The causes, significance and consequences of inflammatory fibrosis in kidney transplantation: The Banff i-IFTA lesion.

Inflammation within areas of interstitial fibrosis and tubular atrophy (i-IFTA) is associated with adverse outcomes in kidney transplantation. We evaluated i-IFTA in 429 indication- and 2052 protocol-driven biopsy samples from a longitudinal cohort of 362 kidney-pancreas recipients to determine its prevalence, time course, and relationships with T cell-mediated rejection (TCMR), immunosuppression, and outcome. Sequential histology demonstrated that i-IFTA was preceded by cellular interstitial inflammation and followed by IF/TA. The prevalence and intensity of i-IFTA increased with developing chronic fibrosis and correlated with inflammation, tubulitis, and immunosuppression era (P < .001). Tacrolimus era-based immunosuppression was associated with reduced histologic inflammation in unscarred and scarred i-IFTA compartments, ameliorated progression of IF, and increased conversion to inactive IF/TA (compared with cyclosporine era, P < .001). Prior acute (including borderline) TCMR and subclinical TCMR were followed by greater 1-year i-IFTA, remaining predictive by multivariate analysis and independent of humoral markers. One-year i-IFTA was associated with accelerated IF/TA, arterial fibrointimal hyperplasia, and chronic glomerulopathy and with reduced renal function (P < .001 versus no i-IFTA). In summary, i-IFTA is the histologic consequence of active T cell-mediated alloimmunity, representing the interface between inflammation and tubular injury with fibrotic healing. Uncontrolled i-IFTA is associated with adverse structural and functional outcomes.

The natural history of chronic allograft nephropathy.

BACKGROUND: With improved immunosuppression and early allograft survival, chronic allograft nephropathy has become the dominant cause of kidney-transplant failure. METHODS: We evaluated the natural history of chronic allograft nephropathy in a prospective study of 120 recipients with type 1 diabetes, all but 1 of whom had received kidney-pancreas transplants. We obtained 961 kidney-transplant-biopsy specimens taken regularly from the time of transplantation to 10 years thereafter. RESULTS: Two distinctive phases of injury were evident as chronic allograft nephropathy evolved. An initial phase of early tubulointerstitial damage from ischemic injury (P<0.05), prior severe rejection (P<0.01), and subclinical rejection (P<0.01) predicted mild disease by one year, which was present in 94.2 percent of patients. Early subclinical rejection was common (affecting 45.7 percent of biopsy specimens at three months), and the risk was increased by the occurrence of a prior episode of severe rejection and reduced by tacrolimus and mycophenolate therapy (both P<0.05) and gradually abated after one year. Both subclinical rejection and chronic rejection were associated with increased tubulointerstitial damage (P<0.01). Beyond one year, a later phase of chronic allograft nephropathy was characterized by microvascular and glomerular injury. Chronic rejection (defined as persistent subclinical rejection for two years or longer) was uncommon (5.8 percent). Progressive high-grade arteriolar hyalinosis with luminal narrowing, increasing glomerulosclerosis, and additional tubulointerstitial damage was accompanied by the use of calcineurin inhibitors. Nephrotoxicity, implicated in late ongoing injury, was almost universal at 10 years, even in grafts with excellent early histologic findings. By 10 years, severe chronic allograft nephropathy was present in 58.4 percent of patients, with sclerosis in 37.3 percent of glomeruli. Tubulointerstitial and glomerular damage, once established, was irreversible, resulting in declining renal function and graft failure. CONCLUSIONS: Chronic allograft nephropathy represents cumulative and incremental damage to nephrons from time-dependent immunologic and nonimmunologic causes.

Delta analysis of posttransplantation tubulointerstitial damage.

BACKGROUND: Chronic interstitial fibrosis (CIF) is an adverse prognostic feature of chronic allograft nephropathy. METHODS: We evaluated the evolution, onset, potential causes, and outcomes of tubulointerstitial damage using 959 protocol kidney biopsy specimens obtained regularly until 10 years after transplantation. Specimens were scored by the Banff schema and analyzed for time-specific change or "delta damage" from sequential biopsy-pairs (n=839). RESULTS: Substantial CIF occurred within 1 year after transplantation, comprising 67.6% of the total burden accumulated during the study period. The maximal intensity of CIF formation occurred within the first 3 months, as a result of acute tubular necrosis and acute and subclinical rejection (all P<0.05), where fibrosis rates exceeded loss from tubular atrophy. By 1 year, diminished CIF formation was accompanied by declining low-level subclinical inflammation (P<0.001) and increasingly prevalent calcineurin inhibitor nephrotoxicity (P<0.01). Banff CIF correlated with tubular atrophy (r=0.82, P<0.001), with tubulointerstitial damage showing a cumulative and irreversible pattern. Mononuclear cell infiltration within areas of tubulointerstitial damage correlated with CIF (r=0.49, P<0.001), tubular atrophy (r=0.43, P<0.001), and Banff i scores (r=0.34, P<0.001) and, most importantly, heralded histologic progression (P<0.001). CIF formation preceded and correlated with glomerulosclerosis (r=0.40, P<0.001), although isotopic glomerular filtration rates underestimated the severity of tubular damage. Cyclosporine (vs. tacrolimus, P<0.001) increased delta CIF, and mycophenolate was protective (vs. azathioprine, P<0.001), independent of their immunosuppressive and nephrotoxic properties when assessed by multivariate analysis of biopsy-pairs (n=849). CONCLUSION: CIF was a result of early ischemia-reperfusion injury, acute, subacute or persistent interstitial inflammation occurring in a time-dependent manner and was considerably modified by immunosuppressive therapy.

Evolution and pathophysiology of renal-transplant glomerulosclerosis.

