A retrospective study of focal segmental glomerulosclerosis: clinical criteria can identify patients at high risk for recurrent disease after first renal transplantation

Abstract Background Focal segmental glomerulosclerosis (FSGS) is a frequent cause of end-stage renal disease. Renal transplantation in patients with FSGS is often complicated by disease recurrence, which is associated with poor outcome. There are no tests that reliably predict recurrence of FSGS after transplantation. The aim of this study was to evaluate if clinical criteria can identify patients at high risk for recurrent disease. Methods We retrospectively studied 94 patients who received a first renal transplant at a median age of 37 years (range 5–69 years). Patients were assigned to one of three groups: familial or genetic FSGS (group I; n=18), secondary FSGS (group II; n=10) and idiopathic FSGS (group III; n=66). Pretransplant clinical characteristics were analyzed to determine predictors of a recurrence after transplantation. Results FSGS only recurred in patients with idiopathic FSGS (group III; 42%). Patients with a recurrence had a significantly lower serum albumin, higher 24-hour proteinuria and higher estimated glomerular filtration rate at diagnosis. Serum albumin at diagnosis was the only independent predictor of a recurrence in patients with idiopathic FSGS. Patients with recurrent FSGS had more acute rejection episodes (54% vs. 27%, P =0.02) and lower five year graft survival compared to patients without a recurrence (50 vs. 82%, P Conclusions Clinical criteria allow identification of patients at high risk of recurrent FSGS after renal transplantation. This information can be used in the counseling and management of patients with FSGS.</p

Causality on longitudinal data: Stable specification search in constrained structural equation modeling

A typical problem in causal modeling is the instability of model structure learning, i.e., small changes in finite data can result in completely different optimal models. The present work introduces a novel causal modeling algorithm for longitudinal data, that is robust for finite samples based on recent advances in stability selection using subsampling and selection algorithms. Our approach uses exploratory search but allows incorporation of prior knowledge, e.g., the absence of a particular causal relationship between two specific variables. We represent causal relationships using structural equation models. Models are scored along two objectives: the model fit and the model complexity. Since both objectives are often conflicting, we apply a multi-objective evolutionary algorithm to search for Pareto optimal models. To handle the instability of small finite data samples, we repeatedly subsample the data and select those substructures (from the optimal models) that are both stable and parsimonious. These substructures can be visualized through a causal graph. Our more exploratory approach achieves at least comparable performance as, but often a significant improvement over state-of-the-art alternative approaches on a simulated data set with a known ground truth. We also present the results of our method on three real-world longitudinal data sets on chronic fatigue syndrome, Alzheimer disease, and chronic kidney disease. The findings obtained with our approach are generally in line with results from more hypothesis-driven analyses in earlier studies and suggest some novel relationships that deserve further researc

Proximal tubular efflux transporters involved in renal excretion of p-cresyl sulfate and p-cresyl glucuronide: Implications for chronic kidney disease pathophysiology

The uremic solutes p-cresyl sulfate (pCS) and p-cresyl glucuronide (pCG) accumulate in patients with chronic kidney disease (CKD), and might contribute to disease progression. Moreover, retention of these solutes may directly be related to renal tubular function. Here, we investigated the role of the efflux transporters Multidrug Resistance Protein 4 (MRP4) and Breast Cancer Resistance Protein (BCRP) in pCS and pCG excretion, and studied the impact of both solutes on the phenotype of human conditionally immortalized renal proximal tubule epithelial cells (ciPTEC). Our results show that p-cresol metabolites accumulate during CKD, with a shift from sulfation to glucuronidation upon progression. Moreover, pCS inhibited the activity of MRP4 by 40% and BCRP by 25%, whereas pCG only reduced MRP4 activity by 75%. Moreover, BCRP-mediated transport of both solutes was demonstrated. Exposure of ciPTEC to pCG caused epithelial-to-mesenchymal transition, indicated by increased expression of vimentin and Bcl-2, and diminished E-cadherin. This was associated with altered expression of key tubular transporters. In conclusion, BCRP is likely involved in the renal excretion of both solutes, and pCG promotes phenotypical changes in ciPTEC, supporting the notion that uremic toxins may be involved in CKD progression by negatively affecting renal tubule cell phenotype and functionality.publisher: Elsevier articletitle: Proximal tubular efflux transporters involved in renal excretion of p-cresyl sulfate and p-cresyl glucuronide: Implications for chronic kidney disease pathophysiology journaltitle: Toxicology in Vitro articlelink: http://dx.doi.org/10.1016/j.tiv.2015.07.020 content_type: article copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.status: publishe

Abdominal aortic calcification in patients with CKD

BACKGROUND: Abdominal aortic calcification (AAC) is independently associated with cardiovascular events in dialysis patients and in the general population. However, data in non-dialysis chronic kidney disease (CKD) patients are limited. We analyzed determinants and prognostic value of AAC in non-dialysis CKD patients. METHODS: We included patients with CKD not receiving renal replacement therapy from the MASTERPLAN study, a randomized controlled trial that started in 2004. In the period 2008-2009, an X-ray to evaluate AAC was performed in a subgroup of patients. We studied AAC using a semi-quantitative scoring system by lateral lumbar X-ray. We used baseline and 2-year data to find determinants of AAC. We used a composite cardiovascular endpoint and propensity score matching to evaluate the prognostic value of AAC. RESULTS: In 280 patients an X-ray was performed. In 79 patients (28 %) the X-ray showed no calcification, in 62 patients (22 %) calcification was minor (<4), while 139 patients (50 %) had moderate or heavy calcification (≥4). Older age, prior cardiovascular disease, higher triglyceride levels, and higher phosphate levels were independent determinants of a calcification score ≥4. AAC score ≥4 was independently associated with cardiovascular events, with a hazard ratio of 5.5 (95 % confidence interval 1.2-24.8). CONCLUSIONS: Assessment of AAC can identify CKD patients at higher cardiovascular risk, and may provide important information for personalized treatment. Whether this approach will ultimately translate into better outcomes remains to be answered

