Revisiting the middle molecule hypothesis of uremic toxicity: A systematic review of beta 2 microglobulin population kinetics and large scale modeling of hemodialysis trials in silico

PLoS ONE

Volumn 11, Issue 4, 2016, Pages

  Roumelioti, Maria Eleni ^a   Nolin, Thomas ^b   Unruh, Mark L ^a   Argyropoulos, Christos ^a  

^a UNIVERSITY OF NEW MEXICO SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BETA 2 MICROGLOBULIN;

ANURIA; ARTICLE; CAUSE OF DEATH; CHRONIC KIDNEY DISEASE; COMPUTER MODEL; END STAGE RENAL DISEASE; HEMODIAFILTRATION; HEMODIALYSIS; HUMAN; KIDNEY FUNCTION; META ANALYSIS; MORTALITY; QUANTITATIVE ANALYSIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); RENAL CLEARANCE; RESIDUAL RENAL FUNCTION; RISK REDUCTION; SIMULATION; SURVIVAL; SYSTEMATIC REVIEW; UREMIA; BIOLOGICAL MODEL; KIDNEY FUNCTION TEST; KINETICS; METABOLISM; PATHOPHYSIOLOGY; PROCEDURES;

BETA 2-MICROGLOBULIN; HUMANS; KIDNEY FUNCTION TESTS; KINETICS; MODELS, BIOLOGICAL; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RENAL DIALYSIS; UREMIA;

EID: 84963776456     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0153157     Document Type: Article

References (91)

1. Cox J, Yewdell J, Eisenlohr L, Johnson P, Bennink J. Antigen presentation requires transport of MHC class I molecules from the endoplasmic reticulum. Science. 1990; 247: 715-718. doi:10.1126/science.2137259 PMID: 2137259.
2. Perarnau B, Siegrist C-A, Gillet A, Vincent C, Kimura S, Lemonnier FA. [beta]2-Microglobulin restriction of antigen presentation. Nature. 1990; 346: 751-754. doi:10.1038/346751a0 PMID: 1697039.
3. Ravnskov U, Johansson BG, Göthlin J. Renal extraction of 2 -microglobulin. Scand J Clin Lab Invest. 1972; 30: 71-75. PMID: 4116283.
4. Wibell LB. Studies on beta2-microglobulin in patients and normal subjects. Acta Clin Belg. 1976; 31: 14-26. PMID: 65885.
5. Bailey RR, Tisch GW, Pearson S. Serum beta2-microglobulin in the assessment of renal function. N Z Med J. 1978; 87: 168-170. PMID: 77514.
6. Karlsson FA, Wibell L, Evrin PE. beta 2-Microglobulin in clinical medicine. Scand J Clin Lab Invest Suppl. 1980; 154: 27-37. PMID: 6163193.
7. François B, Assenat H, Cahen R, Bizollon C. [Is the serum level of beta 2 microglobulin a better marker of glomerular filtration than blood creatinine?]. Nephrologie. 1982; 3: 116-118. PMID: 6183598.
8. Jung K, Schulze BD, Sydow K, Pergande M, Precht K, Schreiber G. Diagnostic value of low-molecular mass proteins in serum for the detection of reduced glomerular filtration rate. J Clin Chem Clin Biochem. 1987; 25: 499-503. PMID: 3320263.
9. Acchiardo S, Kraus AP Jr, Jennings BR. Beta 2-microglobulin levels in patients with renal insufficiency. Am J Kidney Dis. 1989; 13: 70-74. PMID: 2643313.
10. Donadio C, Lucchesi A, Ardini M, Giordani R., Cystatin C, beta 2-microglobulin, and retinol-binding protein as indicators of glomerular filtration rate: comparison with plasma creatinine. J Pharm Biomed Anal. 2001; 24: 835-842. PMID: 11248475.
11. Bianchi C, Donadio C, Tramonti G, Consani C, Lorusso P, Rossi G. Reappraisal of serum beta2-microglobulin as marker of GFR. Ren Fail. 2001; 23: 419-429. PMID: 11499557.
12. Brown PH, Kalra PA, Turney JH, Cooper EH. Serum low-molecular-weight proteins in haemodialysis patients: Effect of residual renal function. Nephrol Dial Transplant. 1988; 3: 169-173. PMID: 2459634.
