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Brian J Nankivell

Publications and source records attributed to Brian J Nankivell.

13 recordsLinked to original sources
PubMed2006

Treatment of subclinical rejection diagnosed by protocol biopsy of kidney transplants.

BACKGROUND: Subclinical rejection (SCR) causes chronic allograft damage, which may be prevented by antirejection therapy. METHODS: A pilot study of the effect of routine treatment of SCR was performed in 88 recipients of either a kidney (n=59) or combined kidney-pancreas transplant (n=29) undergoing protocol biopsy (PBX) surveillance at 1 and 3 months, using calcineurin inhibitors, mycophenolate mofetil, and corticosteroid therapy. RESULTS: SCR was seen in 46.6% (41/88 patients), as 30 borderline and 11 acute SCR. From 279 transplant biopsies, the prevalence of SCR was 25% (22/88) at 1 month, 10.2% (9/88) at 3 months, and 8.3% (2/24) at 12 months PBX. Treatment included bolus intravenous or oral corticosteroids (n=20) and augmented immunosuppression, either by conversion to tacrolimus (n=6) or increased doses of maintenance therapy (n=14), whereas OKT3 was used in one case of subclinical vascular rejection. Borderline episodes were not treated in 12 patients. In biopsies taken to assess therapeutic response, persistent SCR was present in 46.1% (6/13). Treatment of SCR at 1 month was followed by lower acute Banff sum scores at 3 months PBX (P<0.01-0.0001). Early chronic damage was already present in the 1 month PBX, associated with SCR (P<0.0005 versus without SCR), although by 3 months these differences were lost. Rates of opportunistic infections and BK nephropathy were not increased by SCR treatment. CONCLUSION: Early chronic allograft damage was associated with SCR and therapy appeared to ameliorate further immune-mediated injury, although the efficacy of corticosteroids alone may be inadequate. A controlled trial of therapy for SCR is warranted.

Adult↗
PubMed2006

Chronic allograft nephropathy: current concepts and future directions.

The paradigm that chronic rejection causes all progressive late allograft failure has been replaced by a hypothesis of cumulative damage, where a series of time-dependent immune and nonimmune mechanisms injure the kidney and lead to chronic interstitial fibrosis and tubular atrophy, representing a final common pathway of injury and its consequent fibrotic healing response. Allograft damage is common, progressive, time-dependent, clinically important and modified by immunosuppression. Early after transplantation, tubulointerstitial damage is predominantly related to ischemia reperfusion injury, acute tubular necrosis, acute and subclinical rejection and/or calcineurin inhibitor nephrotoxicity, superimposed on preexisting donor disease. Later, cellular inflammation lessens and is replaced by microvascular and glomerular injury from calcineurin inhibitor nephrotoxicity, hypertension, immune-mediated fibrointimal vascular hyperplasia, transplant glomerulopathy and capillary injury, polyoma virus and/or recurrent glomerulonephritis. Additional mechanisms of injury include internal architectural disruption of the kidney, cortical ischemia, persistent chronic inflammation, replicative senescence, cytokine excess and fibrosis induced by epithelial-to-mesenchymal transition. Current understanding of the etiology, pathophysiology and evolution of pathological changes are detailed. An approach to histological assessment of the individual failing graft are presented and a series of postulates are defined for future studies of chronic allograft nephropathy.

Forecasting↗
PubMed2006

Clinical islet transplantation in type 1 diabetes mellitus: results of Australia's first trial.

OBJECTIVE: To determine whether pancreatic islet transplantation can control diabetes and prevent severe life-threatening hypoglycaemia. DESIGN, SETTING AND PARTICIPANTS: A single-arm observation study of six patients undergoing islet transplantation. All patients had had type 1 diabetes mellitus for over 5 years and documented episodes of repeated severe hypoglycaemia. Islets were isolated from donor pancreases digested by Liberase. Separated islets were infused into the recipient's liver via the portal vein. Patients were immunosuppressed with daclizumab, sirolimus and tacrolimus. The transplants were performed at Westmead Hospital, NSW, between October 2002 and February 2005. MAIN OUTCOME MEASURES: Normal blood glucose control without administration of exogenous insulin; demonstration of islet function and abolition of hypoglycaemia. RESULTS: Five of the patients received two islet infusions, and the sixth was withdrawn after one infusion following a portal vein thrombosis. Three patients became insulin-independent, with excellent glycaemic control. Two had islet function with circulating C-peptide, improved glycaemic control, reduced insulin requirement and abolition of severe hypoglycaemia. However, over a 2-year period, graft function deteriorated. Recipients who were initially insulin free remained C-peptide positive but required supplemental insulin. Complications included one postoperative bleed, two portal vein thromboses (which resolved completely), presumed recurrence of tuberculosis in one patient, and deterioration in renal function in one patient. CONCLUSIONS: Islet transplantation is effective at improving glycaemic control and hypoglycaemia unawareness in the short to medium term. However, problems with long-term safety of immunosuppression, islet-induced thrombosis and early detection of loss of islet function remain to be addressed.

Adult↗
PubMed2005

Chronic renal allograft dysfunction.

