Joseph M. Nogueira

Histological patterns of polyomavirus nephropathy: correlation with graft outcome and viral load.

Polyomavirus‐associated nephropathy (PVAN) is a significant cause of allograft loss. The diagnosis requires allograft biopsy, but the impact of the histological features on diagnosis and outcome has not been described. We studied the distribution and extent of PVAN in 90 patients. Viral cytopathic changes, tubular atrophy/fibrosis and inflammation were semi‐quantitatively scored and classified into histological patterns. The histological findings were correlated with viruria, viremia and graft survival. PVAN lesions were random, (multi‐)focal and affected both cortex and medulla. Areas with PVAN coexisted with areas of unaffected parenchyma. In 36.5% (15/41) of biopsies with multiple tissue cores, discordant findings with PVAN‐positive and ‐negative cores were observed. However, all patients with PVAN had decoy cells in urine as well as significant viruria and viremia (mean of 2.5 × 108 and 2.32 × 107 viral copies, respectively). Biopsies showing lesser degrees of renal scarring at the time of diagnosis were associated with, more likely, resolution of the infection, in response to decrease of immunosuppression (p = 0.001). More advanced tubulointerstitial atrophy, active inflammation and higher creatinine level at diagnosis correlated with worse graft outcome (p = 0.0002, 0.0001 and 0.0006). Due to the focal nature of PVAN, correlation of biopsy results with viruria and viremia are required for diagnosis.

A comparison of recipient renal outcomes with laparoscopic versus open live donor nephrectomy.

Background. Laparoscopic donor nephrectomy (laparoNx) has the potential to increase living kidney donation rates by reducing the pain and suffering of the donor. However, renal function outcomes of a large series of recipients of laparoNx have not been studied. Methods. We retrospectively reviewed the records of 132 recipients of laparoNx done at our center between 3/96 and 11/97 and compared them to 99 recipients of kidneys procured by the open technique (openNx) done between 10/93 and 3/96. Results. Significantly more patients in the laparoNx group (25.2%) were taking tacrolimus within the first month than those in the openNx group (2.1%). Mean serum creatinine was higher in laparoNx compared with openNx at 1 week (2.860.3 and 1.860.2 mg/dl, respectively; P50.005) and at 1 month (2.060.1 and 1.660.1 mg/dl, P50.05) after transplant. However, by 3 and 6 months, the mean serum creatinine was similar in the two groups (1.760.1 versus 1.560.05 mg/dl, and 1.760.1 versus 1.760.1, respectively). By 1 year posttransplant, the mean serum creatinine for laparoNx was actually less than that for openNx (1.460.1 and 1.760.1 mg/dl, P50.03). Although patients in the laparoNx compared to the openNx group were more likely to have delayed graft function (7.6 versus 2.0%) and ureteral complications (4.5 versus 1.0%), the rate of other complications, as well as hospital length of stay, patient and graft survival rates were similar in the two groups. Conclusion. Although laparoNx allografts have slower initial function compared with openNx, there was no significant difference in longer term renal function. Kidney transplantation is considered to be the treatment of choice for end-stage renal failure. Insufficient supply of organs for donation has produced long waiting times for many patients who may benefit from transplantation (1). During this period patients accumulate the morbidity of renal failure, they must endure the lifestyle limitations of dialysis, and they often die while waiting for the organ sharing system to grant them this resource. Live donor renal transplantation represents a large potential supply of organs that may relieve much of this shortage. Additionally, recipients of live renal transplants may reap benefits of improved patient and allograft survival that have been clearly demonstrated in this population (2,3). Although unilateral nephrectomy has proven to be safe and the solitary kidney state has been found to be well tolerated in a carefully chosen candidate for donation (4,5), substantial disincentives to donation exist. These include a significant hospitalization, prolonged convalescence period with time away from jobs, intractable perioperative pain, and, for some, cosmetic concerns of the resulting

Polyomavirus BK versus JC replication and nephropathy in renal transplant recipients: a prospective evaluation.

