Comparison between Cystatin C- and Creatinine-Based Estimated Glomerular Filtration Rate in the Follow-Up of Patients Recovering from a Stage-3 AKI in ICU.

Background: Acute kidney injury (AKI) in critically ill patients is associated with a significant increase in mortality as well as long-term renal dysfunction and chronic kidney disease (CKD). Serum creatinine (SCr), the most widely used biomarker to evaluate kidney function, does not always accurately predict the glomerular filtration rate (GFR), since it is affected by some non-GFR determinants such as muscle mass and recent meat ingestion. Researchers and clinicians have gained interest in cystatin C (CysC), another biomarker of kidney function. The study objective was to compare GFR estimation using SCr and CysC in detecting CKD over a 1-year follow-up after an AKI stage-3 event in the ICU, as well as to analyze the association between eGFR (using SCr and CysC) and mortality after the AKI event. Method: This prospective observational study used the medical records of ICU patients diagnosed with AKI stage 3. SCr and CysC were measured twice during the ICU stay and four times following diagnosis of AKI. The eGFR was calculated using the EKFC equation for SCr and FAS equation for CysC in order to check the prevalence of CKD (defined as eGFR < 60 mL/min/1.73 m2). Results: The study enrolled 101 patients, 36.6% of whom were female, with a median age of 74 years (30−92), and a median length of stay of 14.5 days in intensive care. A significant difference was observed in the estimation of GFR when comparing formulas based on SCrand CysC, resulting in large differences in the prediction of CKD. Three months after the AKI event, eGFRCysC < 25 mL/min/1.73 m2 was a predictive factor of mortality later on; however, this was not the case for eGFRSCr. Conclusion: The incidence of CKD was highly discrepant with eGFRCysC versus eGFRSCr during the follow-up period. CysC detects more CKD events compared to SCr in the follow-up phase and eGFRCysC is a predictor for mortality in follow-up but not eGFRSCr. Determining the proper marker to estimate GFR in the post-ICU period in AKI stage-3 populations needs further study to improve risk stratification.

Diagnostic Accuracy of Noninvasive Bone Turnover Markers in Renal Osteodystrophy.

RATIONALE & OBJECTIVE: Bone biopsy remains the gold standard for diagnosing renal osteodystrophy as comparable noninvasive alternatives have yet to be established. This study investigated the diagnostic accuracy of biochemical markers of skeletal remodeling to predict bone turnover. STUDY DESIGN: Cross-sectional retrospective diagnostic test study. SETTING & PARTICIPANTS: Patients with chronic kidney disease glomerular filtration rate categories 4-5, including patients treated with dialysis (G4-G5D) and kidney transplant recipients with successful transiliac bone biopsies. TESTS COMPARED: Bone turnover as determined by bone histomorphometry was compared with the following biochemical markers: full-length (amino acids 1-84) "biointact" parathyroid hormone (PTH), bone-specific alkaline phosphatase (BsAP), intact procollagen type I N-terminal propeptide (PINP), and tartrate-resistant acid phosphatase isoform 5b (TRAP5b). OUTCOME: Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC), sensitivity, specificity, and negative and positive predictive values. Optimal diagnostic cutoffs were determined in an exploration cohort (n = 100) and validated in a separate cohort (n = 99). RESULTS: All biomarkers differed across categories of low 33 (17%), normal 109 (55%), and high 57 (29%) bone turnover. AUC values were in the range of 0.75-0.85. High negative predictive values (≥90%) were found for both high and low bone turnover, indicating the ability to rule out both conditions using the suggested biomarker cutoffs. The highest diagnostic performances were seen with combinations of biomarkers, with overall diagnostic accuracies of 90% for high turnover, and 78% for low turnover. Results were comparable for kidney transplant candidates and recipients in a sensitivity analysis. LIMITATIONS: The single-center approach and heterogeneity of the study cohort are main limitations of this study. CONCLUSIONS: We conclude that the diagnostic performance of biochemical markers of bone turnover is acceptable, with clinical utility in ruling out both high and low turnover bone disease.

Static histomorphometry allows for a diagnosis of bone turnover in renal osteodystrophy in the absence of tetracycline labels.

A bone biopsy with prior tetracycline labeling is the gold standard to diagnose renal osteodystrophy. In cases of missing tetracycline labels, it is still paramount to gain clinically relevant information from the extracted bone sample, by evaluating the static histomorphometry. This study investigates the diagnostic performance of static histomorphometry for the evaluation of high and low bone turnover. Transiliac bone biopsies taken pre- or post- kidney transplantation, of sufficient quality for a full histomorphometric analysis were included (n = 205). The cohort was randomly split to provide separate exploration and validation subsets. Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC). All histomorphometric parameters were significantly different across categories of low (24%), normal (60%), and high (16%) bone turnover, and all were significant predictors of both high and low bone turnover (AUC 0.71-0.84). Diagnostic performance was very good for high turnover, as a combination of static parameters resulted in negative and positive predictive values (NPV and PPV) of 80% and 96%, respectively. For low turnover, the combined model resulted in PPV of 71% and NPV of 82%. We conclude that in the absence of tetracycline labels, static histomorphometry provide an acceptable alternative for a diagnosis of bone turnover in renal osteodystrophy.

Bone histomorphometry in de novo renal transplant recipients indicates a further decline in bone resorption 1 year posttransplantation.

