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Extrarenal determinants of kidney filter function

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Abstract

The kidney is an organ involved in cross talk with many human organs. The link between the immune system and the kidney has been studied in some detail, although data precisely elucidating their interaction are sparse, in particular with regard to the function of the kidney filter apparatus. Current research suggests that an understanding of the impairment of this cross talk between the bone marrow, as a fundament of the immune system and the kidney will provide meaningful insights into the pathophysiological mechanisms of impaired kidney filter function. Circulating factors have long been implicated in the pathogenesis of idiopathic nephrotic syndrome, particularly focal segmental glomerulosclerosis (FSGS) and its recurrence. Soluble urokinase receptor (suPAR) has emerged as a circulating factor responsible for FSGS and also as an early predictive marker for the development of various renal diseases. The bone marrow has recently been revealed as a predominant source of suPAR with deleterious effects on the kidney filter. These new findings have led to bone marrow or hematopoietic stem cell transplants being considered as potential therapeutic options for preventing the post-transplantation recurrence of FSGS or even as a treatment for the original disease associated with high suPAR levels. Whereas bone marrow transplantation for patients with pre-existing chronic kidney disease is challenging, recent clinical trials have demonstrated the promising outcome of combined bone marrow and kidney transplantation in patients with kidney failure. In this review, with its brief update on suPAR, we describe the critical new role of the bone marrow in the pathogenesis of the kidney disease process and the functional connection between these two organs through the soluble mediator, suPAR. We also comment on the feasibility of bone marrow transplants for the treatment of patients with chronic renal failure arising from recurrent FSGS.

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References

  • Alfano M, Cinque P, Giusti G, Proietti S, Nebuloni M, Danese S, D'Alessio S, Genua M, Portale F, Lo Porto M, Singhal PC, Rastaldi MP, Saleem MA, Mavilio D, Mikulak J (2015) Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes. Sci Rep 5:13647

    Article  PubMed  PubMed Central  Google Scholar 

  • Artero ML, Sharma R, Savin VJ, Vincenti F (1994) Plasmapheresis reduces proteinuria and serum capacity to injure glomeruli in patients with recurrent focal glomerulosclerosis. Am J Kidney Dis 23:574–581

    Article  CAS  PubMed  Google Scholar 

  • Blasi F, Carmeliet P (2002) uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 3:932–943

    Article  CAS  PubMed  Google Scholar 

  • Buhler LH, Spitzer TR, Sykes M, Sachs DH, Delmonico FL, Tolkoff-Rubin N, Saidman SL, Sackstein R, McAfee S, Dey B, Colby C, Cosimi AB (2002) Induction of kidney allograft tolerance after transient lymphohematopoietic chimerism in patients with multiple myeloma and end-stage renal disease. Transplantation 74:1405–1409

    Article  PubMed  Google Scholar 

  • Cathelin D, Placier S, Ploug M, Verpont MC, Vandermeersch S, Luque Y, Hertig A, Rondeau E, Mesnard L (2014) Administration of recombinant soluble urokinase receptor per se is not sufficient to induce podocyte alterations and proteinuria in mice. J Am Soc Nephrol 25:1662–1668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cohen EP, Pais P, Moulder JE (2010) Chronic kidney disease after hematopoietic stem cell transplantation. Semin Nephrol 30:627–634

    Article  PubMed  PubMed Central  Google Scholar 

  • Cravedi P, Kopp JB, Remuzzi G (2013) Recent progress in the pathophysiology and treatment of FSGS recurrence. Am J Transplant 13:266–274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Delville M, Sigdel TK, Wei C, Li J, Hsieh SC, Fornoni A, Burke GW, Bruneval P, Naesens M, Jackson A, Alachkar N, Canaud G, Legendre C, Anglicheau D, Reiser J, Sarwal MM (2014) A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. Sci Transl Med 6:256ra136

