Population-based reference values for kidney function and kidney function decline in 25- to 95-year-old Germans without and with diabetes.

Understanding normal aging of kidney function is pivotal to help distinguish individuals at particular risk for chronic kidney disease. Glomerular filtration rate (GFR) is typically estimated via serum creatinine (eGFRcrea) or cystatin C (eGFRcys). Since population-based age-group-specific reference values for eGFR and eGFR-decline are scarce, we aimed to provide such reference values from population-based data of a wide age range. In four German population-based cohorts (KORA-3, KORA-4, AugUR, DIACORE), participants underwent medical exams, interview, and blood draw up to five times within up to 25 years. We analyzed eGFRcrea and eGFRcys cross-sectionally and longitudinally (12,000 individuals, age 25-95 years). Cross-sectionally, we found age-group-specific eGFRcrea to decrease approximately linearly across the full age range, for eGFRcys up to the age of 60 years. Within age-groups, there was little difference by sex or diabetes status. Longitudinally, linear mixed models estimated an annual eGFRcrea decline of -0.80 [95% confidence interval -0.82, -0.77], -0.79 [-0.83, -0.76], and -1.20 mL/min/1.73m2 [-1.33, -1.08] for the general population, "healthy" individuals, or individuals with diabetes, respectively. Reference values for eGFR using cross-sectional data were shown as percentile curves for "healthy" individuals and for individuals with diabetes. Reference values for eGFR-decline using longitudinal data were presented as 95% prediction intervals for "healthy" individuals and for individuals with diabetes, obesity, and/or albuminuria. Thus, our results can help clinicians to judge eGFR values in individuals seen in clinical practice according to their age and to understand the expected range of annual eGFR-decline based on their risk profile.

Development and Validation of a Prediction Model for Future Estimated Glomerular Filtration Rate in People With Type 2 Diabetes and Chronic Kidney Disease.

Importance: Type 2 diabetes increases the risk of progressive diabetic kidney disease, but reliable prediction tools that can be used in clinical practice and aid in patients' understanding of disease progression are currently lacking. Objective: To develop and externally validate a model to predict future trajectories in estimated glomerular filtration rate (eGFR) in adults with type 2 diabetes and chronic kidney disease using data from 3 European multinational cohorts. Design, Setting, and Participants: This prognostic study used baseline and follow-up information collected between February 2010 and December 2019 from 3 prospective multinational cohort studies: PROVALID (Prospective Cohort Study in Patients with Type 2 Diabetes Mellitus for Validation of Biomarkers), GCKD (German Chronic Kidney Disease), and DIACORE (Diabetes Cohorte). A total of 4637 adult participants (aged 18-75 years) with type 2 diabetes and mildly to moderately impaired kidney function (baseline eGFR of ≥30 mL/min/1.73 m2) were included. Data were analyzed between June 30, 2021, and January 31, 2023. Main Outcomes and Measures: Thirteen variables readily available from routine clinical care visits (age, sex, body mass index; smoking status; hemoglobin A1c [mmol/mol and percentage]; hemoglobin, and serum cholesterol levels; mean arterial pressure, urinary albumin-creatinine ratio, and intake of glucose-lowering, blood-pressure lowering, or lipid-lowering medication) were selected as predictors. Repeated eGFR measurements at baseline and follow-up visits were used as the outcome. A linear mixed-effects model for repeated eGFR measurements at study entry up to the last recorded follow-up visit (up to 5 years after baseline) was fit and externally validated. Results: Among 4637 adults with type 2 diabetes and chronic kidney disease (mean [SD] age at baseline, 63.5 [9.1] years; 2680 men [57.8%]; all of White race), 3323 participants from the PROVALID and GCKD studies (mean [SD] age at baseline, 63.2 [9.3] years; 1864 men [56.1%]) were included in the model development cohort, and 1314 participants from the DIACORE study (mean [SD] age at baseline, 64.5 [8.3] years; 816 men [62.1%]) were included in the external validation cohort, with a mean (SD) follow-up of 5.0 (0.6) years. Updating the random coefficient estimates with baseline eGFR values yielded improved predictive performance, which was particularly evident in the visual inspection of the calibration curve (calibration slope at 5 years: 1.09; 95% CI, 1.04-1.15). The prediction model had good discrimination in the validation cohort, with the lowest C statistic at 5 years after baseline (0.79; 95% CI, 0.77-0.80). The model also had predictive accuracy, with an R2 ranging from 0.70 (95% CI, 0.63-0.76) at year 1 to 0.58 (95% CI, 0.53-0.63) at year 5. Conclusions and Relevance: In this prognostic study, a reliable prediction model was developed and externally validated; the robust model was well calibrated and capable of predicting kidney function decline up to 5 years after baseline. The results and prediction model are publicly available in an accompanying web-based application, which may open the way for improved prediction of individual eGFR trajectories and disease progression.

