The endothelial cell in ischemic acute kidney injury: implications for acute and chronic function

Recent evidence suggests that injury to the renal vasculature may play an important role in the pathogenesis of both early and chronic ischemic acute kidney injury (AKI). Established and new data support the suggestion that vascular injury, in particular, endothelial cell injury, participates in the extent and maintenance of AKI by pathways that are related to vascular tone. Early alterations in peritubular capillary blood flow during reperfusion has been documented and associated with loss of normal endothelial cell function, which can be replaced pharmacologically or with cell replacement interventions. Distorted peritubular capillary morphology is associated with loss of barrier function that may contribute to early alterations in vascular stasis. In addition, ischemia induces alterations in endothelial cells that may promote inflammation and procoagulant activity, thus contributing to vascular congestion. Reductions in microvasculature density may play a critical part in the progression of chronic kidney disease following initial recovery from ischemia/reperfusion-induced AKI. The exact nature of how capillary loss alters renal function and predisposes renal disease is thought to be due at least in part to hypoxia. Finally, the loss of endothelial cell function may represent an important therapeutic target in which nitric oxide, vascular trophic support, and/or endothelial progenitor cells may show potential importance in ameliorating the acute and/or chronic effects of ischemic AKI.     

Chronic allograft nephropathy: An update.

Chronic allograft nephropathy is the most prevalent cause of renal transplant failure in the first post-transplant decade, but its pathogenesis has remained elusive. Clinically, it is characterized by a slow but variable loss of function, often in combination with proteinuria and hypertension. The histopathology is also not specific, but transplant glomerulopathy and multilayering of the peritubular capillaries are highly characteristic. Several risk factors have been identified, such as advanced donor age, delayed graft function, repeated acute rejection episodes, vascular rejection episodes, and rejections that occur late after transplantation. A common feature of chronic allograft nephropathy is that it develops in grafts that have undergone previous damage, although the mechanism(s) responsible for the progressive fibrosis and tissue remodeling has not yet been defined. Hypotheses to explain chronic allograft nephropathy include the immunolymphatic theory, the cytokine excess theory, the loss of supporting architecture theory, and the premature senescence theory. The most effective option to prevent chronic allograft nephropathy is to avoid graft injury from both immune and nonimmune mechanisms.     

Acute renal failure after analgesic drugs including paracetamol (acetaminophen)

Seven patients with acute renal failure after ingestion of analgesic drug combinations including paracetamol were seen. They presented with oliguric renal failure and restitution of renal function was complete. Only 2 patients had severe liver damage and 2 patients had no signs of liver abnormality. Renal biopsies, studied by light and electron microscopy, in 3 patients showed focal tubular epithelial cell necrosis. Focal vascular damage, predominantly of endothelial cells, was also present in all specimens. This vascular injury was found in various locations in the kidney, including the glomerular and peritubular capillaries and small arterioles. This suggests that microvascular damage is an important mechanism for the renal injury after analgesic drugs.     

Diagnostic value of C4d in renal allograft biopsies in different clinical settings: absence of C4d in grafts from non-heart-beating donors

Humoral mechanisms of rejection after kidney transplantation (TX) can be identified through the detection of diffuse complement C4d deposits in peritubular capillaries (PTC) in graft biopsies or donor-specific antibodies (DSA) in serum samples. It has been hypothesized that ischemic injury in the graft may facilitate humoral responses. Kidney grafts from non-heart-beating donors (NHBD) present more often severe ischemia lesions than grafts from heart-beating or living donors. METHODS: We reviewed kidney TX biopsies performed from May 2002 to November 2004 with special interest paid to recipients from NHBD. We checked corresponding frozen tissue for the detection of C4d in PTC using immunofluorescence with a monoclonal antibody against C4d. We also collected post-TX contemporaneous DSA data, either flow crossmatches or cytotoxic PRA. RESULTS: During this period, we performed 22 kidney TXs from NHBD of a total of 326 kidney TX (either single or combined with other grafts). Nine patients of this group underwent 12 biopsies for delayed graft function over 15 days or deteriorating scans. All biopsies showed acute tubular necrosis, but one also presented IA Banff acute rejection and another one had neutrophils in PTC. Frozen tissue from these 12 biopsies did not have diffuse C4d deposits in PTC. Serum samples of seven of nine patients were available: four had negative DSA flow crossmatches and three had 0% PRA within the same period. We diagnosed acute humoral rejection (AHR) in 13 patients-with acute renal dysfunction, C4d in biopsies and DSA after kidney TX-of 38 with high clinical suspicion for AHR. We detected C4d in seven biopsies of 30 patients performed more than 6 months after TX. CONCLUSIONS: Severe ischemic injury does not necessarily determine the activation of humoral mechanisms of rejection mediated through DSA. Therefore, C4d is extremely interesting for the identification of humoral rejection in any clinical setting after kidney TX.     

