintage, transplantation era, and donor age to compare all-cause mortality between deceased- or living-donor kidney and SPK transplant recipients. Separately, we analyzed mortality between regions where SPK transplant was the preferred intervention (80% SPK) versus regions where a kidney transplant alone was favored (30% SPK). RESULTS Of 996 transplanted patients, 42%, 16%, and 42% received a deceased- or living-donor kidney or SPK transplant, respectively. Mean (SD) age at transplantation was 50 (11), 48 (11), and 42 (8) years, respectively. Median (95% CI) survival time was 7.3 (6.2; 8.3), 10.5 (7.2; 13.7), and 16.5 (15.1; 17.9) years, respectively. SPK recipients with a functioning pancreas graft at 1 year (91%) had the highest survival (median 17.4 years). Compared with deceased-donor kidney transplant recipients, adjusted hazard ratios (95% CI) for 10- and 20-year all-cause mortality were 0.79 (0.49; 1.29) and 0.98 (0.69; 1.39) for living-donor kidney and 0.67 (0.46; 0.98) and 0.79 (0.60; 1.05) for SPK recipients, respectively. A treatment strategy favoring SPK over kidney transplantation alone showed 10- and 20-year mortality hazard ratios of 0.56 (0.40; 0.78) and 0.69 (0.52; 0.90), respectively. CONCLUSIONS Compared with living- or deceased-donor kidney transplantation, SPK transplant was associated with improved patient survival, especially in recipients with a long-term functioning pancreatic graft, and resulted in an almost twofold lower 10-year mortality rate.

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Background Somatostatin (SST) inhibits intracellular cyclic adenosine monophosphate (cAMP) production and thus may modify cyst formation in autosomal dominant polycystic kidney disease (ADPKD). We investigated whether endogenous plasma SST concentration is associated with disease severity and progression in patients with ADPKD, and whether plasma SST concentrations change during treatment with a vasopressin V2 receptor antagonist or SST analogue. Methods In this observational study, fasting concentrations of SST were measured in 127 ADPKD patients (diagnosed upon the revised Ravine criteria) by ELISA. cAMP was measured in 24 h urine by Radio Immuno Assay. Kidney function was measured (mGFR) as 125I-iothalamate clearance, and total kidney volume was measured by MRI volumetry and adjusted for height (htTKV). Disease progression was expressed as annual change in mGFR and htTKV. Additionally, baseline versus follow-up SST concentrations were compared in ADPKD patients during vasopressin V2 receptor antagonist (tolvaptan) (n = 27) or SST analogue (lanreotide) treatment (n = 25). Results In 127 ADPKD patients, 41 ± 11 years, 44% female, eGFR 73 ± 32 ml/min/1.73m2, mGFR 75 ± 32 ml/min/1.73m2 and htTKV 826 (521–1297) ml/m, SST concentration was 48.5 (34.3–77.8) pg/ml. At baseline, SST was associated with urinary cAMP, mGFR and htTKV (p = 0.02, p = 0.004 and p = 0.02, respectively), but these associations lost significance after adjustment for age and sex or protein intake (p = 0.09, p = 0.06 and p = 0.15 respectively). Baseline SST was not associated with annual change in mGFR, or htTKV during follow-up (st. β = − 0.02, p = 0.87 and st. β = − 0.07, p = 0.54 respectively). During treatment with tolvaptan SST levels remained stable 38.2 (23.8–70.7) pg/mL vs. 39.8 (31.2–58.5) pg/mL, p = 0.85), whereas SST levels decreased significantly during treatment with lanreotide (42.5 (33.2–55.0) pg/ml vs. 29.3 (24.8–37.6), p = 0.008). Conclusions Fasting plasma SST concentration is not associated with disease severity or progression in patients with ADPKD. Treatment with lanreotide caused a decrease in SST concentration. These data suggest that plasma SST cannot be used as a biomarker to assess prognosis in ADPKD, but leave the possibility open that change in SST concentration during lanreotide treatment may reflect therapy efficacy. Electronic supplementary material The online version of this article (10.1186/s12882-018-1176-y) contains supplementary material, which is available to authorized users.