Long-Term Weight Change and Glycemic Control in Patients With Type 2 Diabetes Mellitus and Treated vs. Untreated Sleep-Disordered Breathing-Analysis From the DIAbetes COhoRtE.

Hypothesis: Positive airway pressure (PAP) is the standard treatment for sleep-disordered breathing (SDB), a prevalent condition in patients with type 2 diabetes mellitus (DM2). Recent studies showed that short-term PAP treatment may cause weight gain. However, long-term data for patients with DM2 are scarce. Therefore, the aim of the present analysis was to assess changes in weight and glycemic control in patients with DM2 and treated vs. untreated SDB. Methods: The DIAbetes COhoRtE (DIACORE) study is a prospective population-based cohort study in patients with DM2. At baseline, patients of the DIACORE-SDB sub-study were tested for SDB [defined as apnea-hypopnea-index (AHI) ≥ 15/h] using a two-channel ambulatory SDB-monitoring device. In this observational study, PAP treatment was initiated in a subgroup of patients with SDB (SDB PAP) within clinical routine between the baseline and first follow-up visit [median observation period of 2.3 (2.2; 2.4) years], whereas the other patients with SDB did not receive PAP (SDB untreated). At baseline and first follow-up visit, weight and HbA1c were assessed. Results: Of the 346 patients with SDB [mean age 68 years, 71% male, body-mass index (BMI) 31.9 kg/m2], 17% were in the SDB PAP and 83% in the SDB untreated group. Weight change within the observation period was similar in both groups (-0.2 and -0.9 kg; p = 0.322). The percentage of patients with severe weight gain (≥ 5 kg) within the observation period was significantly higher in the SDB PAP group compared to the SDB untreated group (15.0 vs. 5.6%; p = 0.011). Multivariable regression analysis, accounting for baseline HbA1c, insulin substitution, BMI, waist-to-hip ratio (WHR), physical activity, and AHI, showed that PAP treatment was significantly associated with a weight gain ≥ 5 kg [odds ratio (OR) = 3.497; 95% CI (1.343; 9.106); p = 0.010] and an increase in HbA1c [B = 2.410; 95% CI (0.118; 4.702); p = 0.039]. Conclusion: Median weight change was similar in patients with SDB with and without PAP treatment. However, patients with DM2 and PAP treatment have an increased risk of severe long-term weight gain and an increase in HbA1c. Clinical Trial registration: DRKS00010498.

Sleep apnoea and incident malignancy in type 2 diabetes.