Chronic rejection in renal transplantation

With renal transplantation, chronic rejection is currently the most prevalent cause of late transplant failure. Clinically, chronic rejection presents as chronic transplant dysfunction, characterized by a slow loss of function, often in combination with hypertension and proteinuria. Transplant glomerulopathy and multilayering of the peritubular capillaries are highly characteristic for chronic rejection. Risk factors have been identified and include young recipient age, black race, presensitization, histoincompatibility, and acute rejection episodes, especially vascular rejection episodes and rejections that occur late after transplantation. Chronic rejection develops in grafts that undergo intermittent or persistent damage from cellular and humoral immune responses resulting from indirect recognition of alloantigens. Progression factors such as advanced donor age, renal dysfunction, hypertension, proteinuria, hyperlipidemia, and smoking play an important role. At the tissue level, senescence conditioned by ischemia/reperfusion may contribute to the development of chronic rejection. The most effective option to prevent renal failure from chronic rejection is to avoid graft injury from both immune and nonimmune mechanism together with nonnephrotoxic maintenance immunosuppression.     

Two cases of primary non-functioning kidney from the same donor

Abstract:  We report two cases of primary non-functioning kidney from the same non-heart beating donor (NHBD). A 42-yr-old man received a renal transplant from a NHBD. The donor was a 38-yr-old male who died of neck spinal injury. The warm ischemic time was 61 min. One h after reperfusion, the graft became edematous and congested in the presence of normal and adequate vascular anastomosis and lack of renal vein thrombosis. The one-h biopsy specimen showed acute tubular necrosis and severe congestion with occasional platelet aggregates in glomerular capillaries. The graft was resected on post-transplantation day 6. Graftectomy specimen revealed renal cortical necrosis. The contralateral kidney of the same donor was transplanted into a 54-yr-old male. The one-h biopsy specimen showed tubular degeneration and neutrophil infiltration in peritubular capillaries, but no glomerular congestion or thrombus. The recipient died on post-transplantation day 4. Although the cause of death was unknown, necropsy of the renal graft showed renal cortical necrosis, similar to case 1. Ischemia/reperfusion injury was considered the cause of non-functioning kidney in both cases, because of long warm ischemic time. The biopsy specimens at zero-h from both grafts showed focal tubular degeneration only without distinct necrosis, indicating it is difficult to predict viability based on the pathological findings at zero-h or one-h biopsies. There is a need for further understanding of clinical and histological patterns in order to define the criteria of viability of kidney transplant.     

Propionyl-L-carnitine prevents renal function deterioration due to ischemia/reperfusion

BACKGROUND: Ischemia-reperfusion injury after organ transplantation is a major cause of delayed graft function. Prevention of post-transplant ischemia acute renal failure is still elusive. METHODS: The present study was designed to examine whether propionyl-l-carnitine, an acyl derivative of carnitine involved in fatty acid oxidation pathway and adenosine 5'-triphosphate (ATP) generation of mitochondria, prevented renal function deterioration and structural injury induced by ischemia-reperfusion in an ex vivo rat model of isolated perfused kidney (IPK) preparation and in vivo in a model of syngeneic kidney transplantation. RESULTS: In the model of ischemia (20 or 40 min)/reperfusion (90 or 70 min) in IPK, untreated kidneys showed a marked reduction of glomerular filtration rate (GFR) and renal perfusate flow (RPF) as compared to baseline, when perfusion was established by restoring effective perfusion pressure to 100 mm Hg. Exposure of kidneys to propionyl-l-carnitine before establishing the ischemia insult to tissue, largely prevented renal function impairment. Pre-exposure of ischemic kidneys to propionyl-l-carnitine largely reduced the percent of lactate dehydrogenase (LDH), a cell injury marker, released into the perfusate after reperfusion as compared to untreated ischemic kidneys. Histologic findings showed very mild post-ischemic lesions in kidneys exposed to propionyl-l-carnitine as compared to untreated ischemic kidneys. Immunohistochemical detection of 4-hydroxynonenal protein adduct, a major product of lipid peroxidation, was very low in kidney infused with propionyl-l-carnitine and exposed to ischemia/reperfusion as compared to untreated ischemic kidneys. ATP levels were not affected by propionyl-l-carnitine treatment. Renal function of kidneys exposed for four hours to cold Belzer UW solution added with propionyl-l-carnitine and transplanted to binephrectomized recipients was largely preserved as compared to untreated ischemic grafts. Propionyl-l-carnitine almost completely prevented polymorphonuclear cell graft infiltration and reduced tubular injury at 16 hours post-transplant. CONCLUSIONS: These data indicate that propionyl-l-carnitine is of value in preventing decline of renal function that occurs during ischemia-reperfusion. The beneficial effect of propionyl-l-carnitine possibly relates to lowering lipid peroxidation and free radical generation that eventually results in the preservation of tubular cell structure. The efficacy of propionyl-l-carnitine to modulate ischemia-reperfusion injury in these models opens new perspectives for preventing post-transplant delayed graft function.     