Contains fulltext : 193194.pdf (Publisher’s version ) (Closed access) AIMS: Everolimus is a drug from the class of mammalian target of rapamycin inhibitors used for both immunosuppressant and oncological indications. We postulate that there is room for improvement of dosing, as the optimal immunosuppressive dose in calcineurin-free regimens is unknown and since the once daily dosing regimen for oncological indications is often associated with treatment-limiting toxicity. METHODS: We developed a mechanistic population pharmacokinetic model for everolimus in cancer and transplant patients and explored alternative dosing regimens. RESULTS: We found that formulation did not influence bioavailability and that use of >20 mg prednisolone daily increased everolimus clearance. In transplant patients, the approved dose of 0.75-1 mg twice daily (BID) results in subtherapeutic trough levels (

Mammalian target of rapamycin inhibitors may confer cardioprotective advantages, but clinical data are limited. In the open-label ELEVATE trial, kidney transplant patients were randomized at 10 to 14 weeks after transplant to convert from calcineurin inhibitor (CNI) to everolimus or remain on standard CNI therapy. Prespecified end points included left ventricular mass index and, in a subpopulation of patients, arterial stiffness as measured by pulse wave velocity. The mean change in left ventricular mass index from randomization was similar with everolimus versus CNI (month 24, −4.37 g/m2.7 versus −5.26 g/m2.7; mean difference, 0.89 [p = 0.392]). At month 24, left ventricular hypertrophy was present in 41.7% versus 37.7% of everolimus and CNI patients, respectively. Mean pulse wave velocity remained stable with both everolimus (mean change from randomization to month 12, −0.24 m/s; month 24, −0.03 m/s) and CNI (month 12, 0.11 m/s; month 24, 0.16 m/s). The change in mean ambulatory nighttime blood pressure from randomization showed a benefit for diastolic pressure at month 12 (P = 0.039) but not at month 24. Major adverse cardiac events occurred in 1.1% and 4.2% of everolimus-treated and CNI-treated patients, respectively, by month 12 (P = 0.018) and 2.3% (8/353) and 4.5% by month 24 (P = 0.145). Overall, these data do not suggest a clinically relevant effect on cardiac end points after early conversion from CNI to a CNI-free everolimus-based regimen.

Introduction and Aims The DIPAK-1 Study investigates the reno- and hepatoprotective efficacy of the somatostatin analog lanreotide compared with standard care in patients with later stage autosomal dominant polycystic kidney disease (ADPKD). During this trial, we witnessed several episodes of hepatic cyst infection, all during lanreotide treatment. We describe these events and provide a review of the literature. Methods The DIPAK-1 Study is an ongoing investigator-driven, randomized, controlled, open-label multicenter trial. Patients (ADPKD, ages 18–60 years, estimated glomerular filtration rate 30–60 mL/min/1.73 m2) were randomized 1:1 to receive lanreotide 120 mg subcutaneously every 28 days or standard care during 120 weeks. Hepatic cyst infection was diagnosed by local physicians. Results We included 309 ADPKD patients of which seven (median age 53 years [interquartile range: 48–55], 71% female, median estimated glomerular filtration rate 42 mL/min/1.73 m2 [interquartile range: 41–58]) developed eight episodes of hepatic cyst infection during 342 patient-years of lanreotide use (0.23 cases per 10 patient-years). These events were limited to patients receiving lanreotide (p

Item does not contain fulltext Solid-phase multiplex-bead assays are widely used in transplantation to detect anti-human leukocyte antigen (HLA) antibodies. These assays enable high resolution detection of low levels of HLA antibodies. However, multiplex-bead assays are costly and yield variable measurements that limit the comparison of results between laboratories. In the context of a Dutch national Consortium study we aimed to determine the inter-assay and inter-machine variability of multiplex-bead assays, and we assessed how to reduce the assay reagents costs. Fifteen sera containing a variety of HLA antibodies were used yielding in total 7092 median fluorescence intensities (MFI) values. The inter-assay and inter-machine mean absolute relative differences (MARD) of the screening assay were 12% and 13%, respectively. The single antigen bead (SAB) inter-assay MARD was comparable, but showed a higher lot-to-lot variability. Reduction of screening assay reagents to 50% or 40% of manufacturers' recommendations resulted in MFI values comparable to 100% of the reagents, with an MARD of 12% or 14%, respectively. The MARD of the 50% and 40% SAB assay reagent reductions were 11% and 22%, respectively. From this study, we conclude that the reagents can be reliably reduced at least to 50% of manufacturers' recommendations with virtually no differences in HLA antibody assignments.