BACKGROUND: Sleep apnoea and type 2 diabetes (T2D) have been linked to malignancy. The aim of the present study was to evaluate the association between sleep apnoea and incidence of malignancy in patients with T2D. METHODS: The DIACORE (DIAbetes COhoRtE) study is a prospective, population-based cohort study in T2D patients. In the sleep disordered breathing substudy, the apnoea-hypopnoea index (AHI), oxygen desaturation index (ODI) and percentage of night-time spent with a peripheral oxygen saturation of <90% (t sat90%) were assessed using a two-channel ambulatory monitoring device. Malignancy diagnoses were gathered using self-reported medical history data validated by medical records. Hazard ratios (HRs) for incident malignancy were derived by Cox regression adjusting for sex, age, body mass index, smoking status, alcohol intake, socioeconomic status and HbA1c. RESULTS: Of 1239 patients with T2D (mean age 67 years, 41% female, mean body mass index 30.9 kg·m-2), 79 (6.4%) were first-time diagnosed with a malignancy within a median follow-up period of 2.7 years (interquartile range 2.2-4.5 years). AHI, ODI and t sat90% were not associated with incident malignancy. In subgroup analysis, females showed increased cancer risk per AHI unit (adjusted HR 1.03 per AHI unit, 95% CI 1.00-1.06; p=0.028) and severe sleep apnoea (defined as AHI ≥30 events·h-1; adjusted HR 4.19, 95% CI 1.39-12.77; p=0.012). This was not seen in males, and a significant interaction was observed (interaction terms p=0.048 and p=0.033, respectively). CONCLUSION: Sleep apnoea was not associated with incident malignancy in T2D patients. However, stratified analysis revealed a significant association between sleep apnoea and incident malignancy in females, but not in males.

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

Daytime napping and diabetes-associated kidney disease.

BACKGROUND: Diabetes-associated Kidney Disease (DKD) is a common comorbidity in patients with type 2 diabetes. The present study investigates whether daytime sleeping duration in patients, ill with type 2 diabetes, is associated with DKD. METHODS: A total of 733 outpatients of the cross-sectional baseline survey of the DIACORE study were analyzed with respect to their self-reported daytime sleeping duration, assessed by a standardized questionnaire. DKD was defined as eGFR <60 ml/min/1.73 m2 and/or urinary albumin-to-creatinine-ratio (UACR) > 30 mg/g. RESULTS: Mean daytime sleeping duration was 17 ± 27 min. With increasing daytime sleeping duration a statistically significant decrease in eGFR (p = 0.002) and increase in UACR (p < 0.001) were found, respectively. Prevalence of DKD was significantly higher in patients with longer daytime sleeping duration (31% in patients not napping, 40% in patients napping less than 30 min, 47% in patients napping 30-60 min, 56% in patients napping 60 min or more; p = 0.001). After accounting for known modulators (Age, sex, BMI, waist-hip-ratio, systolic and diastolic blood pressure, physical activity, diabetes duration, HbA1c, homeostasis model assessment (HOMA-Index), nighttime sleeping duration, apnea-hypopnea-index (AHI), Epworth Sleepiness Scale (ESS)), longer daytime sleeping duration was significantly associated with impaired eGFR [B (95% CI) = -0.05 (-0.09; 0.00), p = 0.044] and increased UACR [B (95% CI) = 0.01 (0.01; 0.02), p < 0.001], respectively. CONCLUSION: Increased daytime sleeping duration is significantly associated with reduced eGFR and higher UACR, independent of known modulators of DKD. The direction of this relationship remains unclear.

Association of sleep-disordered breathing with severe chronic vascular disease in patients with type 2 diabetes.

BACKGROUND: Severe chronic vascular disease (CVD) is a major cause of co-morbidity and mortality in patients with type 2 diabetes (DM2). Sleep-disordered breathing (SDB) has been linked to CVD in the general population due to enhanced sympathetic activation, oxidative stress, endothelial dysfunction, and hypertension; however data for DM2 patients is scarce. Therefore, the aim of the present analysis to assess whether SDB is associated with CVD in patients with DM2, independent of other known associated factors. METHODS: We analyzed cross-sectional data of 679 patients with DM2 from the DIACORE-SDB sub-study for association of SDB with CVD. SDB was assessed with a validated 2-channel ambulatory monitoring device. CVD was ascertained as a previous diagnosis of peripheral artery disease (PAD), coronary artery disease (CAD), or stroke via medical records and general practitioners. RESULTS: Of the analyzed 679 patients, 228 (34%) had SDB (respiratory event index [REI] ≥15/hour); and were significantly more often affected by CVD than patients without SDB (38% vs. 23%, p < 0.01; PAD 7% vs. 2%, p = 0.01; CAD 27% vs. 18%, p = 0.01; stroke 11% vs. 6%, p = 0.07). Regression analysis accounting for known modulators of CVD, such as age, body-mass index, systolic blood pressure, duration of DM2, HbA1c, smoking status, and low-density lipoprotein showed that the REI was independently associated with CVD (OR 1.099 per 5 REI points; 95%CI = [1.024, 1.179]). CONCLUSIONS: In patients with DM2, SDB is significantly associated with CVD, independent of other known modulators of atherosclerosis.

