Timothy S. Larson

Using Serum Creatinine To Estimate Glomerular Filtration Rate: Accuracy in Good Health and in Chronic Kidney Disease

Context Experts increasingly use the Modification of Diet in Renal Disease (MDRD) equation to estimate glomerular filtration rate (GFR). Contribution This cross-sectional study compared GFR estimated by the MDRD equation with GFR measured by iothalamate clearance in 320 patients with chronic kidney disease and 580 healthy kidney donor candidates. The MDRD equation underestimated GFR by 6% in patients with kidney disease and by 29% in healthy persons. The authors also derived a quadratic equation that better estimated GFR in the healthy people than did the MDRD equation. Implications The MDRD equation systematically underestimates GFR and may erroneously categorize some healthy persons as having kidney disease. The Editors Recently, the National Kidney Foundation endorsed a series of guidelines to assess patients with chronic kidney disease. These guidelines highlighted problems associated with using creatinine clearance to measure glomerular filtration rate (GFR). They instead recommended estimation of GFR by using prediction equations based on serum creatinine determinations (1, 2). The abbreviated Modification of Diet in Renal Disease (MDRD) equation (3, 4) was advocated because it correlated well with GFR measured by iothalamate clearance (2, 5). It also performed as well as a more complicated MDRD equation that required serum urea nitrogen and albumin determinations (3). The abbreviated MDRD equation has also been used to estimate the prevalence of chronic kidney disease in the U.S. population with serum creatinine determinations adjusted for calibration bias (6, 7). However, this equation was developed by using persons with chronic kidney disease and did not include healthy persons (3, 4). Thus, the MDRD equation may not be appropriate for determining the prevalence of chronic kidney disease. Previous studies have raised the concern that MDRD equations may underestimate GFR in healthier populations (8-12). Furthermore, in a population-based study, the relationship between cardiovascular risk factors and GFR differed when the abbreviated MDRD equation was used instead of creatinine clearance (13). The primary objective of the current study was to determine whether estimated GFR with the MDRD equation was accurate in healthy persons compared to patients with chronic kidney disease. The secondary objective was to develop a new GFR prediction equation based on both healthy persons and patients with chronic kidney disease. Methods Healthy and Chronic Kidney Disease Series Records of all potential living donors for kidney transplantation at the Mayo Clinic from 1996 to 2002 were reviewed, with institutional review board approval; this review was an expansion of a previously reported series (9). Originally, potential kidney recipients had identified the potential donors and had perceived them to be healthy enough to be evaluated for kidney donation. Most donors (71%) were related to the potential kidney recipient (9). A total of 599 potential donors had an iothalamate clearance test to measure GFR, which was routinely obtained before a clinic visit with a nephrologist (Figure 1). After exclusions for missing serum creatinine determinations or for age younger than 17 years, the healthy series consisted of 580 potential donors. Figure 1. Sampling process for healthy series and chronic kidney disease series. Records of 501 consecutive patients who had an iothalamate clearance test for any reason between October 1999 and March 2000 were also reviewed, with institutional review board approval (Figure 1). A nephrologist abstracted these records for a cystatin C study (14). Of these patients, 353 had an iothalamate clearance test to measure GFR as part of an evaluation for known or suspected chronic kidney disease. Iothalamate clearance was routinely and primarily ordered by nephrologists at the Mayo Clinic during outpatient referrals. An elevated serum creatinine level, proteinuria, abnormal urinary sediment, history of kidney disease, or kidney transplantation recipient status were typical indications for the iothalamate clearance test. Thus, chronic kidney disease was defined by clinical presentation and not by a GFR cutoff. In recipients of a nonkidney solid organ transplant, iothalamate clearance for routine monitoring only was not considered an evaluation for chronic kidney disease. After exclusions for missing serum creatinine determinations or for age younger than 17 years, the chronic kidney disease series consisted of 320 patients. Iothalamate Clearance and Serum Creatinine Assays Measurement of GFR with the renal clearance of nonradiolabeled iothalamate has previously been described (15). This test involved the subcutaneous injection of nonradiolabeled iothalamate after oral hydration with 4 to 6 glasses of water. After 2 hours, GFR was determined by the clearance equation (UV/P) using the average of 2 serum samples and 1 urine sample