Abdominal aortic calcification in patients with CKD

BACKGROUND: Abdominal aortic calcification (AAC) is independently associated with cardiovascular events in dialysis patients and in the general population. However, data in non-dialysis chronic kidney disease (CKD) patients are limited. We analyzed determinants and prognostic value of AAC in non-dialysis CKD patients. METHODS: We included patients with CKD not receiving renal replacement therapy from the MASTERPLAN study, a randomized controlled trial that started in 2004. In the period 2008-2009, an X-ray to evaluate AAC was performed in a subgroup of patients. We studied AAC using a semi-quantitative scoring system by lateral lumbar X-ray. We used baseline and 2-year data to find determinants of AAC. We used a composite cardiovascular endpoint and propensity score matching to evaluate the prognostic value of AAC. RESULTS: In 280 patients an X-ray was performed. In 79 patients (28 %) the X-ray showed no calcification, in 62 patients (22 %) calcification was minor (<4), while 139 patients (50 %) had moderate or heavy calcification (≥4). Older age, prior cardiovascular disease, higher triglyceride levels, and higher phosphate levels were independent determinants of a calcification score ≥4. AAC score ≥4 was independently associated with cardiovascular events, with a hazard ratio of 5.5 (95 % confidence interval 1.2-24.8). CONCLUSIONS: Assessment of AAC can identify CKD patients at higher cardiovascular risk, and may provide important information for personalized treatment. Whether this approach will ultimately translate into better outcomes remains to be answered

CKD: A Call for an Age-Adapted Definition

Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m2 This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m2, whereas in elderly people it is increased at levels <45 ml/min per 1.73 m2 Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable.status: publishe

Differences between hospitals in attainment of parathyroid hormone treatment targets in chronic kidney disease do not reflect differences in quality of care

Contains fulltext : 110897.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Transparency in quality of care (QoC) is stimulated and hospitals are compared and judged on the basis of indicators of performance on specific treatment targets. In patients with chronic kidney disease, QoC differed significantly between hospitals. In this analysis we explored additional parameters to explain differences between centers in attainment of parathyroid hormone (PTH) treatment targets. METHODS: Using MASTERPLAN baseline data, we selected one of the worst (center A) and one of the best (center B) performing hospitals. Differences between the two centers were analyzed from the year prior to start of the MASTERPLAN study until the baseline evaluation. Determinants of PTH were assessed. RESULTS: 101 patients from center A (median PTH 9.9 pmol/l, in 67 patients exceeding recommended levels) and 100 patients from center B (median PTH 6.5 pmol/l, in 34 patients exceeding recommended levels), were included. Analysis of clinical practice did not reveal differences in PTH management between the centers. Notably, hyperparathyroidism resulted in a change in therapy in less than 25% of patients. In multivariate analysis kidney transplant status, MDRD-4, and treatment center were independent predictors of PTH. However, when MDRD-6 (which accounts for serum urea and albumin) was used instead of MDRD-4, the center effect was reduced. Moreover, after calibration of the serum creatinine assays treatment center no longer influenced PTH. CONCLUSIONS: We show that differences in PTH control between centers are not explained by differences in treatment, but depend on incomparable patient populations and laboratory techniques. Therefore, results of hospital performance comparisons should be interpreted with great caution

A retrospective study of focal segmental glomerulosclerosis: clinical criteria can identify patients at high risk for recurrent disease after first renal transplantation

Contains fulltext : 118458.pdf (publisher's version ) (Open Access)BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a frequent cause of end-stage renal disease. Renal transplantation in patients with FSGS is often complicated by disease recurrence, which is associated with poor outcome. There are no tests that reliably predict recurrence of FSGS after transplantation. The aim of this study was to evaluate if clinical criteria can identify patients at high risk for recurrent disease. METHODS: We retrospectively studied 94 patients who received a first renal transplant at a median age of 37 years (range 5-69 years). Patients were assigned to one of three groups: familial or genetic FSGS (group I; n=18), secondary FSGS (group II; n=10) and idiopathic FSGS (group III; n=66). Pretransplant clinical characteristics were analyzed to determine predictors of a recurrence after transplantation. RESULTS: FSGS only recurred in patients with idiopathic FSGS (group III; 42%). Patients with a recurrence had a significantly lower serum albumin, higher 24-hour proteinuria and higher estimated glomerular filtration rate at diagnosis. Serum albumin at diagnosis was the only independent predictor of a recurrence in patients with idiopathic FSGS. Patients with recurrent FSGS had more acute rejection episodes (54% vs. 27%, P =0.02) and lower five year graft survival compared to patients without a recurrence (50 vs. 82%, P <0.01). CONCLUSIONS: Clinical criteria allow identification of patients at high risk of recurrent FSGS after renal transplantation. This information can be used in the counseling and management of patients with FSGS