    Article  PubMed  PubMed Central  Google Scholar 

  • Ellis MJ, Parikh CR, Inrig JK, Kanbay M, Patel UD (2008) Chronic kidney disease after hematopoietic cell transplantation: a systematic review. Am J Transplant 8:2378–2390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gallon L, Leventhal J, Skaro A, Kanwar Y, Alvarado A (2012) Resolution of recurrent focal segmental glomerulosclerosis after retransplantation. N Engl J Med 366:1648–1649

    Article  CAS  PubMed  Google Scholar 

  • Gohh RY, Yango AF, Morrissey PE, Monaco AP, Gautam A, Sharma M, McCarthy ET, Savin VJ (2005) Preemptive plasmapheresis and recurrence of FSGS in high-risk renal transplant recipients. Am J Transplant 5:2907–2912

    Article  CAS  PubMed  Google Scholar 

  • Guthoff M, Wagner R, Randrianarisoa E, Hatziagelaki E, Peter A, Haring HU, Fritsche A, Heyne N (2017) Soluble urokinase receptor (suPAR) predicts microalbuminuria in patients at risk for type 2 diabetes mellitus. Sci Rep 7:40627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hahm E, Wei C, Fernandez I, Li J, Tardi NJ, Tracy M, Wadhwani S, Cao Y, Peev V, Zloza A, Lusciks J, Hayek SS, O'Connor C, Bitzer M, Gupta V, Sever S, Sykes DB, Scadden DT, Reiser J (2017) Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease. Nat Med 23:100–106

    Article  CAS  PubMed  Google Scholar 

  • Harris JJ, McCarthy HJ, Ni L, Wherlock M, Kang H, Wetzels JF, Welsh GI, Saleem MA (2013) Active proteases in nephrotic plasma lead to a podocin-dependent phosphorylation of VASP in podocytes via protease activated receptor-1. J Pathol 229:660–671

    Article  CAS  PubMed  Google Scholar 

  • Hayek SS, Sever S, Ko YA, Trachtman H, Awad M, Wadhwani S, Altintas MM, Wei C, Hotton AL, French AL, Sperling LS, Lerakis S, Quyyumi AA, Reiser J (2015) Soluble urokinase receptor and chronic kidney disease. N Engl J Med 373:1916–1925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang CA, Fuchimoto Y, Scheier-Dolberg R, Murphy MC, Neville DM Jr, Sachs DH (2000) Stable mixed chimerism and tolerance using a nonmyeloablative preparative regimen in a large-animal model. J Clin Invest 105:173–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang J, Liu G, Zhang YM, Cui Z, Wang F, Liu XJ, Chu R, Chen Y, Zhao MH (2013) Plasma soluble urokinase receptor levels are increased but do not distinguish primary from secondary focal segmental glomerulosclerosis. Kidney Int 84:366–372

    Article  CAS  PubMed  Google Scholar 

  • Ildstad ST, Sachs DH (1984) Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature 307:168–170

    Article  CAS  PubMed  Google Scholar 

  • Kaplan-Pavlovcic S, Ferluga D, Hvala A, Chwatal-Lakic N, Bren AF, Vizjak A (2002) Recurrent focal segmental glomerulosclerosis after renal transplantation: is early recurrent proteinuria always a surrogate marker for recurrence of the disease? Transplant Proc 34:3122–3124

    Article  CAS  PubMed  Google Scholar 

  • Kato F, Watanabe M (1983) Biochemical study on spontaneous thymoma rats with motor dysfunction. Aust J Pharm 6:275–279

    CAS  Google Scholar 

  • Kawai T, Cosimi AB, Colvin RB, Powelson J, Eason J, Kozlowski T, Sykes M, Monroy R, Tanaka M, Sachs DH (1995) Mixed allogeneic chimerism and renal allograft tolerance in cynomolgus monkeys. Transplantation 59:256–262