BACKGROUND: Glomerulosclerosis (GS) is characteristic of chronic allograft nephropathy and graft failure; however, its natural history and pathophysiology are poorly defined. METHODS: We evaluated 959 prospective protocol kidney-transplant biopsies from 120 recipients taken regularly up to 10 years after transplantation for evidence of glomerular injury. RESULTS: GS exhibited a nonlinear triphasic time course. An intense but limited peak of damage in the first month was associated with cold ischemia (P<0.05) and calcineurin nephrotoxicity (P<0.001). GS then occurred as a late consequence of earlier immune-mediated tubular damage (9.3+/-6.6%, P<0.01 vs. no damage), suggesting delayed sclerosis of atubular glomeruli. Subsequent progressive GS occurred beyond 4 years, associated with increasing arteriolar hyalinosis from calcineurin inhibitor nephrotoxicity (r=0.33, P<0.001). From 5 years after transplantation, 32.4+/-22.2% of glomeruli were globally sclerosed, and segmental GS and periglomerular fibrosis increased by 4.0+/-9.3% and 8.4+/-14.2% per year, respectively. Severe arteriolar hyalinosis resulted in greater GS on sequential biopsies (P<0.001), consistent with vascular narrowing causing glomerular ischemia. Chronic glomerulopathy scores were relatively mild. Glomerular loss was patchy, with a high coefficient of variation of 633%. Isotopic glomerular filtration rate correlated best with Banff chronic interstitial fibrosis (r=-0.30, P<0.001) and chronic glomerulopathy scores (r=-0.23, P<0.001) rather than the percentage of sclerosed glomeruli (r=-0.12, P<0.05). Renal function gradually fell with time, and the hyperfiltration index increased from 1.14+/-0.42 at 3 months to 1.83+/-1.40 by 7 to 10 years after transplantation. CONCLUSIONS: In summary, GS is a time-dependent response to glomerular injury from early ischemia, immune-mediated tubular loss, and late calcineurin nephrotoxicity.

Natural history, risk factors, and impact of subclinical rejection in kidney transplantation.

BACKGROUND: Subclinical rejection (SCR) is defined as histologically proven acute rejection in the absence of immediate functional deterioration. METHODS: We evaluated the impact of SCR in 961 prospective protocol kidney biopsies from diabetic recipients of a kidney-pancreas transplant (n=119) and one kidney transplant alone taken regularly up to 10 years after transplantation. RESULTS: SCR was present in 60.8%, 45.7%, 25.8%, and 17.7% of biopsies at 1, 3, 12, and greater than 12 months after transplantation. Banff scores for acute interstitial inflammation and tubulitis declined exponentially with time. SCR was predicted by prior acute cellular rejection and type of immunosuppressive therapy (P<0.05-0.001). Tacrolimus reduced interstitial infiltration (P<0.001), whereas mycophenolate reduced tubulitis (P<0.05), and the combination effectively eliminated SCR (P<0.001). Persistent SCR of less than 2 years duration on sequential biopsies occurred in 29.2% of patients and was associated with prior acute interstitial rejection (P<0.001) and requirement for antilymphocyte therapy (P<0.05). It resolved by 0.49 +/- 0.33 years and resulted in higher grades of chronic allograft nephropathy (CAN, P<0.05). True chronic rejection, defined as persistent SCR of 2 years or more duration and implying continuous immunologic activation was found in only 5.8% of patients. The presence of SCR increased chronic interstitial fibrosis, tubular atrophy, and CAN scores on subsequent biopsies (P<0.05-0.001). SCR preceded and was correlated with CAN (P<0.001) on sequential analysis. CONCLUSIONS: Histologic evidence of acute rejection in the absence of clinical suspicion resulted in significant tubulointerstitial damage to transplanted kidneys and contributed to CAN.

Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology.

BACKGROUND: The role and burden of cyclosporine (CsA) nephrotoxicity in long-term progressive kidney graft dysfunction is poorly documented. METHODS: The authors evaluated 888 prospective protocol kidney biopsy specimens from 99 patients taken regularly until 10 years after transplantation for evidence of CsA nephrotoxicity. RESULTS: The most sensitive histologic marker of CsA nephrotoxicity was arteriolar hyalinosis, predicted by CsA dose and functional CsA nephrotoxicity. Striped fibrosis was associated with early initiation of CsA and the need for posttransplant dialysis (both P < 0.05). The 10-year cumulative Kaplan-Meier prevalence of arteriolar hyalinosis, striped fibrosis, and tubular microcalcification was 100%, 88.0%, and 79.2% of kidneys, respectively. Beyond 1 year, 53.9% had two or more lesions of CsA nephrotoxicity. Structural CsA nephrotoxicity occurred in two phases, with different clinical and histologic characteristics. The acute phase occurred with a median onset 6 months after transplantation, was usually reversible, and was associated with functional CsA nephrotoxicity (P < 0.05), high CsA levels (P < 0.05), and mild arteriolar hyalinosis (P < 0.001). The chronic phase of CsA nephrotoxicity persisted over several biopsies, occurred at a median onset of 3 years, and was associated with lower CsA doses and trough levels (both P < 0.05). It was largely irreversible and accompanied by severe arteriolar hyalinosis and progressive glomerulosclerosis (both P < 0.001). A threshold CsA dose of 5 mg/kg/day predicted worsening of arteriolar hyalinosis on sequential histology. CONCLUSIONS: Pathologic changes of CsA nephrotoxicity were virtually universal by 10 years and exacerbated chronic allograft nephropathy. CsA is unsuitable as a universal, long-term immunosuppressive agent for kidney transplantation. Strategies to ameliorate or avoid nephrotoxicity are thus urgently needed.