13. Fry AC, Singh DK, Chandna SM, Farrington K. Relative Importance of Residual Renal Function and Convection in Determining Beta-2-Microglobulin Levels in High-Flux Haemodialysis and On-Line Haemodiafiltration. Blood Purif. 2007; 25: 295-302. doi:10.1159/000104870 PMID: 17622712.
14. Eknoyan G, Beck GJ, Cheung AK, Daugirdas JT, Greene T, Kusek JW, et al. Effect of Dialysis Dose and Membrane Flux in Maintenance Hemodialysis. N Engl J Med. 2002; 347: 2010-2019. doi:10.1056/NEJMoa021583 PMID: 12490682.
15. Amici G, Virga G, Da Rin G, Grandesso S, Vianello A, Gatti P, et al. Serum beta-2-microglobulin level and residual renal function in peritoneal dialysis. Nephron. 1993; 65: 469-471. PMID: 8290003.
16. Penne EL, van der Weerd NC, Blankestijn PJ, van den Dorpel MA, Grooteman MPC, Nubé MJ, et al. Role of residual kidney function and convective volume on change in beta2-microglobulin levels inhemodiafiltration patients. Clin J Am Soc Nephrol. 2010; 5: 80-86. doi:10.2215/CJN.03340509 PMID: 19965537.
17. Cianciolo G, Colí L, La Manna G, Donati G, D'Addio F, Comai G, et al. Is beta2-microglobulin-related amyloidosis of hemodialysis patients a multifactorial disease? A new pathogenetic approach. Int J Artif Organs. 2007; 30: 864-878. PMID: 17992647.
18. Jadoul M, Garbar C, van Ypersele de Strihou C. Pathological aspects of beta(2)-microglobulin amyloidosis. Semin Dial. 2001; 14: 86-89. PMID: 11264772.
19. Kiss E, Keusch G, Zanetti M, Jung T, Schwarz A, Schocke M, et al. Dialysis-related amyloidosis revisited. AJR Am J Roentgenol. 2005; 185: 1460-1467. doi:10.2214/AJR.04.1309 PMID: 16303998.
20. Danesh F, Ho LT. Dialysis-related amyloidosis: history and clinical manifestations. Semin Dial. 2001; 14: 80-85. PMID: 11264771.
21. Yamamoto S, Gejyo F. Historical background and clinical treatment of dialysis-related amyloidosis. Biochim Biophys Acta. 2005; 1753: 4-10. doi:10.1016/j.bbapap.2005.09.006 PMID: 16226497.
22. Kazama JJ, Yamamoto S, Takahashi N, Ito Y, Maruyama H, Narita I, et al. Abeta-2M-amyloidosis and related bone diseases. J Bone Miner Metab. 2006; 24: 182-184. doi:10.1007/s00774-005-0669-5 PMID: 16502130.
23. Cheung AK, Greene T, Leypoldt JK, Yan G, Allon M, Delmez J, et al. Association between Serum β2- Microglobulin Level and Infectious Mortality in Hemodialysis Patients. Clin J Am Soc Nephrol. 2008; 3: 69-77. doi:10.2215/CJN.02340607 PMID: 18057309.
24. Okuno S, Ishimura E, Kohno K, Fujino-Katoh Y, Maeno Y, Yamakawa T, et al. Serum beta2-microglobulin level is a significant predictor of mortality in maintenance haemodialysis patients. Nephrol Dial Transplant. 2009; 24: 571-577. doi:10.1093/ndt/gfn521 PMID: 18799606.
25. Liabeuf S, Lenglet A, Desjardins L, Neirynck N, Glorieux G, Lemke HD, et al. Plasma beta-2 microglobulin is associated with cardiovascular disease in uremic patients. Kidney Int. 2012; 82: 1297-303. doi:10.1038/ki.2012.301 PMID: 22895515.
26. Locatelli F, Martin-Malo A, Hannedouche T, Loureiro A, Papadimitriou M, Wizemann V, et al. Effect of membrane permeability on survival of hemodialysis patients. J Am Soc Nephrol. 2009; 20: 645-54. doi:10.1681/ASN.2008060590 PMID: 19092122.
27. Grooteman MPC, van den Dorpel MA, Bots ML, Penne EL, van der Weerd NC, Mazairac AHA, et al. Effect of online hemodiafiltration on all-cause mortality and cardiovascular outcomes. J Am Soc Nephrol. 2012; 23: 1087-1096. doi:10.1681/ASN.2011121140 PMID: 22539829.
