As improvements are made in immunosuppressive therapy and early allograft survival, chronic allograft nephropathy (CAN) has become the dominant cause of late renal allograft failure¹ x 1. Kreis, H.A. and Ponticelli, C. Causes of late renal allograft loss: chronic allograft dysfunction, death, and other factors. Transplantation. 2001; 71: SS5–SS9 PubMed | Google Scholar See all References . There is general agreement that the pathogenic process of CAN is complex, and involves both immunologic and nonimmunologic factors^2. x 2. Halloran, P.F., Melk, A., and Barth, C. Rethinking chronic allograft nephropathy: The concept of accelerated senescence. J Am Soc Nephrol. 1999; 10: 167–181 PubMed | Google Scholar See all References ^{, 3.} x 3. Joosten, S.A., Van Kooten, C., and Paul, L.C. Pathogenesis of chronic allograft rejection. Transpl Int. 2003; 16: 137–145 Crossref | PubMed | Scopus (60) | Google Scholar See all References ^{, 4.} x 4. Nankivell, B.J., Borrows, R.J., Fung, C.L. et al. The natural history of chronic allograft nephropathy. N Engl J Med. 2003; 349: 2326–2333 https://doi.org/10.1056/NEJMoa020009 Crossref | PubMed | Scopus (1398) | Google Scholar See all References ^{, 5.} x 5. Paul, L.C. Immunologic risk factors for chronic renal allograft dysfunction. Transplantation. 2001; 71: SS17–SS23 PubMed | Google Scholar See all References ^{, 6.} x 6. Fellstrom, B. Nonimmune risk factors for chronic renal allograft dysfunction. Transplantation. 2001; 71: SS10–SS16 PubMed | Google Scholar See all References . A variety of alloantigen-dependent immune responses that contribute to the progression of CAN have been reported, including prior severe rejection, subclinical rejection, and chronic rejection^2. x 2. Halloran, P.F., Melk, A., and Barth, C. Rethinking chronic allograft nephropathy: The concept of accelerated senescence. J Am Soc Nephrol. 1999; 10: 167–181 PubMed | Google Scholar See all References ^{, 3.} x 3. Joosten, S.A., Van Kooten, C., and Paul, L.C. Pathogenesis of chronic allograft rejection. Transpl Int. 2003; 16: 137–145 Crossref | PubMed | Scopus (60) | Google Scholar See all References ^{, 4.} x 4. Nankivell, B.J., Borrows, R.J., Fung, C.L. et al. The natural history of chronic allograft nephropathy. N Engl J Med. 2003; 349: 2326–2333 https://doi.org/10.1056/NEJMoa020009 Crossref | PubMed | Scopus (1398) | Google Scholar See all References ^{, 5.} x 5. Paul, L.C. Immunologic risk factors for chronic renal allograft dysfunction. Transplantation. 2001; 71: SS17–SS23 PubMed | Google Scholar See all References . Furthermore, several alloantigen-independent immune reactions and nonimmunologic factors, such as reperfusion-ischemic injury, chronic cytomegalovirus and polyomavirus infection, chronic toxic effects of calcineurin inhibitors, hypertension, hyperlipidemia, and chronic vesicoureteral reflux have also been reported, and are recognized as important causes of CAN^2. x 2. Halloran, P.F., Melk, A., and Barth, C. Rethinking chronic allograft nephropathy: The concept of accelerated senescence. J Am Soc Nephrol. 1999; 10: 167–181 PubMed | Google Scholar See all References ^{, 3.} x 3. Joosten, S.A., Van Kooten, C., and Paul, L.C. Pathogenesis of chronic allograft rejection. Transpl Int. 2003; 16: 137–145 Crossref | PubMed | Scopus (60) | Google Scholar See all References ^{, 4.} x 4. Nankivell, B.J., Borrows, R.J., Fung, C.L. et al. The natural history of chronic allograft nephropathy. N Engl J Med. 2003; 349: 2326–2333 https://doi.org/10.1056/NEJMoa020009 Crossref | PubMed | Scopus (1398) | Google Scholar See all References ^{, 6.} x 6. Fellstrom, B. Nonimmune risk factors for chronic renal allograft dysfunction. Transplantation. 2001; 71: SS10–SS16 PubMed | Google Scholar See all References . However, the process of the development of CAN has not been morphologically characterized. Moreover, the mechanism(s) for CAN remains poorly understood.