Background. JC virus (JCV) viruria is more common than BK virus (BKV) viruria in healthy individuals but in kidney transplants (KT), polyomavirus nephropathy (PVAN) is primarily caused by BKV. Few cases of PVAN have been attributed to JCV. Systematic studies on JCV replication in KT are lacking. Methods. Out of a cohort of KT patients screened with urine cytology, patients shedding decoy cells were studied (n=103). Molecular studies demonstrated BKV, JCV, or BKV+JCV shedding in 58 (56.3%), 28 (27.2%), and 17 (16.5%), respectively. Biopsy was performed when decoy cells persisted 2 months or serum creatinine increased >20%. Results. BKV viruria was strongly associated with BKV viremia (93%), PVAN (48%, P=0.01) and graft loss (P=0.03). Higher BKV viremia correlated with graft dysfunction (P=0.01), more advanced histological pattern of PVAN (P<0.0001), and more infected cells in biopsy (P=0.0001). BKV viremia of ≥10,000 copies/mL was significantly associated with histologically confirmed PVAN (P=0.0001). Reduction of immunosuppression lead to disappearance of decoy cells in patients shedding BK (>93%). JCV viruria, was more often asymptomatic (P=0.002) and affected older patients (P=0.02). JCV PVAN was less common (21.4%) and was characterized by sparse cytopathic changes but significant inflammation and fibrosis. JCV viremia was rare (14.2%), transient, and low (mean 2.0E+03/mL). After reduction of immunosuppression decoy cells persisted in >50% of patients with JCV (P=0.0001), but no graft loss occurred. During the period of the current study, the incidence of BKV-PVAN was 5.5% and the incidence of JCV-PVAN was 0.9%. Conclusions. The data point to significant differences of BKV and JCV biology regarding replication and disease in KT patients, with important implications for screening and management.

Positive Cross-Match Living Donor Kidney Transplantation: Longer-Term Outcomes

The long‐term graft outcomes after positive cross‐match (PXM) living donor kidney transplantation (LDKT) are unknown and the descriptive published data present short‐medium term results. We conducted a retrospective cohort study of LDKT with PXM by flow cytometry performed at our center during February 1999 to October 2006, compared to a control group, matched 1:1 for age, sex, race, retransplantation and transplant year. The PXM group was treated with a course of plasmapheresis/low‐dose intravenous immunoglobulin (IVIg) preoperatively, and OKT3 or thymoglobulin induction.

Glomerular inflammation in renal allografts biopsies after the first year: cell types and relationship with antibody-mediated rejection and graft outcome.

Background. Antibody-mediated rejection manifests with glomerular and peritubular capillary inflammation and transplant glomerulopathy (TG). The role of glomerular inflammation (GI) components in the development of TG and their impact on outcome are incompletely understood. Methods. GI was quantified on hematoxylin-eosin, CD3, CD20, and CD68 stains on biopsies from 240 patients with grafts functioning more than or equal to 1 year. Results. A predominance of CD68+ cells followed by less numerous CD3+ cells was found in TG and glomerulitis. CD68+ cells more than 12 in the most inflamed glomerulus were strongly associated with TG, donor-specific antibody (DSA), and C4d staining. Glomerular CD68+ cells correlated with peritubular capillary multilamellation, and similarly, the Banff g score correlated with light and electron microscopic indexes of chronic microvascular damage. Overall, GI components correlated with the g score, DSA, and peritubular capillary C4d+. The Banff cg 1, 2, and 3 scores showed high levels of GI composed mostly of CD68+ cells, similar to but not higher than cases of g2 and g3 glomerulitis. Glomerular T cells and neutrophils followed similar trends as the predominant macrophages. T-cell–mediated rejection in this cohort did not significantly affect the composition of GI. Prognostically, all types of pronounced GI, g scores, DSA+, C4d+, and capillaropathy were associated with worse prognosis; however, only high level of macrophages was an independent predictor of graft failure. Conclusions. GI in more than or equal to 1 year grafts is mostly antibody-mediated rejection related, correlates with chronic microvascular damage, and consists predominantly of macrophages. The latter seem to represent a pivotal pathogenetic, diagnostic, and prognostic factor in this setting.