    Article  CAS  PubMed  Google Scholar 

  • Kawai T, Cosimi AB, Spitzer TR, Tolkoff-Rubin N, Suthanthiran M, Saidman SL, Shaffer J, Preffer FI, Ding R, Sharma V, Fishman JA, Dey B, Ko DS, Hertl M, Goes NB, Wong W, Williams WW Jr, Colvin RB, Sykes M, Sachs DH (2008) HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 358:353–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kimikawa M, Sachs DH, Colvin RB, Bartholomew A, Kawai T, Cosimi AB (1997) Modifications of the conditioning regimen for achieving mixed chimerism and donor-specific tolerance in cynomolgus monkeys. Transplantation 64:709–716

    Article  CAS  PubMed  Google Scholar 

  • Kitiyakara C, Eggers P, Kopp JB (2004) Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. Am J Kidney Dis 44:815–825

    Article  PubMed  Google Scholar 

  • Le Berre L, Godfrin Y, Gunther E, Buzelin F, Perretto S, Smit H, Kerjaschki D, Usal C, Cuturi C, Soulillou JP, Dantal J (2002) Extrarenal effects on the pathogenesis and relapse of idiopathic nephrotic syndrome in Buffalo/Mna rats. J Clin Invest 109:491–498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leventhal J, Abecassis M, Miller J, Gallon L, Ravindra K, Tollerud DJ, King B, Elliott MJ, Herzig G, Herzig R, Ildstad ST (2012) Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci Transl Med 4:124ra128

    Article  Google Scholar 

  • Maas RJ, Deegens JK, Brand JA van den, Cornelissen EA, Wetzels JF (2013) A retrospective study of focal segmental glomerulosclerosis: clinical criteria can identify patients at high risk for recurrent disease after first renal transplantation. BMC Nephrol 14:47

  • McCarthy ET, Sharma M, Savin VJ (2010) Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 5:2115–2121

    Article  PubMed  Google Scholar 

  • Nakamura T, Oite T, Shimizu F, Matsuyama M, Kazama T, Koda Y, Arakawa M (1986) Sclerotic lesions in the glomeruli of Buffalo/Mna rats. Nephron 43:50–55

    Article  CAS  PubMed  Google Scholar 

  • Newstead CG (2003) Recurrent disease in renal transplants. Nephrol Dial Transplant 18 (Suppl 6):vi68-vi74

    PubMed  Google Scholar 

  • Nishimura M, Toki J, Sugiura K, Hashimoto F, Tomita T, Fujishima H, Hiramatsu Y, Nishioka N, Nagata N, Takahashi Y, Ikehara S (1994) Focal segmental glomerular sclerosis, a type of intractable chronic glomerulonephritis, is a stem cell disorder. J Exp Med 179:1053–1058

    Article  CAS  PubMed  Google Scholar 

  • Ohta T, Kawaguchi H, Hattori M, Komatsu Y, Akioka Y, Nagata M, Shiraga H, Ito K, Takahashi K, Ishikawa N, Tanabe K, Yamaguchi Y, Ota K (2001) Effect of pre- and postoperative plasmapheresis on posttransplant recurrence of focal segmental glomerulosclerosis in children. Transplantation 71:628–633

    Article  CAS  PubMed  Google Scholar 

  • Ponticelli C, Glassock RJ (2010) Posttransplant recurrence of primary glomerulonephritis. Clin J Am Soc Nephrol 5:2363–2372

    Article  PubMed  Google Scholar 

  • Saddadi F, Alidadi A, Hakemi M, Bahar B (2017) Nephrotic syndrome after hematopoietic stem cell transplant: outcomes in Iran. Exp Clin Transplant 15:90–92

    PubMed  Google Scholar 

  • Sakellari I, Barbouti A, Bamichas G, Mallouri D, Kaloyannidis P, Fragidis S, Batsis I, Apostolou C, Karpouza A, Yannaki E, Smias C, Sombolos K, Anagnostopoulos A (2013) GVHD-associated chronic kidney disease after allogeneic haematopoietic cell transplantation. Bone Marrow Transplant 48:1329–1334

