Search PubMed⌕ Search

Biomedical subjects

Jeremy R Chapman

Publications and source records attributed to Jeremy R Chapman.

27 records · Page 2Linked to original sources
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↗
PubMed2004

Compliance: the patient, the doctor, and the medication?

Noncompliance can be defined as covert nonadherence to prescribed medication used for the prophylaxis of allograft rejection and threatening impaired kidney histology or function. It is an increasingly significant long-term problem in transplantation as the failure rates from other causes have diminished. Formal approaches to diagnosis, prophylaxis, and treatment, together with a greater understanding of what should be regarded as a syndrome, are thus increasingly important components of reducing the chronic attrition of graft function and survival. It is possible to classify noncompliant behavior using four facets of the syndrome: timing, frequency, origin, and diagnostic certainty. There are a number of different ways of approaching diagnosis, such as observation of behavior through pill counting or electronic measurements of pill container opening; blood level measurement of relevant drugs; physical examination; and observation of the consequences. However, the only certainty of diagnosis comes from direct patient admission of nonadherence to the prescribed immunosuppression. It is possible to define the highest risk patients through assessment of a number of patient-, drug-, and physician-associated variables, and then to influence the outcome through education, compliance monitoring, and simplified regimens targeted to the highest risk patients. It is important for all transplant units to address the issues raised by noncompliance if the chronic loss of allografts is to be reduced.

Graft Rejection↗
PubMed2004

Interleukin 2 receptor antagonists for renal transplant recipients: a meta-analysis of randomized trials.

BACKGROUND: Interleukin 2 receptor antagonists (IL-2Ra) are increasingly used to treat renal transplant recipients. This study aims to systematically identify and summarize the effects of using IL-2Ra as induction immunosuppression, as an addition to standard therapy, or as an alternative to other antibody therapy. METHODS: Databases, reference lists, and abstracts of conference proceedings were searched extensively to identify relevant randomized controlled trials in all languages. Data were synthesized using the random effects model. Results are expressed as relative risk (RR), with 95% confidence intervals (CI). RESULTS: A total of 117 reports from 38 trials involving 4,893 participants were included. When IL-2Ra were compared with placebo (17 trials; 2,786 patients), graft loss was not significantly different at 1 year (14 trials: RR 0.84; CI 0.64-1.10) or 3 years (4 trials: RR 1.08; CI 0.71-1.64). Acute rejection was significantly reduced at 6 months (12 trials: RR 0.66; CI 0.59-0.74) and at 1 year (10 trials: RR 0.67; CI 0.60-0.75). At 1 year, cytomegalovirus infection (7 trials: RR 0.82; CI 0.65-1.03) and malignancy (9 trials: RR 0.67; CI 0.33-1.36) were not significantly different. When IL-2Ra were compared with other antibody therapy, no significant differences in treatment effects were demonstrated, but IL-2Ra had significantly fewer side effects. CONCLUSIONS: Given a 40% risk of rejection, seven patients would need treatment with IL-2Ra in addition to standard therapy, to prevent one patient from undergoing rejection, with no definite improvement in graft or patient survival. There is no apparent difference between basiliximab and daclizumab.

Graft Survival↗
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↗