assayed for iothalamate concentration via capillary electrophoresis. Glomerular filtration rate was expressed per 1.73 m2 by multiplying the measured value by 1.73 and dividing by body surface area. Nonradiolabeled iothalamate clearance correlates well with radiolabeled iothalamate clearance (r= 0.998) (15) and provides a normal value range similar to that of other GFR measurement techniques (9, 16). Interassay coefficient of variation for nonradiolabeled iothalamate clearance was reported as 5%. Serum creatinine levels were all assayed with the rate-Jaffe reaction on a Hitachi 747 autoanalyzer (Roche Diagnostics Corp., Indianapolis, Indiana). This assay was calibrated daily with a Cfas calibrator (Roche Diagnostics Corp.) by using the uncompensated method during the study period. The interassay coefficient of variation for serum creatinine determinations was reported as 3.1% at 1.3 mg/dL (115 mol/L) and 1.5% at 6.1 mg/dL (539 mol/L) with stability during the study period. The 2.5th to 97.5th percentile of serum creatinine by this assay was 0.7 to 1.2 mg/dL (62 to 106 mol/L) in normal white women and 0.9 to 1.4 mg/dL (80 to 124 mol/L) in normal white men. Estimated GFR was calculated by using the abbreviated MDRD equation (Table 1, equation 1). Table 1. Prediction Equations for Glomerular Filtration Rate Statistical Analysis We compared the baseline characteristics of patients in the healthy and chronic kidney disease series by using the chi-square test (nominal factors), Wilcoxon rank-sum, or Student t-test. We defined bias as the mean of estimated GFR minus measured GFR. We defined percentage bias as the mean of individual ([estimated GFR measured GFR]/measured GFR) 100%. P30% was defined as the percentage of estimated GFR within 30% of measured GFR. We compared estimated GFR and measured GFR in the healthy and chronic kidney disease series by using bias, percentage bias, R2 (coefficient of determination), and P30%. Similar analyses were done with the CockcroftGault equation (17), adjusted for body surface area (mL/min per 1.73 m2) and adjusted to predict GFR instead of creatinine clearance (3). The log-linear form of the abbreviated MDRD equation was refit for new coefficients by using multiple linear regression in the healthy and chronic kidney disease series independently. A log-linear form of the abbreviated MDRD equation was also refit in a combined series (n= 900) with an indicator variable for healthy versus kidney disease status. Each coefficient was compared with the original MDRD study coefficient (4). To develop a new equation for use when the diagnosis of chronic kidney disease is unknown, we used an approach similar to that used to develop the MDRD equations (3, 4). The natural logarithmic (ln) transformed measured GFR was regressed on age, sex, and serum creatinine in the combined series. Because the relationship of ln GFR with ln serum creatinine was nonlinear, the following terms were considered: linear, quadratic, and cubic reciprocal serum creatinine. Linear, quadratic, and logarithmic age terms were also considered. In addition, we examined pairwise interactions between the 3 factors. Because of the large sample size, terms that were statistically significant often added little to the predictive ability of the model. In the interest of parsimony, an increase in R2 of 0.02 or more was arbitrarily required to consider a more complicated model (18). The new equation was internally validated by using bootstrapping (500 replications) to estimate its performance (R2 adjusted for optimism) on independent data sets (19). All statistical analyses were performed with JMP, version 5.1 (SAS Institute, Inc., Cary, North Carolina), except for bootstrapping, which was done with SAS, version 8.2. Role of the Funding Source The study was funded by a National Research Service Award and grants from the Division of Nephrology, Mayo Clinic, Rochester, Minnesota. The funding sources had no role in the collection, analysis, or interpretation of data or in the decision to submit the manuscript for publication. Results Comparison of Healthy and Chronic Kidney Disease Series Table 2 shows the characteristics of the patient samples. Information on race was not available in 14% of the patients. The number of African-American patients was inadequate to analyze the race component in either series. In the chronic kidney disease series, 53% of patients had native kidney disease alone, 16% of patients had a nonkidney solid organ transplant with or without a kidney transplant, and 31% of patients had a kidney transplant alone. In the patients with native kidney disease alone, 36% had hypertension or kidney disease of unknown cause, 24% had glomerulopathy, 13% had diabetes mellitus, and the remaining 27% had miscellaneous causes. Serum creatinine levels were normal (1.4 mg/dL [124 mol/L] in men and 1.2 mg/dL [106 mol/L] in women) in 93 (29%) of the chronic kidney disease series. Table 2. Clinical Characteristics in the Healthy Series and Chronic Kidney Disease Series Figure 2 displays estim