28. Maduell F, Moreso F, Pons M, Ramos R, Mora-Macia J, Carreras J, et al. High-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients. J Am Soc Nephrol. 2013; 24: 487-97. doi:10.1681/ASN.2012080875 PMID: 23411788.
29. Ok E, Asci G, Toz H, Ok ES, Kircelli F, Yilmaz M, et al. Mortality and cardiovascular events in online haemodiafiltration (OL-HDF) compared with high-flux dialysis: Results from the Turkish OL-HDF Study. Nephrol Dial Transplant. 2013; 28: 192-202. doi:10.1093/ndt/gfs407 PMID: 23229932.
30. Cheung AK, Rocco MV, Yan G, Leypoldt JK, Levin NW, Greene T, et al. Serum beta-2 Microglobulin Levels Predict Mortality in Dialysis Patients: Results of the HEMO Study. J Am Soc Nephrol. 2006; 17: 546-555. doi:10.1681/ASN.2005020132 PMID: 16382021.
31. Winchester JF, Salsberg JA, Levin NW. Beta-2 microglobulin in ESRD: An in-depth review. Advances in Renal Replacement Therapy. 2003; 10: 279-309. doi:10.1053/j.arrt.2003.11.003 PMID: 14681859.
32. Stiller S, Xu XQ, Gruner N, Vienken J, Mann H. Validation of a two-pool model for the kinetics of beta2- microglobulin. Int J Artif Organs. 2002; 25: 411-420. PMID: 12074339.
33. Ward RA, Greene T, Hartmann B, Samtleben W. Resistance to intercompartmental mass transfer limits beta2-microglobulin removal by post-dilution hemodiafiltration. Kidney Int. 2006; 69: 1431-1437. doi:10.1038/sj.ki.5000048 PMID: 16395268.
34. Kanamori T, Sakai K. An estimate of beta 2-microglobulin deposition rate in uremic patients on hemodialysis using a mathematical kinetic model. Kidney Int. 1995; 47: 1453-1457. PMID: 7637274.
35. Chertow GM, Levin NW, Beck GJ, Depner TA, Eggers PW, Gassman JJ, et al. In-center hemodialysis six times per week versus three times per week. N Engl J Med. 2010; 363: 2287-2300. doi:10.1056/NEJMoa1001593PMID: 21091062.
36. Rocco MV, Lockridge RS Jr, Beck GJ, Eggers PW, Gassman JJ, Greene T, et al. The effects of frequent nocturnal home hemodialysis: The Frequent Hemodialysis Network Nocturnal Trial. Kidney Int. 2011; 80: 1080-1091. doi:10.1038/ki.2011.213 PMID: 21775973.
37. CHEUNG AK, AGODOA LY, DAUGIRDAS JT, DEPNER TA, GOTCH FA, GREENE T, et al. Effects of Hemodialyzer Reuse on Clearances of Urea and {beta}2-Microglobulin. J Am Soc Nephrol. 1999; 10: 117-127. PMID: 9890317.
38. Rubin DB. Estimating causal effects of treatments in randomized and nonrandomized studies. Journal of Educational Psychology. 1974; 66: 688-701. doi: 10.1037/h0037350.
39. Pearl J. Causal inference in statistics: An overview. Statist Surv. 2009; 3: 96-146. doi:10.1214/09-SS057.
40. Gotch F, Levin N, Zasuwa G, Tayeb J. Kinetics of beta-2-microglobulin in hemodialysis. Contrib Nephrol. 1989; 74: 132-138. PMID: 2702130.
41. Lee CJ, Hsiong CH, Chang YL, Cheng CH, Lian JD. Statistical and parametric analysis of beta-2-microglobulin removal from uremic patients in high flux hemodialysis. ASAIO J. 1994; 40: 62-66. PMID: 8186494.
42. Takesawa S, Hidai S, Ogawa H, Takagi T, Saito A, Sakai K. Kinetic analysis of beta-2-microglobulin behavior for hemodialysis patients. Jpn J Artif Organs. 1988; 17: 42-45.
43. Karlsson FA, Groth T, Sege K, Wibell L, Peterson PA. Turnover in humans of beta 2-microglobulin: The constant chain of HLA-antigens. Eur J Clin Invest. 1980; 10: 293-300. PMID: 6159213.
44. Vincent C, Pozet N, Revillard JP. Plasma beta 2 microglobulin turnover in renal insufficiency. Acta Clin Belg Suppl. 1980; 35: 2-12.