Biomarker-guided Intervention to Prevent Acute Kidney Injury After Major Surgery: The Prospective Randomized BigpAK Study.

OBJECTIVE: To determine the impact of renal biomarker-guided implementation of the Kidney Disease Improving Global Outcomes (KDIGO) care bundle on the incidence of acute kidney injury (AKI) after major noncardiac surgery in a single-center unblinded randomized clinical trial. BACKGROUND: Early optimization of volume status and discontinuation of nephrotoxic medication before the occurrence of AKI may be the crucial step to reduce preventable AKI. METHODS: The urinary biomarker-triggered KDIGO care bundle (early optimization of fluid status, maintenance of perfusion pressure, discontinuation of nephrotoxic agents) was compared to standard intensive care unit (ICU) care in 121 patients with an increased AKI risk after major abdominal surgery that was determined by urinary biomarker (inhibitor of metalloproteinase-2 × insulin-like growth factor-binding protein 7) >0.3. Incidence of overall AKI, severity of AKI, length of stay, major kidney events at discharge, and cost effectiveness were evaluated. RESULTS: The overall stages of AKI were not statistically different between the 2 groups, but in patients with inhibitor of metalloproteinase-2 × insulin-like growth factor-binding protein 7 values of 0.3 to 2.0 a subgroup analysis demonstrated a significantly reduced incidence of AKI 13/48 (27.1%) in the intervention group compared to control 24/50 (48.0%, P = 0.03). Incidence of moderate and severe AKI (P = 0.04), incidence of creatinine increase >25% of baseline value (P = 0.01), length of ICU, and hospital stay (P = 0.04) were significantly lower in the intervention group. Intervention was associated with cost reduction. There were no significant differences regarding renal replacement therapy, in-hospital mortality, or major kidney events at hospital discharge. CONCLUSIONS: Early biomarker-based prediction of imminent AKI followed by implementation of KDIGO care bundle reduced AKI severity, postoperative creatinine increase, length of ICU, and hospital stay in patients after major noncardiac surgery.

Infiltration of Macrophages Correlates with Severity of Allograft Rejection and Outcome in Human Kidney Transplantation.

OBJECTIVE: Despite substantial progress in recent years, graft survival beyond the first year still requires improvement. Since modern immunosuppression addresses mainly T-cell activation and proliferation, we studied macrophage infiltration into the allografts of 103 kidney transplant recipients during acute antibody and T-cell mediated rejection. Macrophage infiltration was correlated with both graft function and graft survival until month 36 after transplantation. RESULTS: Macrophage infiltration was significantly elevated in antibody-mediated and T-cell mediated rejection, but not in kidneys with established IFTA. Treatment of rejection with steroids was less successful in patients with more prominent macrophage infiltration into the allografts. Macrophage infiltration was accompanied by increased cell proliferation as well as antigen presentation. With regard to the compartmental distribution severity of T-cell-mediated rejection was correlated to the amount of CD68+ cells especially in the peritubular and perivascular compartment, whereas biopsies with ABMR showed mainly peritubular CD68 infiltration. Furthermore, severity of macrophage infiltration was a valid predictor of resulting creatinine values two weeks as well as two and three years after renal transplantation as illustrated by multivariate analysis. Additionally performed ROC curve analysis showed that magnitude of macrophage infiltration (below vs. above the median) was a valid predictor for the necessity to restart dialysis. Having additionally stratified biopsies in accordance to the magnitude of macrophage infiltration, differential CD68+ cell infiltration was reflected by striking differences in overall graft survival. CONCLUSION: The differences in acute allograft rejection have not only been reflected by different magnitudes of macrophage infiltration, but also by compartment-specific infiltration pattern and subsequent impact on resulting allograft function as well as need for dialysis initiation. There is a robust relationship between macrophage infiltration, accompanying antigen-presentation and resulting allograft function.

