Emilio D. Poggio

Profile and prevalence of aspirin resistance in patients with cardiovascular disease

We determined the prevalence and clinical predictors of aspirin resistance by prospectively studying 325 patients with stable cardiovascular disease who were receiving aspirin (325 mg/day for > or =7 days) but no other antiplatelet agents. We also compared the detection of aspirin resistance with optical platelet aggregation, a widely accepted method, with a newer, more rapid method, the platelet function analyzer (PFA)-100, a whole blood test that measures platelet adhesion and aggregation ex vivo. Blood samples were analyzed in a blinded fashion for aspirin resistance by optical aggregation using adenosine diphosphate (ADP) and arachidonic acid, and by PFA-100 using collagen and/or epinephrine and collagen and/or ADP cartridges to measure aperture closure time. Aspirin resistance was defined as a mean aggregation of > or =70% with 10 microM ADP and a mean aggregation of > or =20% with 0.5 mg/ml arachidonic acid. Aspirin semiresponders were defined as meeting one, but not both of the above criteria. Aspirin resistance by PFA-100 was defined as having a normal collagen and/or epinephrine closure time (< or =193 seconds). By optical aggregation, 5.5% of the patients were aspirin resistant and 23.8% were aspirin semiresponders. By PFA-100, 9.5% of patients were aspirin resistant. Of the 18 patients who were aspirin resistant by aggregation, 4 were also aspirin resistant by PFA-100. Patients who were either aspirin resistant or aspirin semiresponders were more likely to be women (34.4% vs 17.3%, p = 0.001) and less likely to be smokers (0% vs 8.3%, p = 0.004) compared with aspirin-sensitive patients. There was a trend toward increased age in patients with aspirin resistance or aspirin semiresponders (65.7 vs 61.3 years, p = 0.06). There were no differences in aspirin sensitivity by race, diabetes, platelet count, renal disease, or liver disease.

Performance of the Modification of Diet in Renal Disease and Cockcroft-Gault Equations in the Estimation of GFR in Health and in Chronic Kidney Disease

The performance of the Modification of Diet in Renal Disease (MDRD) and the Cockcroft-Gault (CG) equations as compared with measured (125)I-iothalamate GFR (iGFR) was analyzed in patients with chronic kidney disease (CKD) and in potential kidney donors. All outpatients (n = 1285) who underwent an iGFR between 1996 and 2003 were considered for analysis. Of these, 828 patients had CKD and 457 were potential kidney donors. Special emphasis was put on the calibration of the serum creatinine measurements. In CKD patients with GFR <60 ml/min per 1.73 m(2), the MDRD equation performed better than the CG formula with respect to bias (-0.5 versus 3.5 ml/min per 1.73 m(2), respectively) and accuracy within 30% (71 versus 60%, respectively) and 50% (89 versus 77%, respectively). Similar results are reported for 249 CKD patients with diabetes. In the kidney donor group, the MDRD equation significantly underestimated the measured GFR when compared with the CG formula, with a bias of -9.0 versus 1.9 ml/min per 1.73 m(2), respectively (P < 0.01), and both the MDRD and CG equations overestimated the strength of the association of GFR with measured serum creatinine. The present data add further validation of the MDRD equation in outpatients with moderate to advanced kidney disease as well as in those with diabetic nephropathy but suggest that its use is problematic in healthy individuals. This study also emphasizes the complexity of laboratory calibration of serum creatinine measurements, a determining factor when estimating GFR in both healthy individuals and CKD patients with preserved GFR.