    Article  CAS  PubMed  Google Scholar 

  • Savin VJ, Sharma R, Sharma M, McCarthy ET, Swan SK, Ellis E, Lovell H, Warady B, Gunwar S, Chonko AM, Artero M, Vincenti F (1996) Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 334:878–883

    Article  CAS  PubMed  Google Scholar 

  • Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Millan MT, Shizuru JA, Hoppe RT, Lowsky R, Engleman EG, Strober S (2008) Tolerance and chimerism after renal and hematopoietic-cell transplantation. N Engl J Med 358:362–368

    Article  CAS  PubMed  Google Scholar 

  • Scandling JD, Busque S, Shizuru JA, Lowsky R, Hoppe R, Dejbakhsh-Jones S, Jensen K, Shori A, Strober JA, Lavori P, Turnbull BB, Engleman EG, Strober S (2015) Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation. Am J Transplant 15:695–704

    Article  CAS  PubMed  Google Scholar 

  • Schulz C, Persson M, Christensso A, Hindy G, Almgren P, Nilsson P, Melander O, Engström G, Orho-Melander M (2017) Soluble urokinase-type plasminogen activator receptor (suPAR) and impaired kidney function in the population-based Malmö diet and cancer study. Kidney Int Rep 2:239–247

    Article  PubMed  PubMed Central  Google Scholar 

  • Sellier-Leclerc AL, Duval A, Riveron S, Macher MA, Deschenes G, Loirat C, Verpont MC, Peuchmaur M, Ronco P, Monteiro RC, Haddad E (2007) A humanized mouse model of idiopathic nephrotic syndrome suggests a pathogenic role for immature cells. J Am Soc Nephrol 18:2732–2739

    Article  PubMed  Google Scholar 

  • Sharma M, Sharma R, McCarthy ET, Savin VJ (1999) “The FSGS factor:” enrichment and in vivo effect of activity from focal segmental glomerulosclerosis plasma. J Am Soc Nephrol 10:552–561

    CAS  PubMed  Google Scholar 

  • Sharma M, Sharma R, Reddy SR, McCarthy ET, Savin VJ (2002) Proteinuria after injection of human focal segmental glomerulosclerosis factor. Transplantation 73:366–372

    Article  PubMed  Google Scholar 

  • Smith HW, Marshall CJ (2009) Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol 11:23–36

    Article  Google Scholar 

  • Spinale JM, Mariani LH, Kapoor S, Zhang J, Weyant R, Song PX, Wong HN, Troost JP, Gadegbeku CA, Gipson DS, Kretzler M, Nihalani D, Holzman LB, Nephrotic Syndrome Study Network (2015) A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease. Kidney Int 87:564–574

    Article  CAS  PubMed  Google Scholar 

  • Spitzer TR, Delmonico F, Tolkoff-Rubin N, McAfee S, Sackstein R, Saidman S, Colby C, Sykes M, Sachs DH, Cosimi AB (1999) Combined histocompatibility leukocyte antigen-matched donor bone marrow and renal transplantation for multiple myeloma with end stage renal disease: the induction of allograft tolerance through mixed lymphohematopoietic chimerism. Transplantation 68:480–484

    Article  CAS  PubMed  Google Scholar 

  • Staeck O, Slowinski T, Lieker I, Wu K, Rudolph B, Schmidt D, Brakemeier S, Neumayer HH, Wei C, Reiser J, Budde K, Halleck F, Khadzhynov D (2015) Recurrent primary focal segmental glomerulosclerosis managed with intensified plasma exchange and concomitant monitoring of soluble urokinase-type plasminogen activator receptor-mediated podocyte beta3-integrin activation. Transplantation 99:2593–2597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Strober S (2016) Use of hematopoietic cell transplants to achieve tolerance in patients with solid organ transplants. Blood 127:1539–1543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thuno M, Macho B, Eugen-Olsen J (2009) suPAR: the molecular crystal ball. Dis Markers 27:157–172