Early Withdrawal of Calcineurin Inhibitors and Rescue Immunosuppression with Sirolimus-Based Therapy in Renal Transplant Recipients with Moderate to Severe Renal Dysfunction

Mammalian Target‐of‐Rapamycin inhibitors (mTOR inhibitors) can be used to replace the calcineurin inhibitors (CNIs) to prevent progression in chronic kidney disease (CKD) following organ transplantation. Discontinuation of tacrolimus in 136 recipients of kidney transplants with progressive renal dysfunction significantly decreased the rate of loss of estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) (pre‐intervention vs. post‐intervention slopes, −0.013 vs. −0.002, p < 0.0001). Discontinuation of tacrolimus was associated with a sustained and significant improvement in graft function (pre‐eGFR vs. post‐eGFR; 26.0 ± 1.1 vs. 47.4 ± 2.1, p < 0.0001) in 74% of patients. This intervention was ineffective if the mean and (median) values of creatinine (mg/dL) and eGFR were 3.8 ± 0.2 (3.4) and 18.4 ± 1.9 (22.4), respectively, at the time of conversion therapy. During the follow‐up (range, 1.5–34.6, months), a total of 13 patients had their first acute rejection following the conversion therapy, an annual incidence of less than 10% and none of these episodes resulted in graft loss. The salutary effects of sirolimus therapy following discontinuation of tacrolimus in patients with moderate to severe graft dysfunction due to allograft nephropathy even in high‐risk patients improves kidney function and prevents acute rejection.

A study of renal outcomes in obese living kidney donors.

Background. Little is known about the long-term outcomes of obese living kidney donors (OLKDs). We undertook this study to describe renal outcomes of OLKDs several years after donation. Methods. We invited 101 OLKDs for follow-up health evaluation. Results. Thirty-six subjects (35.6%) completed evaluation at 6.8±1.5 years postdonation. The mean estimated glomerular filtration rate (eGFR) using the abbreviated modification of diet in renal disease (MDRD) equation (MDRD-eGFR) at follow-up was 72.1±16.3 (range: 42–106) mL/min per 1.73 m2, and 47.2% of subjects had an MDRD-eGFR of 30 to 59. The absolute decrease in MDRD-eGFR from the time of donation to follow-up was 27.2±13.1 mL/min per 1.73 m2 (P<0.001 on paired t test), which represents a 29.2% drop in the serial MDRD-eGFRs. Seven subjects (19.4%) had microalbuminuria (30–300 &mgr;g/mg creatinine). Subjects with microabuminuria were more likely to have MDRD-eGFR of less than 60 mL/min per 1.73 m2 (P=0.021). Subjects whose body mass index was greater than or equal to 35 kg/m2 (n=14) were found to have an absolute decrement in MDRD-eGFR similar to those with body mass index less than 35 kg/m2 (31.5±15.6 and 24.7±11.0 mL/min/1.73 m2, respectively; P=not significant). Fifteen (41.6%) were hypertensive at follow-up. Conclusions. On medium-term follow-up, a large proportion of OLKDs will have a MDRD-eGFR of less than 60 mL/min per 1.73 m2, and the likelihood increases markedly among those who develop microalbuninuria. This raises concern for hyperfiltration injury. Furthermore, OLKDs experience a substantial incidence of hypertension. Caution is advised in selecting OLKDs pending further data on long-term outcomes.

The Detrimental Effect of Poor Early Graft Function After Laparoscopic Live Donor Nephrectomy on Graft Outcomes

We undertook this study to assess the rate of poor early graft function (EGF) after laparoscopic live donor nephrectomy (lapNx) and to determine whether poor EGF is associated with diminished long‐term graft survival. The study population consisted of 946 consecutive lapNx donors/recipient pairs at our center. Poor EGF was defined as receiving hemodialysis on postoperative day (POD) 1 through POD 7 (delayed graft function [DGF]) or serum creatinine ≥ 3.0 mg/dL at POD 5 without need for hemodialysis (slow graft function [SGF]). The incidence of poor EGF was 16.3% (DGF 5.8%, SGF 10.5%), and it was stable in chronologic tertiles. Poor EGF was independently associated with worse death‐censored graft survival (adjusted hazard ratio (HR) 2.15, 95% confidence interval (CI) 1.34–3.47, p = 0.001), worse overall graft survival (HR 1.62, 95% CI 1.10–2.37, p = 0.014), worse acute rejection‐free survival (HR 2.75, 95% CI 1.92–3.94, p < 0.001) and worse 1‐year renal function (p = 0.002). Even SGF independently predicted worse renal allograft survival (HR 2.54, 95% CI 1.44–4.44, p = 0.001). Risk factors for poor DGF included advanced donor age, high recipient BMI, sirolimus use and prolonged warm ischemia time. In conclusion, poor EGF following lapNx has a deleterious effect on long‐term graft function and survival.