Association between delayed graft function and allograft and patient survival: a systematic review and meta-analysis

BACKGROUND Delayed graft function (DGF) is a common complication of renal transplantation. The short-term consequences of DGF are well known, but the long-term relationship between DGF and patient and graft survival is controversial in the published literature. We conducted a systematic review and meta-analysis to precisely estimate these relationships. METHODS We performed a literature search for original studies published through March 2007 pertaining to long-term (>6 months) outcomes of DGF. The primary outcome was graft survival. Secondary outcomes were patient survival, acute rejection and kidney function. RESULTS When compared to patients without DGF, patients with DGF had a 41% increased risk of graft loss (RR 1.41, 95% CI 1.27-1.56) at 3.2 years of follow-up. There was no significant relationship between DGF and patient survival at 5 years (RR 1.14, 95% CI 0.94-1.39). The mean creatinine in the non-DGF group was 1.6 mg/dl. Patients with DGF had a higher mean serum creatinine (0.66 mg/dl, 95% CI 0.57-0.74) compared to patients without DGF at 3.5 years of follow-up. DGF was associated with a 38% relative increase in the risk of acute rejection (RR 1.38, 95% CI 1.29-1.47). CONCLUSION The results of this meta-analysis emphasize and quantify the long-term detrimental association between DGF and important graft outcomes like graft survival, acute rejection and renal function. Efforts to prevent and treat DGF should be aggressively investigated in order to improve graft survival given the deficit in the number of kidney donors.

Factors Predicting Renal Functional Outcome After Partial Nephrectomy

PURPOSE Compared to radical nephrectomy, partial nephrectomy better preserves renal parenchyma and function. Although several clinical factors may impact renal function after partial nephrectomy including preoperative function, age, gender and comorbidities, the contributions of tumor and surgical factors have not been well studied. We evaluate independent factors predicting functional outcomes after partial nephrectomy. MATERIALS AND METHODS Preoperative and all postoperative serum creatinine values for 1,169 patients undergoing partial nephrectomy were used to estimate glomerular filtration rate. Postoperative nadir glomerular filtration rate and ultimate glomerular filtration rate were analyzed using multiple pertinent covariates. RESULTS Median preoperative, postoperative nadir and ultimate glomerular filtration rates were 77, 57 and 71 ml per minute per 1.73 m(2), respectively. Increasing age, gender, lower preoperative glomerular filtration rate, solitary kidney, tumor size, ischemia time and longer time to nadir glomerular filtration rate significantly predicted postoperative nadir glomerular filtration rate and ultimate glomerular filtration rate. Acute loss of renal function predicted lower ultimate glomerular filtration rate. In the entire cohort, in patients with normal preoperative renal function, and in those with baseline stage 3 and those with stage 4 chronic kidney disease the incidence of postoperative acute kidney injury after partial nephrectomy was 3.6%, 0.8%, 6.2% and 34%, and the incidence of chronic end stage renal disease after partial nephrectomy was 2.5%, 0.1%, 3.7% and 36%, respectively. CONCLUSIONS Lower preoperative glomerular filtration rate, solitary kidney, older age, gender, tumor size and longer ischemic interval all predicted lower glomerular filtration rate after partial nephrectomy. Therefore, duration of renal ischemia is the strongest modifiable surgical risk factor for decreased renal function after partial nephrectomy, and efforts to limit ischemic time and injury should be pursued in open and laparoscopic partial nephrectomy.

Marked variation in the definition and diagnosis of delayed graft function: a systematic review

BACKGROUND The term delayed graft function (DGF) is commonly used to describe the need for dialysis after receiving a kidney transplant. DGF increases morbidity after transplantation, prolongs hospitalization and may lead to premature graft failure. Various definitions of DGF are used in the literature without a uniformly accepted technique to identify DGF. METHODS We performed a systematic review of the literature to identify all of the different definitions and diagnostic techniques to identify DGF. RESULTS We identified 18 unique definitions for DGF and 10 diagnostic techniques to identify DGF. CONCLUSIONS The utilization of heterogeneous clinical criteria to define DGF has certain limitations. It will lead to delayed and sometimes inaccurate diagnosis of DGF. Hence a diagnostic test that identifies DGF reliably and early is necessary. Heterogeneity, in the definitions used for DGF, hinders the evolution of a diagnostic technique to identify DGF, which requires a gold standard definition. We are in need of a new definition that is uniformly accepted across the kidney transplant community. The new definition will be helpful in promoting better communication among transplant professionals and aids in comparing clinical studies of diagnostic techniques to identify DGF and thus may facilitate clinical trials of interventions for the treatment of DGF.