A 62-year-old woman with a history of genetically confirmed hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) was admitted because of chronic diarrhoea. During admission she developed a rapidly progressive nephrotic syndrome. Reactive amyloid A (AA) amyloidosis was confirmed after colonic and renal biopsy which showed deposition of amyloid. After initial treatment with high-dosed corticosteroids, therapy was switched to anakinra, an IL-1 receptor antagonist, but her symptoms persisted. After cessation of anakinra, a marked exacerbation of the intestinal symptoms was noted. Nine months after the initial diagnosis of reactive amyloidosis without any amelioration of the symptoms and a decreasing quality of life, our patient declined further treatment and died soon after. This case demonstrates that AA amyloidosis does occur in patients with HIDS and can present with intestinal symptoms and proteinuria. Once amyloidosis is diagnosed the goal of treatment is to prevent further complications. In this case report we give an overview of previous cases with amyloidosis complicating HIDS with the treatments received and propose a step-up treatment plan for future cases.

Background: There are limited therapeutic options to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Recent clinical studies indicate that somatostatin analogues are promising for treating polycystic liver disease and potentially also for the kidney phenotype. We report on the design of the DIPAK 1 (Developing Interventions to Halt Progression of ADPKD 1) Study, which will examine the efficacy of the somatostatin analogue lanreotide on preservation of kidney function in ADPKD.Study Design: The DIPAK 1 Study is an investigator-driven, randomized, multicenter, controlled, clinical trial.Setting & Participants: We plan to enroll 300 individuals with ADPKD and estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m(2) who are aged 18-60 years.Intervention: Patients will be randomly assigned (1: 1) to standard care or lanreotide, 120 mg, subcutaneously every 28 days for 120 weeks, in addition to standard care.Outcomes: Main study outcome is the slope through serial eGFR measurements starting at week 12 until end of treatment for lanreotide versus standard care. Secondary outcome parameters include change in eGFR from pretreatment versus 12 weeks after treatment cessation, change in kidney volume, change in liver volume, and change in quality of life.Measurements: Blood and urine will be collected and questionnaires will be filled in following a fixed scheme. Magnetic resonance imaging will be performed for assessment of kidney and liver volume.Results: Assuming an average change in eGFR of 5.2 +/- 4.3 (SD) mL/min/1.73 m(2) per year in untreated patients, 150 patients are needed in each group to detect a 30% reduction in the rate of kidney function loss between treatment groups with 80% power, 2-sided a = 0.05, and 20% protocol violators and/or dropouts.Limitations: The design is an open randomized controlled trial and measurement of our primary end point does not begin at randomization.Conclusions: The DIPAK 1 Study will show whether subcutaneous administration of lanreotide every 4 weeks attenuates disease progression in patients with ADPKD. (C) 2014 by the National Kidney Foundation, Inc.

M.G.J. de Boer, F.P. Kroon, S. le Cessie, J.W. de Fijter, J.T. van Dissel. Risk factors for Pneumocystis jirovecii pneumonia in kidney transplant recipients and appraisal of strategies for selective use of chemoprophylaxis. Transpl Infect Dis 2011. All rights reserved Abstract: Risk stratification-based duration of trimethoprim-sulfamethoxazole (TMP-SMX) chemoprophylaxis to prevent Pneumocystis pneumonia (PCP) in kidney transplant recipients is not a universally adapted strategy and supporting evidence-based sources are limited. We performed a large retrospective study to identify risk factors for PCP in kidney transplant recipients and to define parameters for use in clinical prophylaxis guidelines. Fifty consecutive patients with confirmed PCP and 2 time-matched controls per case were enrolled. All patients were participants of the kidney transplantation program of the Leiden University Medical Center, a tertiary care hospital in the Netherlands. Potential risk factors were compared between groups by uni- and multivariate matched analyses. At transplantation, age >55 years (adjusted odds ratio [OR] 2.7, 95% confidence interval [CI] 1.3-5.9) and not receiving basiliximab induction therapy (adjusted OR 4.3, 95% CI 1.1-17.1) predicted development of PCP. In the final multivariate analysis, only cytomegalovirus infection (adjusted OR 3.0, 95% CI 1.2-7.9) and rejection treatment (adjusted OR 5.8, 95% CI 1.9-18) were found to be independently associated with PCP. Using the variables identified by the multivariate analyses, effects of different hypothetical chemoprophylaxis strategies were systematically evaluated. Exploring different scenarios showed that chemoprophylaxis in the first 6 months for all renal transplant patients - and during the first year posttransplantation for patients >55 years of age or those treated for rejection - would result in very low PCP incidence and optimal avoidance of TMP-SMX toxicity. The results provide a rationale for further prospective study on targeted provision of chemoprophylaxis to prevent PCP in kidney transplant patients.