Complete avoidance of calcineurin inhibitors in renal transplantation : A randomized trial comparing sirolimus and tacrolimus

Calcineurin inhibitors have decreased acute rejection and improved early renal allograft survival, but their use has been implicated in the development of chronic nephrotoxicity. We performed a prospective, randomized trial in kidney transplantation comparing sirolimus‐MMF‐prednisone to tacrolimus‐MMF‐prednisone. Eighty‐one patients in the sirolimus group and 84 patients in the tacrolimus group were enrolled (mean follow‐up = 33 months; range 13–47 months). At 1 year, patient survival was similar in the groups (98% with sirolimus, 96% with tacrolimus; p = 0.42) as was graft survival (94% sirolimus vs. 92% tacrolimus, p = 0.95). The incidence of clinical acute rejection was 10% in the tacrolimus group and 13% in the sirolimus group (p = 0.58). There was no difference in mean GFR measured by iothalamate clearance between the tacrolimus and sirolimus groups at 1 year (61 ± 19 mL/min vs. 63 ± 18 mL/min, p = 0.57) or 2 years (61 ± 17 mL/min vs. 61 ± 19 mL/min, p = 0.84). At 1 year, chronicity using the Banff schema showed no difference in interstitial, tubular or glomerular changes, but fewer chronic vascular changes in the sirolimus group. This study shows that a CNI‐free regimen using sirolimus‐MMF‐prednisone produces similar acute rejection rates, graft survival and renal function 1–2 years after transplantation compared to tacrolimus‐MMF‐prednisone.

Transplant Glomerulopathy: Subclinical Incidence and Association with Alloantibody

Transplant glomerulopathy (TG) usually has been described as part of a constellation of late chronic histologic abnormalities associated with proteinuria and declining function. The current study used both protocol and clinically‐indicated biopsies to investigate clinical and subclinical TG, their prognosis and possible association with alloantibody. We retrospectively studied 582 renal transplants with a negative pre‐transplant T‐cell complement dependent cytotoxicity crossmatch. TG was diagnosed in 55 patients, 27 (49%) based on protocol biopsy in well‐functioning grafts. The cumulative incidence of TG increased over time to 20% at 5 years. The prognosis of subclinical TG was equally as poor as TG diagnosed with graft dysfunction, with progressive worsening of histopathologic changes and function. Although TG was associated with both acute and chronic histologic abnormalities, 14.5% of TG biopsies showed no interstitial fibrosis or tubular atrophy, while 58% (7/12) of biopsies with severe TG showed only minimal abnormalities. TG was associated with acute rejection, pretransplant hepatitis C antibody positivity and anti‐HLA antibodies (especially anti‐Class II), with the risk increasing if the antibodies were donor specific. We suggest that subclinical TG is an under‐recognized cause of antibody‐mediated, chronic renal allograft injury which may be mechanistically distinct from other causes of nephropathy.

Predicting subsequent decline in kidney allograft function from early surveillance biopsies

Identifying factors that are predictive of allograft loss might be an important step toward prolonging kidney allograft survival. In this study we sought to determine the association between histologic changes on 1‐year surveillance biopsies, changes in graft function and survival. This analysis included 292 adults, recipients of kidneys from living donors (69%) or deceased donors (31%), transplanted between 1998 and 2001 and followed up for 46 ± 14 months. The primary end point was death‐censored graft loss or a >50% reduction in GFR beyond 1 year. One‐year biopsies were classified as: (i) Normal (N = 87, 30%), (ii) inflammation (N = 6, 2%), (iii) fibrosis (N = 131, 45%), (iv) fibrosis and inflammation (N = 53, 18%) and (v) transplant glomerulopathy (N = 15, 5%). By multivariate Cox analysis, survival related to biopsy classification (HR = 4.2, p = 0.001), graft function (HR = 0.97, p = 0.001) and HLA mismatches (HR = 1.003, p = 0.004). Using normal histology as a reference, fibrosis and inflammation (HR = 8.5, p < 0.0001) and glomerulopathy (HR = 10, p < 0.0001) related to poorer survival but mild fibrosis alone did not. Importantly, the degree of inflammation associated with fibrosis generally did not qualify for the diagnosis of borderline rejection. In conclusion, inflammation and glomerulopathy 1 year post‐transplant predict loss of graft function and graft failure independently of function and other variables.