The major causes of renal transplant loss are death from vascular, malignant or infectious disease, and loss of the allograft from chronic renal dysfunction associated with the development of graft fibrosis and glomerulosclerosis. Chronic allograft nephropathy (CAN) is the histologic description of the fibrosis, vascular and glomerular damage occurring in renal allografts. Clinical programs rely on monitoring change in serum creatinine for identification of patients at risk of CAN, but this change occurs late in the course of the disease, and underestimates the severity of pathologic change. CAN has several causes: ischemia-reperfusion injury, ineffectively or untreated clinical and subclinical rejection, and superimposed calcineurin inhibitor nephrotoxicity, exacerbating pre-existing donor disease. Once established, interstitial fibrosis and arteriolar hyalinosis lead to progressive glomerulosclerosis over the subsequent years. There have been a number of approaches to treatment aimed at reducing the impact of CAN, mostly centered around avoidance of calcineurin inhibitors through their elimination in all, or just selected, patients. These immunosuppression strategies combine corticosteroids with azathioprine or mycophenolate mofetil, and/or sirolimus and everolimus. Late identification of CAN in individual patients has meant that strategies for intervening to prevent chronic renal allograft dysfunction and subsequent graft loss tend to be "too little and far too late."

Chronic Disease↗
PubMed2005

Nephrotic syndrome after stem cell transplantation.

Nephrotic syndrome occurs rarely after bone marrow transplantation. We describe three patients with myeloid malignancy who developed nephrotic syndrome from 5, 22 and 25 months after allogeneic stem cell transplantation (SCT), confirmed by electron microscopy as membranous glomerulonephritis in two and minimal change glomerulonephritis in one. Proteinuria was initially severe in all and clinically distinct from prior graft-vs.-host disease in two patients. While all responded initially to prednisolone and cyclosporine therapy, two recipients with high-risk leukemia developed late solid organ and bone marrow relapse of their disease, which ultimately proved fatal. The third patient remains alive and disease-free with minimal proteinuria off immunosuppressive therapy. Hence, the onset of de novo high-grade proteinuria after allogeneic SCT should prompt renal histological confirmation, and a trial of immunosuppressive therapy after other causes of nephritic syndrome have been excluded.

Adult↗
PubMed2004

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.

Adult↗
PubMed2004

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.

Biopsy↗
PubMed2004

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.

Adult↗
PubMed2004

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.

Acute Disease↗
PubMed2004

Oral cyclosporine but not tacrolimus reduces renal transplant blood flow.

BACKGROUND: Calcineurin inhibitors are important immunosuppressive agents, but cause nephrotoxicity. METHODS: Instantaneous intra-renal transplant hemodynamics were assessed in 22 patients using quantitative cineloop color Doppler imaging after dosing with microemulsion cyclosporine (CSA) or tacrolimus (TAC). RESULTS: CSA dosing resulted in renal hypoperfusion, with a mean relative reduction of 43%+/-20% (range 22-76%) in maximal fractional area (MFA) of color pixels to nadir, compared to baseline. The mean effect occurred 1.1+/-0.9 hr (median 1 hr) after CSA dosing and was abrogated by calcium channel blockers (P <0.05). The main renal artery velocities, resistive index and small vessel perfusion were unchanged, suggestive of medium-sized arteries mediated vasoconstriction. In contrast, TAC did not alter renal vascularity (2.3+/-4.0% absolute reduction of MFA color pixels vs. 10.7+/-6.5% with CSA, P <0.01). CONCLUSION: CSA, but not TAC, induces phasic hypoperfusion of variable severity within small to medium sized intra-renal arteries soon after dosing, mitigated by calcium channel blockade.

Administration, Oral↗
PubMed2003

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.

Biopsy↗
PubMed2002

Detection of chronic allograft nephropathy by quantitative doppler imaging.

BACKGROUND: Chronic allograft nephropathy (CAN) is the major cause of graft loss, and early detection is desirable to avoid irreversible graft damage. We have evaluated a new technique of color Doppler quantification using Cineloop (Philips Medical Systems, Bothell, WA) imaging for noninvasive diagnosis of CAN. METHODS: Provisional normal ranges were defined by pilot study (n=13) and prospectively tested in stable recipients in whom CAN was independently quantified by contemporaneous histology (n=67), using the Banff schema. RESULTS: The maximal fractional area (MFA, systolic color pixels/total area) was 28.7+/-9.7% in normal subjects and reduced to 18.8+/-8.0% in grade 1 and 12.5+/-6.4% in grade 2 CAN (both P<0.001). The minimum color fractional area was reduced from 10.3+/-5.3% in normal subjects to 3.1+/-2.6% in grade 2 CAN (P<0.001), but was less useful. Distance from peripheral color pixels to capsule increased in CAN grade 2 versus 0 (6.0+/-1.6 vs. 3.9+/-1.0 mm, respectively; P<0.001). Calcineurin inhibitor nephrotoxicity reduced MFA (18.0+/-9.3 vs. 26.9+/-10.7%; P<0.001) and other dynamic measurements. Parenchymal damage exerted minimal effect on resistance index, mean variance, and peak Doppler velocity. MFA (cutoff<17.3%) can diagnose CAN (sensitivity 69%, specificity 88%, positive predictive value 86%) and severe CAN (sensitivity 87%, specificity 71%, negative predictive value 95%). Distance to capsule >5 mm was less sensitive (49%) but more specific (91% alone, and 97% combined with MFA). CONCLUSIONS: In conclusion, quantitative Doppler ultrasound can reliably detect CAN and, although imperfect at correctly grading, allows recognition of significant tubulointerstitial damage for initiation of a confirmatory needle core biopsy.

Adult↗