In this thesis we showed the clinical impact of several methodological issues that should be taken into account when studying chronic kidney disease progression and in order to find an answer to... Show moreIn this thesis we showed the clinical impact of several methodological issues that should be taken into account when studying chronic kidney disease progression and in order to find an answer to the question when to start dialysis. From a methodological point of view, the observations from this thesis provide several recommendations for future research with regard to studying associations of risk factors with CKD progression: the use of an inception cohort of incident patients, and using linear mixed effects models for analyses. Ultimately, patients with kidney failure could be subjected to dialysis. The optimal timing for dialysis initiation is unclear. Ideally, a randomized trial with all possible starting moments would be performed. However, this seems to be unfeasible due to the high patient number needed in each treatment arm. We have to rely on observational data, where methodological issues such as lead-time and immortal time bias arise. In this thesis, we showed the clinical impact of lead-time bias and how both types of bias were avoided by emulating a randomized trial using observational data in a pilot study. The methodology and recommendations provided in the thesis will be highly useful to find a more definitive answer in future research. Show less
Messchendorp, A.L.; Meijer, E.; Visser, F.W.; Engels, G.E.; Kappert, P.; Losekoot, M.; ... ; DIPAK-1 Study Investigators 2019
Background: Markers currently used to predict the likelihood of rapid disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) are expensive and time consuming to... Show moreBackground: Markers currently used to predict the likelihood of rapid disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) are expensive and time consuming to assess and often have limited sensitivity. New, easy-to-measure markers are therefore needed that alone or in combination with conventional risk markers can predict the rate of disease progression. In the present study, we investigated the ability of tubular damage and inflammation markers to predict kidney function decline. Methods: At baseline, albumin, immunoglobulin G, kidney injury molecule 1, beta 2 microglobulin (beta 2MG), heart-type fatty acid-binding protein, neutrophil gelatinase-associated lipocalin, and monocyte chemotactic protein-1 -(MCP-1) were measured in 24-h urine samples of patients participating in a study investigating the therapeutic efficacy of lanreotide in ADPKD. Individual change in estimated glomerular filtration rate (eGFR) during follow-up was calculated using mixed-model analysis taking into account 13 -eGFRs (chronic kidney disease EPIdemiology) per patient. Logistic regression analysis was used to select urinary biomarkers that had the best association with rapidly progressive disease. The predictive value of these selected urinary biomarkers was compared to other risk scores using C-statistics. Results: Included were 302 patients of whom 53.3% were female, with an average age of 48 +/- 7 years, eGFR of 52 +/- 12 mL/min/1.73 m(2), and a height-adjusted total kidney volume (htTKV) of 1,082 (736-1,669) mL/m. At baseline, all urinary damage and inflammation markers were associated with baseline eGFR, also after adjustment for age, sex and baseline htTKV. For longitudinal analyses only patients randomized to standard care were considered (n = 152). A stepwise backward analysis revealed that beta 2MG and MCP-1 showed the strongest association with rapidly progressive disease. A urinary biomarker score was created by summing the ranking of tertiles of beta 2MG and MCP-1 excretion. The predictive value of this urinary biomarker score was higher compared to that of the Mayo htTKV classification (area under the curve [AUC] 0.73 [0.64-0.82] vs. 0.61 [0.51-0.71], p = 0.04) and comparable to that of the predicting renal outcomes in -ADPKD score (AUC 0.73 [0.64-0.82] vs. 0.65 [0.55-0.75], p = 0.18). In a second independent cohort with better kidney function, similar results were found for the urinary biomarker score. Conclusion: Measurement of urinary beta 2MG and MCP-1 excretion allows selection of ADPKD patients with rapidly progressive disease, with a predictive value comparable to or even higher than that of TKV or PKD mutation. Easy and inexpensive to measure urinary markers therefore hold promise to help predict prognosis in ADPKD. Show less