45. Maeda K, Shinzato T, Ota T, Kobayakawa H, Takai I, Fujita Y, et al. Beta-2-microglobulin generation rate and clearance rate in maintenance hemodialysis patients. Nephron. 1990; 56: 118-125. PMID: 2243566.
46. Floege J, Bartsch A, Schulze M, Shaldon S, Koch KM, Smeby LC. Clearance and synthesis rates of beta 2-microglobulin in patients undergoing hemodialysis and in normal subjects. J Lab Clin Med. 1991; 118: 153-165. PMID: 1856578.
47. Odell RA, Slowiaczek P, Moran JE, Schindhelm K. Beta 2-microglobulin kinetics in end-stage renal failure. Kidney Int. 1991; 39: 909-919. PMID: 2067207.
48. Vincent C, Chanard J, Caudwell V, Lavaud S, Wong T, Revillard JP. Kinetics of 125I-beta 2-microglobulin turnover in dialyzed patients. Kidney Int. 1992; 42: 1434-1443. PMID: 1474777.
49. Xu XQ, Gruner N, Al-Bashir A, Trutt-Ibing CH, Melzer H, Fassbinder W, et al. Determination of extra renal clearance and generation rate of beta2-microglobulin in hemodialysis patients using a kinetic model. ASAIO J. 2001; 47: 623-627. PMID: 11730200.
50. Wizemann V, Lotz C, Techert F, Uthoff S. On-line haemodiafiltration versus low-flux haemodialysis. A prospective randomized study. Nephrol Dial Transplant. 2000; 15 Suppl 1: 43-48. PMID: 10737166.
51. McCarthy JT, Williams AW, Johnson WJ. Serum beta 2-microglobulin concentration in dialysis patients: importance of intrinsic renal function. J Lab Clin Med. 1994; 123: 495-505. PMID: 8144998.
52. Leypoldt JK, Cheung AK, Deeter RB. Single compartment models for evaluating beta 2-microglobulin clearance during hemodialysis. ASAIO J. 1997; 43: 904-909. PMID: 9386841.
53. Ward RA, Schmidt B, Hullin J, Hillebrand GF, Samtleben W. A Comparison of On-Line Hemodiafiltration and High-Flux Hemodialysis: A Prospective Clinical Study. JASN. 2000; 11: 2344-2350. PMID: 11095657.
54. Tattersall J. Clearance of beta-2-microglobulin and middle molecules in haemodiafiltration. Contributions to nephrology. 2007; 158: 201-9. PMID: 17684359.
55. Kim KM, Kim S-S, Kim H, Koo T, Im EY, Kim SB. Higher serum beta2-microglobulin levels are associated with better survival in chronic hemodialysis patients: A reverse epidemiology. Clin Nephrol. 2011; 75: 458-465. PMID: 21543026.
56. Foster MC, Inker LA, Levey AS, Selvin E, Eckfeldt J, Juraschek SP, et al. Novel Filtration Markers as Predictors of All-Cause and Cardiovascular Mortality in US Adults. Am J Kidney Dis. 2013; Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list-uids=23518194.
57. Astor BC, Shafi T, Hoogeveen RC, Matsushita K, Ballantyne CM, Inker LA, et al. Novel markers of kidney function as predictors of ESRD, cardiovascular disease, and mortality in the general population. Am J Kidney Dis. 2012; 59: 653-662. doi:10.1053/j.ajkd.2011.11.042 PMID: 22305758.
58. Zumrutdal A, Sezer S, Demircan S, Seydaoglu G, Ozdemir FN, Haberal M. Cardiac troponin I and beta 2 microglobulin as risk factors for early-onset atherosclerosis in patients on haemodialysis. Nephrology (Carlton). 2005; 10: 453-458. doi:10.1111/j.1440-1797.2005.00475.x.
59. Amighi J, Hoke M, Mlekusch W, Schlager O, Exner M, Haumer M, et al. Beta 2 microglobulin and the risk for cardiovascular events in patients with asymptomatic carotid atherosclerosis. Stroke. 2011; 42: 1826-33. doi:10.1161/STROKEAHA.110.600312 PMID: 21546482.
60. Wilson AM, Kimura E, Harada RK, Nair N, Narasimhan B, Meng XY, et al. Beta2-microglobulin as a biomarker in peripheral arterial disease: proteomic profiling and clinical studies. Circulation. 2007; 116: 1396-403. PMID: 17724262.