Vascular endothelial growth factor (VEGF) is essential for maintenance of the glomerular capillary network. The present study investigated the effects of VEGF in rats with progressive crescentic glomerulonephritis (GN). Necrotizing and crescentic GN was induced in rats by injection of anti-rat glomerular basement membrane (GBM) antibody. The alterations of glomerular capillaries and glomerular VEGF expression were assessed. In addition, the effects of continuous VEGF₁₆₅ administration (10 μg/100 g per d) on glomerular capillaries, glomerular inflammation, and the course of crescentic GN were examined. The appropriate timing of VEGF administration in progressive GN also was evaluated. In anti-GBM GN, necrotizing and crescentic glomerular lesions occurred by day 7, and newly formed necrotizing lesions reoccurred by week 3. Expression of VEGF was markedly reduced in necrotizing and crescentic lesions. Capillary repair was impaired after capillary destruction in necrotizing and crescentic glomeruli, which rapidly progressed to sclerotic glomeruli with chronic renal failure. In contrast, in the rats that received VEGF₁₆₅ administration from day 7, the necrotizing and crescentic lesions recovered and renal function significantly improved in week 4. This was evident by proliferating endothelial cells and glomerular capillary repair. In addition, VEGF administration decreased intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 expression in glomeruli (particularly on endothelial cells), reduced glomerular infiltrating CD8-postive and ED-1–positive cells, and inhibited the newly formed necrotizing lesions. VEGF administration was apparently effective against both the inflammatory and necrotizing glomerular lesions. These results suggest that VEGF administration resolves glomerular inflammation and accelerates glomerular recovery in the progressive necrotizing and crescentic GN. The therapeutic application of VEGF may be clinically useful for severe GN accompanied by extensive glomerular inflammation and endothelial injury.

Xenotransplantation represents a possible solution to the organ shortage crisis and is an imminent clinical reality with long-term xenograft survival in pig-to-nonhuman primate (NHP) heart and kidney large animal models, and short-term success in recent human decedent and clinical studies. However, concerns remain about safe clinical translation of these results, given the inconsistency in published survival as well as key differences between preclinical procurement and immunosuppression and clinical standards-of-care. Notably, no studies of solid organ pig-to-NHP transplantation have achieved xenograft survival longer than one month without CD40/CD154 costimulatory blockade, which is not currently an FDA-approved immunosuppression strategy. We now present consistent survival in consecutive cases of pig-to-NHP kidney xenotransplantation, including long-term survival after >3 hours of xenograft cold preservation time as well as long-term survival using FDA-approved immunosuppression. These data provide critical supporting evidence for the safety and feasibility of clinical kidney xenotransplantation. Moreover, long-term survival without CD40/CD154 costimulatory blockade may provide important insights for immunosuppression regimens to be considered for first-in-human clinical trials.

It has been suggested that low nephron number contributes to glomerular hypertension and hyperperfusion injury in progressive chronic kidney disease (CKD). The incidence of CKD in Japan is among the highest in the world, but the reasons remain unclear. We estimated total nephron (glomerular) number (Nglom _TOTAL ) as well as numbers of nonsclerosed (Nglom _NSG ) and globally sclerosed glomeruli (Nglom _GSG ), and the mean volume of nonsclerosed glomeruli (Vglom _NSG ) in Japanese normotensive, hypertensive, and CKD subjects and investigated associations between these parameters and estimated glomerular filtration rate (eGFR). Autopsy kidneys from age-matched Japanese men (9 normotensives, 9 hypertensives, 9 CKD) had nephron number and Vglom _NSG estimated using disector/fractionator stereology. Subject eGFR, single-nephron eGFR (SNeGFR), and the ratio SNeGFR/Vglom _NSG were calculated. Nglom _NSG in Japanese with hypertension (392,108 ± 87,605; P < 0.001) and CKD (268,043 ± 106,968; P < 0.001) was less than in normotensives (640,399 ± 160,016). eGFR was directly correlated with Nglom _NSG ( r = 0.70, P < 0.001) and inversely correlated with Vglom _NSG ( r = –0.53, P < 0.01). SNeGFR was higher in hypertensives than normotensives ( P = 0.03), but was similar in normotensives and CKD, while the ratio SNeGFR/Vglom _NSG was similar in normotensives and hypertensives but markedly reduced in CKD. Nephron number in Japanese with hypertension or CKD was low. This results in a higher SNeGFR in hypertensives compared with normotensive and CKD subjects, but lowered SNeGFR/Vglom _NSG in CKD subjects, suggesting that changes in GFR are accommodated by glomerular hypertrophy rather than glomerular hypertension. These findings suggest glomerular hypertrophy is a dominant factor in maintenance of GFR under conditions of low nephron number.