Wound-healing complications after kidney transplantation: a prospective, randomized comparison of sirolimus and tacrolimus.

Background. Sirolimus has been associated with an increased risk of wound-healing complications in several retrospective analyses. The authors compared the rates of wound-healing complications in renal allograft recipients in a prospective, randomized trial of sirolimus-mycophenolate mofetil-prednisone versus tacrolimus-mycophenolate mofetil-prednisone. Methods. All patients received antithymocyte globulin induction. In the first phase of the study, patients (n=77) were included regardless of body mass index (BMI). In the second phase (n=46 patients), the authors excluded patients with a BMI greater than 32 kg/m2, and the target trough sirolimus level was lowered to 10 to 15 ng/mL (previously 15–20 ng/mL). Multivariate logistic regression analyses were performed to identify predictors of wound complications. Results. Fifty-nine patients received tacrolimus and 64 received sirolimus and were included in subsequent analyses. The incidence of complications was 8% (5 of 59) in the tacrolimus group and 47% (30 of 64) in the sirolimus group (P <0.0001). Rates of perigraft fluid collections, superficial wound infections, and incisional herniae were significantly higher in the sirolimus group. Multivariate logistic regression showed only sirolimus (P =0.0001) and BMI (P =0.0021) to independently correlate with complications. In the first phase of the study, the wound complication rate in the sirolimus group was 55% (21 of 38 patients). After excluding obese recipients and decreasing the target sirolimus level, the wound complication rate in the sirolimus group was 35% (9 of 26 patients; P =0.1040). Conclusions. The use of sirolimus-based immunosuppressive regimens leads to a higher incidence of wound-healing complications and will require new approaches to patient selection and management to decrease their incidence.

Overcoming a Positive Crossmatch in Living‐Donor Kidney Transplantation

Many patients who have an otherwise acceptable living‐kidney donor do not undergo transplantation because of the presence of antibodies against the donor cells resulting in a positive crossmatch. In the current study, 14 patients with a positive cytotoxic crossmatch (titer ≤ 1 : 16) against their living donor underwent a regimen including pretransplant plasmapheresis, intravenous immunoglobulin, rituximab and splenectomy. Eleven of 14 grafts (79%) are functioning well 30–600 days after transplantation. Two grafts were lost to accelerated vasculopathy and one was lost to death with good function. No hyperacute or cellular rejections occurred. Antibody‐mediated rejection occurred in six patients [two clinical (14%) and four subclinical (29%)] and was reversible with plasmapheresis and steroids. Our results suggest that selected crossmatch‐positive patients can be transplanted successfully with living‐donor kidney allografts, using a protocol of pretransplant plasmapheresis, intravenous immunoglobulin, rituximab and splenectomy. Longer follow‐up will be needed, but the absence of anti‐donor antibody and good early outcomes are encouraging.

Allograft Rejection Predicts the Occurrence of Late-Onset Cytomegalovirus (CMV) Disease among CMV-Mismatched Solid Organ Transplant Patients Receiving Prophylaxis with Oral Ganciclovir

The natural history of cytomegalovirus (CMV) disease associated with solid organ transplantation has been modified as a result of the widespread use of antiviral prophylaxis. Anecdotal reports have indicated a reduction of CMV disease at the expense of its later occurrence after completion of ganciclovir prophylaxis. The present study investigated the occurrence of CMV disease and its risk factors among 37 liver and kidney transplant recipients with CMV D+/R- status who received oral ganciclovir during the first 100 days posttransplantation. CMV disease occurred in 9 patients (24.3%) at a median of 144 days posttransplantation (range, 95-190 days). Allograft rejection was found to be strongly associated with the occurrence of late-onset CMV disease (risk ratio, 6.6; 95% confidence interval, 1.4-32.1; P=.02). Thus, CMV D+/R- solid organ transplant recipients receiving 3 months of oral ganciclovir who develop allograft rejection during the period of antiviral prophylaxis may benefit from extended and/or enhanced antiviral prophylaxis to prevent late-onset CMV disease.

