David A. Goldfarb

Single port transumbilical (E-NOTES) donor nephrectomy.

PURPOSE We present the initial 4 patients undergoing single port transumbilical live donor nephrectomy. Scar-free abdominal surgery via natural body orifices is called NOTES (natural orifice translumenal endoscopic surgery). In a similar manner the umbilicus, an embryonic (E) natural orifice, permits abdominal access with hidden scar of entry. We propose the term E-NOTES for embryonic natural orifice transumbilical endoscopic surgery. MATERIALS AND METHODS Through an intra-umbilical incision a novel single access tri-lumen R-port was inserted into the abdomen. No extra-umbilical skin incisions were made whatsoever. A 2 mm Veress needle port, inserted via skin needle puncture to establish pneumoperitoneum, was used to selectively insert a needlescopic grasper for tissue retraction. Donor kidney was pre-entrapped and extracted transumbilically. RESULTS E-NOTES donor nephrectomy was successful in all 4 patients. Median operating time was 3.3 hours, blood loss was 50 cc, warm ischemia time was 6.2 minutes and hospital stay was 3 days. Median length of harvested renal artery was 3.3 cm, renal vein 4 cm and ureter 15 cm. No intraoperative complications occurred. Donor visual analog scores were 0/10 at 2 weeks. Each allograft functioned immediately on transplantation. CONCLUSIONS The initial experience with E-NOTES donor nephrectomy is encouraging. Excellent donor vascular and tissue dissection could be performed, and a quality donor kidney was retrieved transumbilically without any extra-umbilical skin incision. E-NOTES donor nephrectomy appears to have relevance and promise, especially for this typically younger, altruistic population. Natural orifices present an unprecedented opportunity for scar-free surgery.

RENAL OUTCOME 25 YEARS AFTER DONOR NEPHRECTOMY

PURPOSE The extended outcome after kidney donation has been a particular concern ever since the recognition of hyperfiltration injury. Few published reports have examined donor renal outcome after 20 years or greater. Kidney transplantation has been performed at the Cleveland Clinic Foundation since 1963, at which there is extensive experience with live donor transplantation. We assess the impact of donor nephrectomy on renal function, urinary protein excretion and development of hypertension postoperatively to examine whether renal deterioration occurs with followup after 20 years or greater. MATERIALS AND METHODS From 1963 to 1975, 180 live donor nephrectomies were performed at the Cleveland Clinic. We attempted to contact all patients to request participation in our study. Those 70 patients who agreed to participate in the study were mailed a package containing a 24-hour urine container (for assessment of creatinine, and total protein and albumin), a vial for blood collection (for assessment of serum creatinine) and a medical questionnaire. All specimens were returned to and processed by the Cleveland Clinic medical laboratories. Blood pressure was taken and recorded by a local physician. A 24-hour creatinine clearance and the Cockcroft-Gault formula were used to estimate renal function, and values were compared with an age adjusted glomerular filtration rate for a solitary kidney. RESULTS Mean patient followup was 25 years. The 24-hour urinary creatinine clearance decreased to 72% of the value before donation. For the entire study cohort serum creatinine and systolic blood pressure after donation were significantly increased compared with values before, although still in the normal range. The overall incidence of hypertension was comparable to that expected in the age matched general population. There was no gender or age difference (younger or older than 50 years) for 24-hour urinary creatinine clearance, or change in serum creatinine before or after donation. Urinary protein and albumin excretion after donation was significantly higher in males compared with females. There were 13 (19%) subjects who had a 24-hour urinary protein excretion that was greater than 0.15 gm./24 hours, 5 (7%) of whom had greater than 0.8. No gender difference was noted in blood pressure, and there were no significant changes in diastolic pressure based on gender or age. CONCLUSIONS Overall, renal function is well preserved with a mean followup of 25 years after donor nephrectomy. Males had significantly higher protein and albumin excretion than females but no other clinically significant differences in renal function, blood pressure or proteinuria were noted between them or at age of donation. Proteinuria increases with marginal significance but appears to be of no clinical consequence in most patients. Patients with mild or borderline proteinuria before donation may represent a subgroup at particular risk for the development of significant proteinuria 20 years or greater after donation. The overall incidence of proteinuria in our study is in the range of previously reported values after donor nephrectomy.