Renal transplantation is believed to have a major impact on bone health. The present prospective observational bone biopsy study aimed to define the natural history of bone histomorphometry parameters in contemporaneous de novo renal transplant recipients. Paired bone biopsies were performed at the time of transplantation and at one-year posttransplantation in an unselected cohort of 36 patients referred for deceased kidney replacement. Parameters of mineral metabolism and circulating bone turnover markers were monitored as well. Static parameters of bone formation and especially bone resorption being already low-normal in the majority of patients at the time of renal transplantation, further declined during the first posttransplant year. However, interindividual variation was substantial, and significance was reached only for bone resorption parameters. Bone mineralization and trabecular bone volume were within the normal range at the time of transplantation (83.3% and 91.7% of graft recipients, respectively) and showed little change one-year posttransplantation. Changes in osteoclast number were paralleled by changes in circulating tartrate-resistant acid phosphatase 5b levels. Finally, cumulative glucocorticoid dose, but not the posttransplantation parathyroid hormone level, associated with trabecular bone loss. Thus, the impact of renal transplantation on bone histomorphometry is limited with only bone resorption, being already low at the time of transplantation, showing a further decline.

Cardiovascular disease relates to intestinal uptake of p-cresol in patients with chronic kidney disease.

BACKGROUND: Serum p-cresyl sulfate (PCS) associates with cardiovascular disease in patients with chronic kidney disease. PCS concentrations are determined by intestinal uptake of p-cresol, human metabolism to PCS and renal clearance. Whether intestinal uptake of p-cresol itself is directly associated with cardiovascular disease in patients with renal dysfunction has not been studied to date. METHODS: We performed a prospective study in patients with chronic kidney disease stage 1 - 5 (NCT00441623). Intestinal uptake of p-cresol, under steady state conditions, was estimated from 24 h urinary excretion of PCS. Primary endpoint was time to first cardiovascular event, i.e., cardiac death, myocardial infarction/ischemia, ventricular arrhythmia, cardiovascular surgery, ischemic stroke or symptomatic peripheral arterial disease. Statistical analysis was done using Kaplan-Meier estimates and Cox proportional hazard analyses. RESULTS: In a cohort of 200 patients, median 24 h urinary excretion of PCS amounted to 457.47 µmol (IQR 252.68 - 697.17). After a median follow-up of 52 months, 25 patients reached the primary endpoint (tertile 1/2/3: 5/6/14 events, log rank P 0.037). Higher urinary excretion of PCS was directly associated with cardiovascular events (univariate hazard ratio per 100 µmol increase: 1.112, P 0.002). In multivariate analysis, urinary excretion of PCS remained a predictor of cardiovascular events, independent of eGFR (hazard ratio 1.120, P 0.002). CONCLUSIONS: In patients with chronic kidney disease, intestinal uptake of p-cresol associates with cardiovascular disease independent of renal function. The intestinal generation and absorption of p-cresol may be therapeutic targets to reduce cardiovascular disease risk in patients with renal dysfunction.

Uremia suppresses immune signal-induced CYP27B1 expression in human monocytes.

BACKGROUND: Local production of 1,25-dihydroxyvitamin D (1,25(OH)(2)D) regulated by the CYP27B1 enzyme in monocytes contributes to the immunomodulatory effects of vitamin D. Uremia suppresses renal CYP27B1, but its impact on monocytic CYP27B1 is incompletely understood. The present study aimed to elucidate this issue and to define the pathogenic role of p-cresyl sulfate (PCS), indoxyl sulfate (IndS), and fibroblast growth factor 23 (FGF23). METHODS: Resting or immune (interferon-γ + lipopolysaccharide)-stimulated THP1 cells and monocytes, isolated from healthy donors, were cultured in the presence of either healthy serum, uremic serum, PCS, IndS or FGF23. RNA expression levels for CYP27B1 and cytokines were quantified by RT-PCR and enzymatic CYP27B1 activity was measured 24 h after incubation. RESULTS: Culturing THP1 cells or human monocytes in the presence of uremic serum led to higher inflammatory cytokine and CYP27B1 expression. Immune signal-induced CYP27B1 expression and activity, conversely, was impaired in the presence of uremic serum. Similar effects were observed in the presence of FGF23, although significance was reached in immune-stimulated cells only. PCS and IndS failed to show any effect. CONCLUSIONS: Monocytic baseline CYP27B1 expression is increased in uremia, probably reflecting the microinflammatory state. Immune signal-induced CYP27B1 expression, conversely, is impaired in uremic conditions. Elevated FGF23 levels, but not PCS and IndS, may account, at least partly, for the dysregulation of monocytic CYP27B1 in uremia and, as such, may contribute to the high cardiovascular and infectious burden in chronic kidney disease.

Calcium requirements after parathyroidectomy in patients with refractory secondary hyperparathyroidism.

BACKGROUND/AIMS: Calcium supplements are often required following successful parathyroidectomy (PTX) in order to prevent overt hypocalcemia. The current study aims to quantify these calcium needs and to identify predictors of a high calcium need present at the time of surgery. METHODS: Charts of 42 patients with chronic kidney disease stage 5D, who underwent a successful subtotal PTX, were reviewed in detail. Biochemical indices of mineral metabolism available within a time frame of 4 weeks before and 6 weeks after the surgery were registered. Details concerning active vitamin D (1-alpha-calcidiol and calcitriol) and calcium supplementation were recorded as well. RESULTS: Serum calcium, phosphorus and PTH levels declined whereas total alkaline phosphatase levels increased significantly in the early post-PTX period. Transient hypocalcemia was observed in 83% of the patients. The median daily postoperative elemental calcium requirements amounted to 3.2 g during week 1, and declined to 2.4 g during week 6. A high preoperative PTH level and a low serum calcium level were identified as independent predictors of a high postoperative calcium need. CONCLUSION: Substantial amounts of elemental calcium are required following successful subtotal PTX in order to avoid frank hypocalcemia, especially in patients with a high PTH level and a low calcium level before surgery.