Therapeutic strategy with a membrane-localizing complement regulator to increase the number of usable donor organs after prolonged cold storage

A shortage of donor organs and increasing dependence on marginal grafts with prolonged ischemic times have meant that new methods are needed to prevent postischemic damage. Herein is reported a new strategy aimed to protect donor kidney from complement-mediated postischemic damage and therefore increase the number of successful transplants. Rat donor kidneys were perfused with a membrane-localizing complement regulator derived from human complement receptor type 1 (APT070) and then subjected to prolonged periods of cold storage (at 4 degrees C). A relationship was found between the duration of cold ischemia and the extent of complement-mediated tubule damage and loss of graft function. After 16 h of cold storage, APT070-treated kidneys that were transplanted into syngeneic recipients showed a significant increase in the number of surviving grafts, compared with control-treated grafts (63.6 versus 26.3%). Surviving grafts also displayed less acute tubular injury and better preservation of renal function. These results not only enhance the understanding of the mechanism by which prolonged cold ischemia reduces immediate graft survival but also provide essential information about the effectiveness of membrane-localizing complement regulator with prolonged cold storage. This could lead to more effective strategies for improving the use of severely ischemic donor organs.     

Effect of histological damage on long-term kidney transplant outcome

BACKGROUND: Chronic renal allograft failure remains a major challenge to overcome. Factors such as donor quality, delayed graft function (DGF), acute rejection, and immunosuppression are known to affect long-term outcome, but their relationship to histological damage to graft outcome is unclear. METHODS: Protocol kidney biopsies (n=112) obtained at 3 months after transplantation yielded 102 with adequate tissue. Histology was scored by the Banff schema, and compared with implantation biopsies (n=91), repeat 12-month histology (n=39), decline in serum creatinine and serial isotopic glomerular filtration rate, onset of chronic allograft nephropathy (CAN), and actuarial graft survival censored for death with a functioning graft. RESULTS: At a median follow-up of 9.3 years, 20 patients had graft failure and 26 died with a functioning graft. Banff chronic nephropathy was present in 24% of 3-month biopsies, and was predicted by microvascular disease in the donor, cold ischemia, DGF, and acute vascular rejection (P<0.001). Acute glomerulitis at 3 months correlated with segmental glomerulosclerosis at 12 months, subsequent recurrent glomerulonephritis, and graft failure (P<0.01). Subclinical rejection at 3 months occurred in 29% of biopsies, correlated with prior acute rejection and HLA mismatch, and led to chronic histological damage by 12 months (r=0.25-0.67, P<0.05-0.001). Subclinical rejection, arteriolar hyalinosis, and tubulitis present at 3 months had resolved by 12 months. The 10-year survival rates for Banff chronic nephropathy were 90.4% for grade 0, 81.0% grade 1, and 57.9% for grades 2 or greater (P<0.01). Early tubulointerstitial damage at 3 months profoundly influenced graft survival beyond 10 years. CAN was predicted by kidney ischemia, 3-month chronic intimal vascular thickening, tubular injury, proteinuria, and late rejection. Chronic fibrointimal thickening of the small arteries and chronic interstitial fibrosis at 3 months independently predicted graft loss and decline in renal function (P<0.05-0.001). CONCLUSIONS: Early transplant damage occurs in the tubulointerstitial compartment from preexisting donor kidney injury and discrete events such as vascular rejection and DGF. Subsequent chronic damage and graft failure reflect accumulated previous injury and chronic interstitial fibrosis, vascular impairment, subclinical rejection, and injury from late rejection. CAN may be conceptualized as the sequelae of incremental and cumulative damage to the transplanted kidney. The duration of graft survival is dependent and predicted by the quality of the transplanted donor kidney combined with the intensity, frequency, and irreversibility of these damaging insults.     