Assessing Glomerular Filtration Rate by Estimation Equations in Kidney Transplant Recipients

Surveillance of glomerular filtration rate (GFR) is crucial in the management of kidney transplant recipients. With especial emphasis on serum creatinine (SCr) calibration assay, we assessed the performance of estimation equations as compared to iothalamate GFR (iGFR) in 209 patients using the modification of diet in renal disease (MDRD), Nankivell and Cockcroft‐Gault methods. Fifty‐five percent of patients were treated with a calcineurin inhibitor (CNI) and all were taken trimethroprim‐sulfametoxazole at the time of SCr measurement. The mean iGFR was 44 ± 26 mL/min/1.73 m2. The MDRD equation showed a median difference of 0.9 mL/min/1.73 m2 with 53% of estimated GFR within 20% of iGFR. Median differences were 7.5 and 7.0 mL/min/1.73 m2 for Nankivell and Cockcroft‐Gault formulas, respectively. The accuracy of the Nankivell and Cockcroft‐Gault formulas was such that only 38% and 37% of estimations, respectively, fell within 20% of iGFR. The performance of all equations was not uniform throughout the whole range of GFR, with some deterioration at the extremes of GFR levels. In addition, good performance of the MDRD equation was seen in subjects taking CNI. In conclusion, the overall performance of the MDRD equation was superior to the Nankivell and Cockcroft‐Gault formulas in renal transplant recipients including subjects treated with CNI.

Donor Kidney Volume and Outcomes Following Live Donor Kidney Transplantation

Pre‐donation kidney volume and function may be crucial factors in determining graft outcomes in kidney transplant recipients. We measured living donor kidney volumes by 3D helical computed tomography scanning and glomerular filtration rate (GFR) by 125I‐iothalamate clearances in 119 donors, and correlated these values with graft function and incidence of acute rejection at 2 years post‐transplantation. Kidney volume strongly correlated with GFR (Pearson r= 0.71, p < 0.001). Body size and male gender were independent correlates of larger kidney volumes, and body size and age were predictors of kidney function. The effects of transplanted kidney volume on graft outcome were studied in 104 donor‐recipient pairs. A transplanted kidney volume greater than 120 cc/1.73 m2 was independently associated with better estimated GFR at 2 years post‐transplant when compared to recipients of lower transplanted kidney volumes (64 ± 19 vs. 48 ± 14 mL/min/1.73 m2, p < 0.001). Moreover, recipients of lower volumes had a higher incidence of acute cellular rejection (16% vs. 3.7%, p = 0.046). In conclusion, kidney volume strongly correlates with function in living kidney donors and is an independent determinant of post‐transplant graft outcome. The findings suggest that (1) transplantation of larger kidneys confers an outcome advantage and (2) larger kidneys should be preferred when selecting from otherwise similar living donors.

Demographic and clinical characteristics associated with glomerular filtration rates in living kidney donors.

Due to the shortage of organs, living donor acceptance criteria are becoming less stringent. An accurate determination of the glomerular filtration rate (GFR) is critical in the evaluation of living kidney donors and a value exceeding 80 ml/min per 1.73 m(2) is usually considered suitable. To improve strategies for kidney donor screening, an understanding of factors that affect GFR is needed. Here we studied the relationships between donor GFR measured by (125)I-iothalamate clearances (mGFR) and age, gender, race, and decade of care in living kidney donors evaluated at the Cleveland Clinic from 1972 to 2005. We report the normal reference ranges for 1057 prospective donors (56% female, 11% African American). Females had slightly higher mGFR than males after adjustment for body surface area, but there were no differences due to race. The lower limit of normal for donors (5th percentile) was less than 80 ml/min per 1.73 m(2) for females over age 45 and for males over age 40. We found a significant doubling in the rate of GFR decline in donors over age 45 as compared to younger donors. The age of the donors and body mass index increased over time, but their mGFR, adjusted for body surface area, significantly declined by 1.49+/-0.61 ml/min per 1.73 m(2) per decade of testing. Our study shows that age and gender are important factors determining normal GFR in living kidney donors.