    Article  PubMed  PubMed Central  Google Scholar 

  • Vanikar AV, Trivedi HL, Shah PR, Kanodia KV, Patel RD, Modi PR, Dave SD, Singhai AM, Shah VR, Trivedi VB, Shankar V (2013) Single-center experience on renal transplantation in primary focal and segmental glomerulosclerosis using hematopoietic stem cell transplantation in thymus, bone marrow, portal and peripheral circulation. Saudi J Kidney Dis Transpl 24:15–21

    Article  PubMed  Google Scholar 

  • Vinai M, Waber P, Seikaly MG (2010) Recurrence of focal segmental glomerulosclerosis in renal allograft: an in-depth review. Pediatr Transplant 14:314–325

    Article  CAS  PubMed  Google Scholar 

  • Vincenti F, Ghiggeri GM (2005) New insights into the pathogenesis and the therapy of recurrent focal glomerulosclerosis. Am J Transplant 5:1179–1185

    Article  CAS  PubMed  Google Scholar 

  • Weber S, Tonshoff B (2005) Recurrence of focal-segmental glomerulosclerosis in children after renal transplantation: clinical and genetic aspects. Transplantation 80:S128–S134

    Article  PubMed  Google Scholar 

  • Wei C, Moller CC, Altintas MM, Li J, Schwarz K, Zacchigna S, Xie L, Henger A, Schmid H, Rastaldi MP, Cowan P, Kretzler M, Parrilla R, Bendayan M, Gupta V, Nikolic B, Kalluri R, Carmeliet P, Mundel P, Reiser J (2008) Modification of kidney barrier function by the urokinase receptor. Nat Med 14:55–63

    Article  CAS  PubMed  Google Scholar 

  • Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, Maiguel D, Karumanchi SA, Yap HK, Saleem M, Zhang Q, Nikolic B, Chaudhuri A, Daftarian P, Salido E, Torres A, Salifu M, Sarwal MM, Schaefer F, Morath C, Schwenger V, Zeier M, Gupta V, Roth D, Rastaldi MP, Burke G, Ruiz P, Reiser J (2011) Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 17:952–960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei C, Trachtman H, Li J, Dong C, Friedman AL, Gassman JJ, McMahan JL, Radeva M, Heil KM, Trautmann A, Anarat A, Emre S, Ghiggeri GM, Ozaltin F, Haffner D, Gipson DS, Kaskel F, Fischer DC, Schaefer F, Reiser J (2012) Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol 23:2051–2059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weiss AS, Sandmaier BM, Storer B, Storb R, McSweeney PA, Parikh CR (2006) Chronic kidney disease following non-myeloablative hematopoietic cell transplantation. Am J Transplant 6:89–94

    Article  CAS  PubMed  Google Scholar 

  • Zimmerman SW (1984) Increased urinary protein excretion in the rat produced by serum from a patient with recurrent focal glomerular sclerosis after renal transplantation. Clin Nephrol 22:32–38

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, Rush University Medical Center, Chicago, Ill., USA

    Eunsil Hahm, Vasil Peev & Jochen Reiser

  2. Rush University Transplant Program, 1725 W. Harrison Street, Suite 161, Chicago, IL, 60612, USA

    Vasil Peev

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  1. Eunsil Hahm
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Correspondence to Vasil Peev.

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All authors equally contributed to the creation of this manuscript.

J.R. is given as inventor on pending and issued patents relating to anti-proteinuric therapies. He stands to gain royalties from present and future commercialization. J.R. is also co-founder and advisor to TRISAQ, a biotechnology company. The remaining authors report no conflicts of interest.

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Hahm, E., Peev, V. & Reiser, J. Extrarenal determinants of kidney filter function. Cell Tissue Res 369, 211–216 (2017). https://doi.org/10.1007/s00441-017-2635-7

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