Rabbit anti‐rat thymocyte immunoglobulin preserves renal function during ischemia/reperfusion injury in rat kidney transplantation

Ischemia/reperfusion (I/R) injury is an important cause of renal graft dysfunction in humans. Increases in cold and warm ischemia times lead to a higher risk of early post‐transplant complications including delayed graft function and acute rejection. Moreover, prolonged cold ischemia is a predictor of long‐term kidney graft loss. The protective effect of rabbit anti‐rat thymocyte immunoglobulin (rATG) was evaluated in a rat model of I/R injury following syngeneic kidney transplantation. Serum creatinine concentration was evaluated at 16 h and 24 h post‐transplant. Animals were sacrificed 24 h post‐transplant for evaluation of histology, infiltrating leukocytes, nitrotyrosine staining, and apoptosis. rATG was effective in preventing renal function impairment, tissue damage and tubular apoptosis associated with I/R only when was given 2 h before transplantation but not at the time of reperfusion. Pretransplant rATG treatment of recipient animals effectively reduced the amount of macrophages, CD4⁺, CD8⁺ T cells and LFA‐1⁺ cells infiltrating renal graft subjected to cold ischemia as well as granzyme‐B expression within ischemic kidney. On the other hand, granulocyte infiltration and oxidative stress were not modified by rATG. If these results will be translated into the clinical setting, pretransplant administration of Thymoglobuline^® could offer the additional advantage over peri‐transplant administration of limiting I/R‐mediated kidney graft damage.     

Clinical and pathological assessment of acute vascular rejection in the transplant kidney

Koike J, Yamaguchi Y, Horita S, Tanabe K, Fuchinoue S, Toma H, Nihei H. Clinical and pathological assessment of acute vascular rejection in the transplant kidney. Clin Transplantation 2001: 15 (Supplement 5): 41–44. ©Munksgaard, 2001
Acute vascular rejection (AVR) in kidney transplan- tation is the most important factor influencing graft prognosis. We focus on patients whose grafts were lost because of AVR, and assessed their clinical characteristics and histological findings of biopsied renal grafts. Biopsied specimens exhibited AVR in 43 patients who underwent kidney transplantation in the Kidney Center of Tokyo Women's Medical University from 1995 to 1999. In the follow-up from 1 to 5 yr (median: 2.5 yr) we classified these patients into three groups: favourable prog- nosis group (FPG), relatively poor prognosis group (RPPG) and poor prognosis group (PPG). Light microscopic study for histological grading of acute rejection according to the Banff scheme and detection of the C4d complement deposition on peritubular capillaries by the immunofluorescence method were performed. Based on the results, the donors of RPPG and PPG were significantly older than those of FPG, and all factors of acute rejection according to the Banff scheme were not statistically significantly different among the three groups. However, an acute tubular injury mimicking acute tubular necrosis (ATN) was observed in the biopsy specimens from PPG. In conclusion, an older donor is a risk factor of poor prognosis of the graft with AVR, and acute tubular injury mimicking ATN is one of the important features that enables the prediction of graft failure originating from AVR in kidney transplantation.     

Angiopoietin-1 therapy enhances fibrosis and inflammation following folic acid-induced acute renal injury

The loss of interstitial capillaries is a feature of several experimental models of renal disease and this contributes to secondary kidney injury. Angiopoietin-1 is a secreted growth factor which binds to Tie-2 present on endothelia to enhance cell survival thereby stabilizing capillary architecture in-vitro. Previous studies showed that angiopoietin-1 prevented renal capillary and interstitial lesions following experimental ureteric obstruction. We tested here the effect of angiopoietin-1 treatment on capillary loss and associated tubulointerstitial damage known to follow recovery from folic acid-induced tubular necrosis and acute renal injury. We found that delivery of angiopoietin-1 by adenoviral vectors stabilized peritubular capillaries in folic acid nephropathy but this was accompanied by profibrotic and inflammatory effects. These results suggest that the use of endothelial growth factor therapy for kidney disease may have varying outcomes that depend on the disease model tested.     