61. Fung ET, Wilson AM, Zhang F, Harris N, Edwards KA, Olin JW, et al. A biomarker panel for peripheral arterial disease. Vasc Med. 2008; 13: 217-224. doi:10.1177/1358863X08089276 PMID: 18687758.
62. Kals J, Zagura M, Serg M, Kampus P, Zilmer K, Unt E, et al. β2-microglobulin, a novel biomarker of peripheral arterial disease, independently predicts aortic stiffness in these patients. Scand J Clin Lab Invest. 2011; 71: 257-263. doi:10.3109/00365513.2011.558108 PMID: 21314441.
63. Hiatt WR, Zakharyan A, Fung ET, Crutcher G, Smith A, Stanford C, et al. A validated biomarker panel to identify peripheral artery disease. Vasc Med. 2012; 17: 386-393. doi:10.1177/1358863X12463491 PMID: 23086582.
64. Nead KT, Zhou MJ, Caceres RD, Sharp SJ, Wehner MR, Olin JW, et al. Usefulness of the addition of beta-2-microglobulin, cystatin C and C-reactive protein to an established risk factors model to improve mortality risk prediction in patients undergoing coronary angiography. Am J Cardiol. 2013; 111: 851- 856. doi:10.1016/j.amjcard.2012.11.055 PMID: 23290308.
65. Zhang L, Pfister M, Meibohm B. Concepts and Challenges in Quantitative Pharmacology and Model- Based Drug Development. AAPS J. 2008; 10: 552-559doi:10.1208/s12248-008-9062-3 PMID: 19003542.
66. USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, . Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2013.
67. van der Wal WM, Noordzij M, Dekker FW, Boeschoten EW, Krediet RT, Korevaar JC, et al. Full loss of residual renal function causes higher mortality in dialysis patients; findings from a marginal structural model. Nephrol Dial Transplant. 2011; 26: 2978-2983. doi:10.1093/ndt/gfq856 PMID: 21317411.
68. Sirich TL, Luo FJ-G, Plummer NS, Hostetter TH, Meyer TW. Selectively increasing the clearance of protein- bound uremic solutes. Nephrol Dial Transplant. 2012; 27: 1574-1579. doi:10.1093/ndt/gfr691 PMID: 22231033.
69. Eloot S, Dhondt A, Van Landschoot M, Waterloos M- A, Vanholder R. Removal of water-soluble and protein-bound solutes with reversed mid-dilution versus post-dilution haemodiafiltration. Nephrol Dial Transplant. 2012; 27: 3278-3283. doi:10.1093/ndt/gfs060 PMID: 22492823.
70. Bammens B, Evenepoel P, Verbeke K, Vanrenterghem Y. Removal of middle molecules and proteinbound solutes by peritoneal dialysis and relation with uremic symptoms. Kidney Int. 2003; 64: 2238- 2243. doi:10.1046/j.1523-1755.2003.00310.x PMID: 14633148.
71. Blankestijn PJ, Ledebo I, Canaud B. Hemodiafiltration: clinical evidence and remaining questions. Kidney Int. 2010; 77: 581-7. doi:10.1038/ki.2009.541 PMID: 20130529.
72. Maduell F, Arias M, Durán CE, Vera M, Fontseré N, Azqueta M, et al. Nocturnal, every-other-day, online haemodiafiltration: An effective therapeutic alternative. Nephrol Dial Transplant. 2012; 27: 1619-1631. doi:10.1093/ndt/gfr491 PMID: 21931125.
73. Lesko LJ, Schmidt S. Individualization of drug therapy: history, present state, and opportunities for the future. Clin Pharmacol Ther. 2012; 92: 458-466. doi:10.1038/clpt.2012.113 PMID: 22948891.
74. Vilar E, Farrington K. Emerging importance of residual renal function in end-stage renal failure. Semin Dial. 2011; 24: 487-494. doi:10.1111/j.1525-139X.2011.00968.x PMID: 21999737.
75. Daugirdas JT, Greene T, Rocco MV, Kaysen GA, Depner TA, Levin NW, et al. Effect of frequent hemodialysis on residual kidney function. Kidney Int. 2013.
76. Schiffl H, Lang SM, Fischer R. Effects of high efficiency post-dilution on-line hemodiafiltration or conventional hemodialysis on residual renal function and left ventricular hypertrophy. Int Urol Nephrol. 2012; doi:10.1007/s11255-012-0336-4.