ABO-incompatible kidney transplantation using both A2 and non-A2 living donors

Background. Given the scarcity of cadaveric organs, efforts are intensifying to increase the availability of living donors. The current study assessed the feasibility of using ABO-incompatible living-donor kidneys to expand the donor pool. Methods. The authors performed 18 ABO-incompatible living-donor kidney transplants between May 1999 and April 2001. Ten patients received living-donor kidneys from A2 and eight patients received kidneys from non-A2 blood group donors. Immunosuppression consisted of Thymoglobulin antibody induction, tacrolimus, mycophenolate mofetil, and prednisone. Eight non-A2 and two A2 kidney recipients also received a pretransplant conditioning regimen of four plasmapheresis treatments followed by intravenous immunoglobulin and splenectomy at the time of transplantation. Antidonor blood group antibody titer was measured at baseline, pretransplant, at 1- to 3-month and 1-year follow-up, and at the time of diagnosis of antibody-mediated rejection. Results. No hyperacute rejection episodes occurred. One-year graft and patient survival rates in the 18 ABO-incompatible recipients were only slightly lower than those of 81 patients who received ABO-compatible kidney transplants during the same period (89% vs. 96% and 94% vs. 99%, respectively). Glomerular filtration rate and serum creatinine levels did not differ between the groups. Antibody-mediated rejection occurred in 28% of ABO-incompatible recipients, and was reversible with plasmapheresis, intravenous immunoglobulin, and increasing immunosuppression in all patients except one. Conclusions. ABO-incompatible living donor kidney transplants can achieve an acceptable 1-year graft survival rate using an immunosuppressive regimen consisting of Thymoglobulin induction, tacrolimus, mycophenolate mofetil, and prednisone combined with pretransplant plasmapheresis, intravenous immunoglobulin, and splenectomy.

Improved Scoring System to Assess Adult Donors For Cadaver Renal Transplantation

We previously proposed a quantitative approach to assess donor organs for cadaver renal transplantation. To improve on our original scoring system, we studied 34 324 patients who received cadaver renal transplants from adult donors between 1994 and 1999 and were reported to the UNOS Scientific Renal Transplant Registry. A scoring system was developed from five donor variables (age, 0–25 points; history of hypertension, 0–4; creatinine clearance before procurement, 0–4; cause of death, 0–3; HLA mismatch, 0–3) that showed a significant correlation with renal function and long‐term graft survival. Cadaver kidneys were stratified by cumulative donor score: grade A, 0–9 points; grade B, 10–19; grade C, 20–29; and grade D, 30–39. The influence of donor score on renal function and graft survival was most severe above 20 points, designated ‘marginal’ kidneys. In summary, a donor scoring system developed from a large population database was useful in predicting outcome after cadaver renal transplantation. The improved system provides a quantitative approach to evaluation of marginal kidneys and may improve allocation of these organs in cadaver renal transplantation.

Efficacy and Safety of Axitinib in Patients With Advanced Non–Small-Cell Lung Cancer: Results From a Phase II Study

PURPOSE This phase II study evaluated efficacy and safety of single-agent axitinib, an oral, potent, selective inhibitor of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3, in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This was an open-label, single-arm, multicenter, phase II study with a Simon two-stage minimax design. Patients received a starting dose of axitinib 5 mg orally BID. The primary end point was Response Evaluation Criteria in Solid Tumors (RECIST) -defined objective response rate. Secondary end points included safety and tolerability, overall survival (OS), and progression-free survival (PFS). RESULTS Thirty-two patients were enrolled, with a median age of 66.5 years. The majority of patients (75%) had adenocarcinoma. Nine patients (28%) had received no prior chemotherapy for metastatic disease, and 23 (72%) had received > or = one regimen. Three patients (9%) had a RECIST investigator-assessed, confirmed partial response (PR); disease control rate (PR + stable disease) was 41%. Median PFS was 4.9 months overall (95% CI, 3.6 to 7.0 months). Median OS was 14.8 months (95% CI, 10.7 months to not estimable) overall and 14.8 months (95% CI, 12.5 months to not estimable) in patients receiving first-line axitinib. One-year survival rates for patients with or without prior therapy for metastatic disease were 57% and 78%, respectively. Grade 3 treatment-related adverse events in > or = 5% of patients comprised fatigue (22%), hypertension (9%), and hyponatremia (9%). CONCLUSION Axitinib demonstrated single-agent activity in patients with advanced NSCLC. Therapy was well tolerated with manageable toxicities. Further investigation of this VEGFR inhibitor in NSCLC is of interest.