Protection of endothelial cells by dextran sulfate in rats with thrombotic microangiopathy

The characteristic features of thrombotic microangiopathy (TMA) include glomerular and peritubular capillary endothelial cell injury in association with loss of heparan sulfate proteoglycans on the cell surface and thrombus formation, followed by subsequent ischemic tubulointerstitial damage. It therefore was hypothesized that dextran sulfate (DXS) may protect the kidney against endothelial damage in a model of TMA. TMA was induced in rats by renal artery perfusion of an antiglomerular endothelial antibody, followed by the administration of DXS or vehicle. Renal damage was assessed by histologic analysis and measurements of blood urea nitrogen and creatinine. Whereas control rats developed severe renal failure with extensive glomerular and tubular injury, administration of DXS significantly protected renal function and preserved the glomerular endothelium and peritubular capillaries. The beneficial effect of DXS could be attributed to the ability of DXS to protect endothelial cells from coagulation and complement activation, as demonstrated by the histologic analysis. In addition, binding of the administered DXS to the surface of the glomerular endothelium was confirmed in TMA rats, suggesting that DXS acts as a "repair coat" of injured glomerular endothelium. In conclusion, DXS protects the kidney from experimental TMA. This protection may be mediated by DXS's binding directly to the surface of glomerular endothelium and amelioration of coagulation, complement activation, and cellular matrix loss.     

ET(B) receptor protects the tubulointerstitium in experimental thrombotic microangiopathy

BACKGROUND: The characteristic features of thrombotic microangiopathy (TMA) include glomerular and peritubular capillary endothelial cell injury with thrombus formation and subsequent ischemic tubulointerstitial damage. The endothelin ET(B) receptor has been shown to mediate both endothelial cell proliferation and vasodilation, and we therefore hypothesized that blockade of this receptor might promote more severe injury in this model. METHODS: TMA was induced in recently established transgenic rats that lack expression of ET(B) receptor in the kidney; these animals were compared to control rats with TMA both in the short-term (days 1 and 3) when acute glomerular injury was most manifest, and the long-term (day 17) when glomeruli have recovered but tubulointerstitial injury is still present. Renal damage was assessed by histological analysis and blood urea nitrogen (BUN) measurements. RESULTS: No difference in the TMA model was observed between rats with and without ET(B) receptor on days 1 or 3. At day 17, however, rats without the ET(B) receptor showed more severe tubulointerstitial injury compared with those with ET(B) receptor, which was associated with higher BUN levels. The tubulointerstitial damage was associated with a more severe loss of peritubular capillaries. CONCLUSIONS: These findings suggest that the ET(B) receptor may protect peritubular capillaries under the ischemic insult, and serve a defensive role in the tubulointerstitium induced by renal microvascular injury.     

Kidney clamp,perfuse, re‐implant: a useful technique for graft salvage after vascular complications during kidney transplantation

Although intra‐operative vascular complications during renal transplantation are rare, injuries associated with prolonged ischemia may lead to graft threatening early and late complications. This series describes a novel technique for intra‐operative repair of vascular complications in five patients over a three‐yr period. The method consists of rapid graft nephrectomy and re‐preservation of the graft with cold University of Wisconsin solution, which allows for controlled/precise back table repair of the vascular injury without incurring prolonged warm ischemia time. In three cases, the donor renal vein (2) and donor renal artery (1) were damaged and required back table reconstruction. In two cases, the recipient iliac artery needed reconstruction. Three of the five cases used deceased donor iliac vessels from another donor for reconstruction. Two patients required postoperative dialysis for delayed graft function for three to nine d (average six d) and two patients had slow graft function. All grafts were functioning at 17 months (mean) after transplant, with a median serum of 1.61 mg/dL (0.74–3.69). This series demonstrates the effectiveness of kidney clamp, perfuse, resuscitate as an effective intra‐operative technique to salvage grafts after vascular injury. Although the grafts may suffer from delayed or slow graft function, excellent long‐term function is attainable.     

Prediction by postrevascularization biopsies of cadaveric kidney allografts of rejection, graft loss, and preservation nephropathy.