Multicenter Validation of Urinary CXCL9 as a Risk‐Stratifying Biomarker for Kidney Transplant Injury

Noninvasive biomarkers are needed to assess immune risk and ultimately guide therapeutic decision‐making following kidney transplantation. A requisite step toward these goals is validation of markers that diagnose and/or predict relevant transplant endpoints. The Clinical Trials in Organ Transplantation‐01 protocol is a multicenter observational study of biomarkers in 280 adult and pediatric first kidney transplant recipients. We compared and validated urinary mRNAs and proteins as biomarkers to diagnose biopsy‐proven acute rejection (AR) and stratify patients into groups based on risk for developing AR or progressive renal dysfunction. Among markers tested for diagnosing AR, urinary CXCL9 mRNA (odds ratio [OR] 2.77, positive predictive value [PPV] 61.5%, negative predictive value [NPV] 83%) and CXCL9 protein (OR 3.40, PPV 67.6%, NPV 92%) were the most robust. Low urinary CXCL9 protein in 6‐month posttransplant urines obtained from stable allograft recipients classified individuals least likely to develop future AR or a decrement in estimated glomerular filtration rate between 6 and 24 months (92.5–99.3% NPV). Our results support using urinary CXCL9 for clinical decision‐making following kidney transplantation. In the context of acute dysfunction, low values can rule out infectious/immunological causes of injury. Absent urinary CXCL9 at 6 months posttransplant defines a subgroup at low risk for incipient immune injury.

The Role of Proteasome Inhibition With Bortezomib in the Treatment of Antibody-Mediated Rejection After Kidney-Only or Kidney-Combined Organ Transplantation

Background. We report our initial experience in using the proteasome inhibitor, bortezomib, to treat established antibody-mediated rejection (AMR) in 20 patients. Methods. There were 16 kidney-only and 4 kidney-combined organ recipients with de novo donor-specific antibody (DSA) and histologic evidence of AMR with peritubular capillaries C4d deposition. AMR was diagnosed 19.8 months (range 1-71 months) posttransplant. Patients received intravenous corticosteroids followed by a 2-week cycle on days 1-4-8-11 of plasmapheresis and 1.3 mg/m2 bortezomib; then 0.5 mg/kg intravenous immunoglobulin four times. Results. De novo class I DSA was detected in 11 (55%) and class II DSA in 18 (90%) recipients. The absolute mean difference between peak-nadir dominant DSA was 68,171 molecules of equivalent soluble fluorochrome (P<0.0001), representing 55%±22%. Only two patients (10%) had undetectable DSA after treatment. Patient survival is 100%, and graft survival is 85% with a mean follow-up of 9.8 months (range 2-20 months). The treatment was generally well tolerated but caused fatigue, gastrointestinal complaints, fluid retention, and thrombocytopenia in a number of patients. The last follow-up estimated glomerular filtration rate was 41.9±16.8 mL/min (range 20.6-72.2 mL/min). However, only 25% returned to their baseline renal function before AMR, and many have proteinuria with urine protein/creatinine more than 0.5 in 41% and more than 1.0 in 18%. Conclusions. The bortezomib-containing regimen demonstrated activity in AMR but seems to be most effective before the onset of significant renal dysfunction (serum creatinine <3 mg/dL) or proteinuria (<1 g/day). The best use of bortezomib to treat AMR should be evaluated in controlled trials using dosing strategies that include longer courses or retreatment schedules.