Antibody-mediated allograft rejection: morphologic spectrum and serologic correlations in surveillance and for cause biopsies.

Background Subclinical antibody-mediated allograft rejection (AMR) has been characterized in serial biopsies from presensitized recipients but has not been systematically studied in conventional renal transplants. Methods We evaluated 1101 consecutive kidney transplant biopsies (400 surveillance biopsies [SBx] and 701 for cause biopsies [FCBx]) with concurrent donor-specific antibody (DSA) studies, C4d staining, and ultrastructural examination. Results A comparison of AMR-related features (DSA and DSA class, C4d staining, and microvascular injury) demonstrated that these were qualitatively and quantitatively associated with each other and with graft dysfunction. A major difference between SBx and FCBx was that the complete AMR phenotype was more common in FCBx. Among SBx, 8.5% showed complete or incomplete AMR with predominance of an incomplete phenotype (according to the Banff schema, these were acute AMR [23.5%], chronic active AMR [14.7%], suspicious for acute AMR [41.1%], suspicious for chronic active AMR [2.9%], and only microvascular injury insufficient to consider AMR [17.5%]). Persistence or worsening of AMR in a subsequent biopsy occurred in 38.2% of cases independently of the strength of AMR findings in the first biopsy (e.g., progression to chronic AMR occurred also in cases with suspicious or nondiagnostic findings). Temporal progression from subclinical to clinically evident AMR is consistent with the fact that, overall, the biopsies with incomplete phenotype (DSA±C4d) occurred between 14.52 and 20.86 months, whereas the complete phenotype occurred much later (36.71 months). Conclusion An accurate diagnostic interpretation of the potentially important but incomplete, subclinical, AMR phenotype represents a serious challenge that may impact clinical management.

A Prospective Controlled Study of Kidney Donors: Baseline and 6-Month Follow-up

BACKGROUND Most previous studies of living kidney donors have been retrospective and have lacked suitable healthy controls. Needed are prospective controlled studies to better understand the effects of a mild reduction in kidney function from kidney donation in otherwise healthy individuals. STUDY DESIGN Prospective, controlled, observational cohort study. SETTING & PARTICIPANTS Consecutive patients approved for donation at 8 transplant centers in the United States were asked to participate. For every donor enrolled, an equally healthy control with 2 kidneys who theoretically would have been suitable to donate a kidney also was enrolled. PREDICTOR Kidney donation. MEASUREMENTS At baseline predonation and at 6 months after donation, medical history, vital signs, measured (iohexol) glomerular filtration rate, and other measurements were collected. There were 201 donors and 198 controls who completed both baseline and 6-month visits and form the basis of this report. RESULTS Compared with controls, donors had 28% lower glomerular filtration rates at 6 months (94.6 ± 15.1 [SD] vs 67.6 ± 10.1 mL/min/1.73 m(2); P < 0.001), associated with 23% greater parathyroid hormone (42.8 ± 15.6 vs 52.7 ± 20.9 pg/mL; P < 0.001), 5.4% lower serum phosphate (3.5 ± 0.5 vs 3.3 ± 0.5 mg/dL; P < 0.001), 3.7% lower hemoglobin (13.6 ± 1.4 vs 13.1 ± 1.2 g/dL; P < 0.001), 8.2% greater uric acid (4.9 ± 1.2 vs 5.3 ± 1.1 mg/dL; P < 0.001), 24% greater homocysteine (1.2 ± 0.3 vs 1.5 ± 0.4 mg/L; P < 0.001), and 1.5% lower high-density lipoprotein cholesterol (54.9 ± 16.4 vs 54.1 ± 13.9 mg/dL; P = 0.03) levels. There were no differences in albumin-creatinine ratios (5.0 [IQR, 4.0-6.6] vs 5.0 [IQR, 3.3-5.4] mg/g; P = 0.5), office blood pressures, or glucose homeostasis. LIMITATIONS Short duration of follow-up and possible bias resulting from an inability to screen controls with kidney and vascular imaging performed in donors. CONCLUSIONS Kidney donors have some, but not all, abnormalities typically associated with mild chronic kidney disease 6 months after donation. Additional follow-up is warranted.