This prospective study of postrevascularization biopsies was undertaken to determine if pathological changes might be correlated with subsequent allograft rejection and loss. Such a relationship, if identified, could be used to predict graft outcome, thus permitting earlier intervention for individuals at an increased risk for rejection or graft loss. Fifty-seven biopsies were obtained, and the number of polymorphonuclear leukocytes marginating in the glomerular loops and peritubular capillaries was documented along with risk factors associated with the recipients' immunological status and with risk factors associated with ischemic preservation injury. The presence of seven PMN leukocytes in the peritubular capillaries is related to the subsequent occurrence of cellular rejection and accurately predicted in 82% of the patients studied whether or not rejection would occur. Mean glomerular PMN leukocyte count was related to cold ischemia time and subsequent graft loss, while an elevated mean glomerular PMN leukocyte count in conjunction with an elevated peritubular PMN leukocyte count was always associated with hyperacute rejection. Focal glomerular thrombosis (less than 50%) and tubular cast formation are manifestations of preservation nephropathy and had no effect on graft outcome. These findings suggest that the peritubular capillaries are a more sensitive target for immune changes and that minor donor/recipient disparities can be detected in the peritubular capillaries while preexisting sensitization to the donor is reflected by concurrent changes in the glomerular and peritubular capillaries.     

Persistent renal and extrarenal immune changes after severe ischemic injury

BACKGROUND: Renal ischemia/reperfusion (I/R) injury is associated with delayed graft function and decreased long-term allograft function. However, most experimental studies evaluating renal I/R injury have focused on acute events after ischemia. T cells are potential candidates to link preservation injury, alloimmunity, and fibrosis. We hypothesized that severe renal I/R injury would generate long-term kidney damage and immune changes. METHODS: C57BL/6 mice underwent 60 minutes of warm unilateral I/R injury or sham surgery and were studied for 6 weeks. Serum creatinine, renal histology, and albumin excretion were measured. Phagocyte infiltration, CD4+ infiltration, renal cytokine expression, and splenic lymphocyte intracellular cytokine production were also measured in mice at 6 weeks. RESULTS: Serum creatinine levels rose following 60 minutes of unilateral I/R injury compared to sham mice. Histologic analysis of ischemic kidneys at 6 weeks revealed a pronounced loss of tubular architecture and infiltration of inflammatory cells. Phagocyte and CD4+ T-cell infiltration were significantly increased in ischemic kidneys. This was accompanied by a significant increase in interleukin (IL)-1beta and regulated upon activation, normal T-cell expressed and secreted (RANTES) expression. Despite similar splenic CD4 and CD8 numbers, intracellular cytokine staining of T cells revealed a significant increase in interferon-gamma (IFN-gamma) in I/R injury mice compared to sham mice. CONCLUSION: Persistent renal and extrarenal immune responses occur after a single episode of severe I/R injury. These immune processes resulting from injury could in turn have long-term consequences on progression of renal disease in transplanted and native kidneys.     

Acute transplant glomerulopathy is associated with antibody-mediated rejection and poor graft outcome

Transplant glomerulopathy (TG) is traditionally considered to be a chronic entity. However, in our practice we observed patients who presented with features of TG as early as 14 days posttransplantation. We investigated the clinicopathological features of these cases. During a 4-year period, all patients with acute rejection were identified. Charts were reviewed to identify patients with antibody-mediated rejection and biopsy features of TG within 6 months posttransplantation. Three patients met the above- mentioned criteria. All of them had diffuse margination of inflammatory cells in peritubular capillaries in the setting of acute renal failure or delayed graft function. Monocyte (CD68-positive) margination in peritubular capillaries was a common feature. All 3 patients had donor-specific antibodies and features suggestive of antibody-mediated rejection. C4d stain in peritubular capillaries was focal and mild or absent in serial biopsies. Occlusive endothelial swelling of glomerular capillary loops (endotheliosis) preceded TG. None of the patients had evidence for other causes of similar glomerular changes in a transplant, such as calcineurin inhibitor toxicity, ischemia, hepatitis C, or immune complex glomerulonephritis. They did not have other biopsy features of chronicity when TG appeared and as it progressed. TG can occur as an acute phenomenon. We propose that endotheliosis is a more accurate and specific precursor of TG than mere glomerulitis. These cases of acute TG may represent a form of antibody-mediated rejection associated with proteinuria and poor response to treatment.