77. Jahn B, Betz M, Deppisch R, Janssen O, Hänsch GM, Ritz E. Stimulation of beta 2-microglobulin synthesis in lymphocytes after exposure to Cuprophan dialyzer membranes. Kidney Int. 1991; 40: 285- 290. PMID: 1942777.
78. Schoels M, Jahn B, Hug F, Deppisch R, Ritz E, Hänsch GM. Stimulation of mononuclear cells by contact with cuprophan membranes: further increase of beta 2-microglobulin synthesis by activated late complement components. Am J Kidney Dis. 1993; 21: 394-399. PMID: 8465819.
79. Campistol JM, Molina R, Bernard DB, Rodriguez R, Mirapeix E, Munoz-Gomez JM, et al. Synthesis of beta 2-microglobulin in lymphocyte culture: Role of hemodialysis, dialysis membranes, dialysis-amyloidosis, and lymphokines. Am J Kidney Dis. 1993; 22: 691-699. PMID: 8238015.
80. Zingraff J, Beyne P, Ureña P, Uzan M, Man Nguyen Khoa, Descamps-Latscha B, et al. Influence of haemodialysis membranes on beta 2-microglobulin kinetics: in vivo and in vitro studies. Nephrol Dial Transplant. 1988; 3: 284-290. PMID: 3140102.
81. Haufe CC, Eismann U, Deppisch RM, Stein G. Expression of beta2-microglobulin and c-fos mRNA: is there an influence of high- or low-flux dialyzer membranes? Kidney Int Suppl. 2001; 78: S177-S181. PMID: 11169006.
82. Chanard J, Vincent C, Caudwell V, Lavaud S, Toupance O, Wong T, et al. Beta 2-microglobulin metabolism in uremic patients who are undergoing dialysis. Kidney Int Suppl. 1993; 41: S83-S87. PMID: 8320953.
83. Shafi T, Parekh RS, Jaar BG, Plantinga LC, Oberai PC, Eckfeldt JH, et al. Serum β-trace protein and risk of mortality in incident hemodialysis patients. Clin J Am Soc Nephrol. 2012; 7: 1435-1445. doi:10.2215/CJN.02240312 PMID: 22745274.
84. Shin MJ, Song SH, Kwak IS, Lee SB, Lee DW, Seong EY, et al. Serum cystatin C as a predictor for cardiovascular events in end-stage renal disease patients at the initiation of dialysis. Clin Exp Nephrol. 2012; 16: 456-463. doi:10.1007/s10157-011-0583-1 PMID: 22278599.
85. Meert N, Eloot S, Schepers E, Lemke H-D, Dhondt A, Glorieux G, et al. Comparison of removal capacity of two consecutive generations of high-flux dialysers during different treatment modalities. Nephrol Dial Transplant. 2011; 26: 2624-2630doi:10.1093/ndt/gfq803 PMID: 21310741.
86. Vanholder R, Van Laecke S, Glorieux G. The middle-molecule hypothesis 30 years after: lost and rediscovered in the universe of uremic toxicity? J Nephrol. 2008; 21: 146-160. PMID: 18446708.
87. Eloot S, Van Biesen W, Vanholder R. A sad but forgotten truth: The story of slow-moving solutes in fast hemodialysis. Semin Dial. 2012; 25: 505-9. doi:10.1111/j.1525-139X.2012.01107.x PMID: 22925227.
88. Dobre M, Meyer TW, Hostetter TH. Searching for uremic toxins. Clin J Am Soc Nephrol. 2013; 8: 322- 327. doi:10.2215/CJN.04260412 PMID: 23024165.
89. Pan H, Ardini MA, Bakalov V, Delatte M, Eggers P, Ganapathi L, et al. "What"s in the NIDDK CDR?'- public query tools for the NIDDK central data repository. Database (Oxford). 2013; bas058.
90. Turner CF, Pan H, Silk GW, Ardini MA, Bakalov V, Bryant S, et al. The NIDDK Central Repository at 8 years-ambition, revision, use and impact. Database (Oxford). 2011; bar043.
91. Vanholder R, Abou-Deif O, Argiles A, Baurmeister U, Beige J, Brouckaert P, et al. The role of EUTox in uremic toxin research. Semin Dial. 2009; 22: 323-328. doi:10.1111/j.1525-139X.2009.00574.x PMID: 19708975.