Urine Marker Analysis Identifies Evidence for Persistent Glomerular Podocyte Injury Across Allograft Lifespan

Overview

Journal Clin Transplant

Specialty General Surgery

Date 2021 Aug 13

PMID 34387906

Citations 5

Authors

Abhijit S Naik

Jawad Aqeel

Su Q Wang

Mahboob Chowdhury

Kevin He

Roger C Wiggins

Affiliations

Soon will be listed here.

Abstract

Long-term kidney transplant (KT) survival has remained relatively stagnant. Protocol biopsy studies suggest that glomerulosclerosis is a significant contributor to long-term graft failure. We previously demonstrated that podocyte loss in the first year post-transplantation predicted long-term allograft survival. However, whether increased podocyte loss continues over the lifespan of a KT remains unclear. We performed a cross-sectional analysis of 1182 urine samples from 260 KT recipients up to 19-years after transplantation. Urine pellet (UP) mRNAs were assayed for podocyte (NPHS2/podocin and nephrin/NPHS1), distal tubule (aquaporin2), and profibrotic cytokine (TGFbeta1). Multivariable generalized estimating equations were used to obtain "population-averaged" effects for these markers over time post-KT. Consistent with early stresses both podocyte and tubular markers increased immediately post-KT. However, only podocyte markers continued to increase long-term. A role for hypertrophic stresses in driving podocyte loss over time is implied by their association with donor BMI, recipient BMI, and donor-recipient BMI mismatch at transplantation. Furthermore, UP podocin mRNA was associated with urine TGFbeta1, proteinuria, and reduced estimated glomerular filtration rate, thereby linking podocyte injury to allograft fibrosis and survival. In conclusion we observed that podocyte loss continues long-term post-KT suggesting an important role in driving late graft loss.

Citing Articles

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References

Giral M, Foucher Y, Karam G, Labrune Y, Kessler M, Hurault de Ligny B . Kidney and recipient weight incompatibility reduces long-term graft survival. J Am Soc Nephrol. 2010; 21(6):1022-9. PMC: 2900958. DOI: 10.1681/ASN.2009121296. View

Levey A, Coresh J, Greene T, Marsh J, Stevens L, Kusek J . Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values. Clin Chem. 2007; 53(4):766-72. DOI: 10.1373/clinchem.2006.077180. View

Sato Y, Wharram B, Lee S, Wickman L, Goyal M, Venkatareddy M . Urine podocyte mRNAs mark progression of renal disease. J Am Soc Nephrol. 2009; 20(5):1041-52. PMC: 2678045. DOI: 10.1681/ASN.2007121328. View

Sellares J, de Freitas D, Mengel M, Reeve J, Einecke G, Sis B . Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant. 2011; 12(2):388-99. DOI: 10.1111/j.1600-6143.2011.03840.x. View

Fukuda A, Wickman L, Venkatareddy M, Wang S, Chowdhury M, Wiggins J . Urine podocin:nephrin mRNA ratio (PNR) as a podocyte stress biomarker. Nephrol Dial Transplant. 2012; 27(11):4079-87. PMC: 3494841. DOI: 10.1093/ndt/gfs313. View

Fukuda A, Wickman L, Venkatareddy M, Sato Y, Chowdhury M, Wang S . Angiotensin II-dependent persistent podocyte loss from destabilized glomeruli causes progression of end stage kidney disease. Kidney Int. 2011; 81(1):40-55. PMC: 3739490. DOI: 10.1038/ki.2011.306. View

Naik A, Afshinnia F, Aqeel J, Cibrik D, Samaniego M, Wickman L . Accelerated podocyte detachment early after kidney transplantation is related to long-term allograft loss of function. Nephrol Dial Transplant. 2018; 34(7):1232-1239. PMC: 6603364. DOI: 10.1093/ndt/gfy350. View

Fukuda A, Sato Y, Iwakiri T, Komatsu H, Kikuchi M, Kitamura K . Urine podocyte mRNAs mark disease activity in IgA nephropathy. Nephrol Dial Transplant. 2015; 30(7):1140-50. PMC: 4479668. DOI: 10.1093/ndt/gfv104. View

Amer H, Fidler M, Myslak M, Morales P, Kremers W, Larson T . Proteinuria after kidney transplantation, relationship to allograft histology and survival. Am J Transplant. 2007; 7(12):2748-56. DOI: 10.1111/j.1600-6143.2007.02006.x. View

10.

Loupy A, Hill G, Nochy D, Legendre C . Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure. Am J Transplant. 2010; 10(4):952. DOI: 10.1111/j.1600-6143.2009.02974.x. View

11.

Wiggins J, Goyal M, Sanden S, Wharram B, Shedden K, Misek D . Podocyte hypertrophy, "adaptation," and "decompensation" associated with glomerular enlargement and glomerulosclerosis in the aging rat: prevention by calorie restriction. J Am Soc Nephrol. 2005; 16(10):2953-66. DOI: 10.1681/ASN.2005050488. View

12.

Bosma R, Kwakernaak A, van der Heide J, de Jong P, Navis G . Body mass index and glomerular hyperfiltration in renal transplant recipients: cross-sectional analysis and long-term impact. Am J Transplant. 2007; 7(3):645-52. DOI: 10.1111/j.1600-6143.2006.01672.x. View

13.

Einecke G, Sis B, Reeve J, Mengel M, Campbell P, Hidalgo L . Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure. Am J Transplant. 2009; 9(11):2520-31. DOI: 10.1111/j.1600-6143.2009.02799.x. View

14.

Wharram B, Goyal M, Wiggins J, Sanden S, Hussain S, Filipiak W . Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol. 2005; 16(10):2941-52. DOI: 10.1681/ASN.2005010055. View

15.

Brenner B, Lawler E, Mackenzie H . The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int. 1996; 49(6):1774-7. DOI: 10.1038/ki.1996.265. View

16.

Naik A, Le D, Aqeel J, Wang S, Chowdhury M, Walters L . Podocyte stress and detachment measured in urine are related to mean arterial pressure in healthy humans. Kidney Int. 2020; 98(3):699-707. PMC: 10440835. DOI: 10.1016/j.kint.2020.03.038. View

17.

Naik A, Sakhuja A, Cibrik D, Ojo A, Samaniego-Picota M, Lentine K . The Impact of Obesity on Allograft Failure After Kidney Transplantation: A Competing Risks Analysis. Transplantation. 2015; 100(9):1963-9. DOI: 10.1097/TP.0000000000000983. View

18.

Fukuda A, Chowdhury M, Venkatareddy M, Wang S, Nishizono R, Suzuki T . Growth-dependent podocyte failure causes glomerulosclerosis. J Am Soc Nephrol. 2012; 23(8):1351-63. PMC: 3402293. DOI: 10.1681/ASN.2012030271. View

19.

Stegall M, Cornell L, Park W, Smith B, Cosio F . Renal Allograft Histology at 10 Years After Transplantation in the Tacrolimus Era: Evidence of Pervasive Chronic Injury. Am J Transplant. 2017; 18(1):180-188. DOI: 10.1111/ajt.14431. View

20.

Lamb K, Lodhi S, Meier-Kriesche H . Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant. 2010; 11(3):450-62. DOI: 10.1111/j.1600-6143.2010.03283.x. View