Traditional and nontraditional cardiovascular risk factors and estimated risk for coronary artery disease in renal transplant recipients: a single-center experience.

BACKGROUND/AIMS: The prevalence of cardiovascular disease in renal transplant recipients is markedly higher than in the general population due to the high prevalence of traditional cardiovascular risk factors, renal transplant function impairment and treatment with immunosuppressive drugs that affect blood pressure, cholesterol and blood glucose levels. METHODS: Cross-sectional analysis using our renal transplant clinic cohort investigating (1) the cardiovascular risk factors present in this cohort, and (2) estimating their impact on the risk of coronary artery disease (CAD) by using the Framingham algorithm. RESULTS: Control of modifiable cardiovascular risk factors in 231 renal transplant recipients is suboptimal, i.e. 47.2% of patients are hypertensive, 10.3% actively smoke, 39.4% have serum cholesterol concentrations >200 mg/dl, and 19.7% have diabetes mellitus. Blood pressure, age, hyperlipidemia, smoking and diabetes modulate the estimated CAD risk in males and females. Furthermore, a short time period (less than 1 year) since transplantation and increased serum creatinine levels negatively influenced the CAD risk in this patient population. CONCLUSION: According to current guidelines, the control of modifiable cardiovascular risk factors in renal transplant recipients is suboptimal. The decreasing CAD risk over time after transplantation may be due to the reduction of immunosuppressive drugs with time and survival bias.

Impact of Toll-like receptor 2 expression in renal allograft rejection.

BACKGROUND: An important role of TLR2 has been shown in various experimental models of renal ischaemia/reperfusion injury. To study the expression of TLR2 in renal allograft rejection systematically, we established an experimental rat transplantation model. METHODS: TLR2 expression was analysed in 99 human renal allograft biopsies, and in rat allografts at Day 6 and 28 after experimental renal transplantation. To discriminate whether regulation of TLR2 was following immunological processes after allogeneic transplantation or was a consequence from ischaemia/reperfusion injury, control animals subjected to syngeneic transplantation or to ischaemia/reperfusion damage were also investigated. RESULTS: TLR2 mRNA was significantly elevated in rat allografts with acute rejection on Day 6 and decreased spontaneously towards Day 28. TLR2 induction correlated with renal function and TLR2 excretion in the urine of transplanted rats. TLR2 staining was also significantly increased in human allografts with acute rejection. TLR2 protein could be localized in tubular epithelial cells and vascular endothelial cells, and in CD68- and CD4-positive infiltrating cells. CONCLUSIONS: TLR2 is markedly up-regulated in both experimental and human acute renal allograft rejection. Our data suggest a role for TLR2 during allogen-dependent graft damage after renal transplantation.

Synthesis and pharmacological evaluation of SNC80 analogues with a bridged piperazine ring.

To discover novel delta-opioid receptor ligands derived from SNC80 (1), a series of 6,8-diazabicyclo[3.2.2]nonane derivatives bearing two aromatic moieties was prepared, and the affinity toward delta, mu, and kappa receptors, as well as sigma receptors, was investigated. After removal of the 4-methoxybenzyl and 2,4-dimethoxybenzyl protecting groups, the pharmacophoric N,N-diethylcarbamoylbenzyl residue was attached to the 6,8-diazabicyclo[3.2.2]nonane framework to yield the designed delta receptor ligands. In a first series of compounds the benzhydryl moiety of SNC80 was dissected, and one phenyl ring was attached to the bicyclic framework. In a second series of delta ligands the complete benzhydryl moiety was introduced into the bicyclic scaffold. The determined delta receptor affinities show that compounds based on an (R)-glutamate-derived bicyclic scaffold possess higher delta receptor affinity than their (S)-glutamate-derived counterparts. Furthermore, an intact benzhydryl moiety leads to delta receptor ligands that are more potent than compounds with two separated aromatic moieties. Compound 24, with the same spatial arrangement of substituents around the benzhydryl stereocenter as SNC80, shows the highest delta receptor affinity of this series: K(i)=24 nM. Whereas the highly potent delta ligands reveal good selectivity against mu and kappa receptors, the sigma(1) and/or sigma(2) affinities of some compounds are almost in the same range as their delta receptor affinities, such as compound 25 (sigma(2): K(i)=83 nM; delta: K(i)=75 nM). In [(35)S]GTPgammaS assays the most potent delta ligands 24 and 25 showed almost the same intrinsic activity as the full agonist SNC80, proving the agonistic activity of 24 and 25. The enantiomeric 4-benzylidene derivatives 15 and ent-15 showed selective cytotoxicity toward the 5637 (bladder) and A-427 (small-cell lung) human tumor cell lines.

Is postcontrast trueFISP imaging advantageous?

RATIONALE AND OBJECTIVES: Contrast of trueFISP images depends mainly on the T2/T1 ratio. Consequently, there is a potential gain in signal intensity after administration of paramagnetic contrast medium despite the strong T2 weighting. The purpose of this study was to analyze signal intensities of abdominal organs after applying contrast medium and to determine whether this yields an improved contrast for pathologies compared with precontrast trueFISP. MATERIALS AND METHODS: Fifty patients underwent an abdominal examination, including the trueFISP sequence before and after the administration of contrast medium. All images were obtained with a 1.5 T system. The mean signal-to-noise ratio before and after contrast medium was assessed for abdominal organs, vessels, muscle, and fat. The contrast-to-noise ratio (CNR) of pathologic lesions was calculated. RESULTS: The trueFISP sequence yielded a higher signal-to-noise ratio after application of contrast medium for all organs except for fat and the aorta. CNR of solid lesions (angiomyolipoma, liver adenoma, liver hemangioma, hepatocellular carcinoma) increased whereas contrast of cysts decreased. CONCLUSIONS: TrueFISP imaging after application of contrast medium led to better CNR for many solid lesions while cysts showed a diminished contrast. We advise trueFISP imaging sequences before and after contrast medium application.

[An unusual cause of pulmonary fibrosis in a 71-year-old patient]. / Ungewöhnliche Ursache einer Lungenfibrose bei einer 71-jährigen Patientin.

CASE REPORT: A 71-year-old woman, suffering from spinal stenosis presented interstitial lung disease, albinism, and severe loss of visual acuity. On physical examination she showed tic-like automatism predominantly periorbital in the face and in the fingers. A computed tomography of the chest revealed typical findings of interstitial lung disease and additional mediastinal lymphomas and ground-glass attenuation in the lower regions of the lung. The findings of a transbronchial lung biopsy, presenting alveolar macrophages with ceroid-like material and platelet function studies proving slightly impaired platelet aggregation confirmed the clinical diagnosis of Hermansky-Pudlak syndrome. Sufficient pain control could be achieved without surgery and the patient was discharged home. 11 months after discharge, severe dyspnea and fever developed and finally the patient died of respiratory failure. CONCLUSION: The Hermansky-Pudlak syndrome is a rare cause of interstitial lung disease. In general, the lung disease presents in younger patients, but it may emerge in the elderly as well. Alveolar macrophages containing ceroid-like material are typical findings in BAL or lung biopsy. Furthermore impaired platelet aggregation and bleeding diathesis may be present. Both findings are useful to identify this rare disorder.