Kidney transplantation with sirolimus and mycophenolate mofetil-based immunosuppression: 5-year results of a randomized prospective trial compared to calcineurin inhibitor drugs.

Background. We report the 5-year outcomes from a randomized prospective trial in primary adult renal allograft recipients, designed to evaluate calcineurin inhibitor (CNI)-free immunosuppression on kidney transplant function. Methods. Sixty-one patients were randomized to either sirolimus (n=31) or cyclosporine (n=30) after basiliximab induction and mycophenolate mofetil (MMF) with steroids. Sirolimus was concentration controlled at 10–12 ng/mL for at least 6 months. Results. After 5 years, sirolimus-MMF-steroids compared to cyclosporine-MMF-steroids provides similar patient survival (87.1 vs. 90%, P=0.681), acute rejection rates (12.9 vs. 23.3%, P=0.22), total cholesterol (209.1 vs. 204.3 mg/dL, P=0.973), urine protein/creatinine ratios (0.398 vs. 0.478 mg/dL, P=0.72), and overall medical and surgical morbidity (P=NS). Although unadjusted patient survival was similar, sirolimus based CNI-free patients had longer death censored graft survival (96.4 vs. 76.7%, P=0.0265), higher glomerular filtration rate (GFR) by the abbreviated Modified Diet in Renal Disease (66.7 vs. 50.7 cc/min, P=0.0075), and fewer graft losses from chronic allograft nephropathy. The Banff chronic scores at two years were strong predictors of 5-year GFR. At 5 years, there were six de novo (three solid organ, three skin) cancers in the CNI group and only two de novo (one skin, one leukemia, no solid organ) cancers in the sirolimus group (P=NS). Conclusions. This study of low to moderate risk patients demonstrates that excellent 5-year kidney transplant outcomes can be achieved without CNI drugs, when therapeutic drug monitoring of sirolimus is employed. The application of CNI drug avoidance protocols to high-risk recipients (retransplants, highly sensitized, etc.), extrarenal allograft recipients, or alternative drug regimens such as steroid or MMF elimination should be subjected to controlled trials.

The impact of sirolimus, mycophenolate mofetil, cyclosporine, azathioprine, and steroids on wound healing in 513 kidney-transplant recipients

Background. The aim of this study was to determine whether there has been an increase in the incidence or severity of wound-healing complications that can be attributed to the introduction of newer immunosuppressive drugs. Methods. Consecutive series of adult kidney-only transplant recipients were selected from our Unified Transplant Database backward from September 2002. There were 513 patients divided into groups on the basis of their maintenance immunosuppression given for at least the first 30 days posttransplant. Group I (152) was given sirolimus, mycophenolate mofetil, and prednisone (SRL/MMF/P) between March 2000 and September 2002; group II (168) was given cyclosporine A (CsA)/MMF/P between January 1999 and July 2002; and group III (193) was given azathioprine (AzA)/CsA/P between January 1993 and December 1997. A classification system for wound-healing problems was developed, and each of the three groups was analyzed by univariate and multivariate analysis. Results. From groups III to II to I, there was a significant increase in mean age (42.4 vs. 49 years), percent of patients diabetic (17% vs. 29%), mean body mass index (BMI) (24.2 vs. 27.1 kg/m2), and percent BMI greater than 30 (13.5% vs. 27%). The cumulative percentage of all wound-healing problems between group I (19.7%) vs. group II (16.1%) and group III (15.6%) was not significantly different. The most significant risk factor was a recipient BMI greater than 30 (P =0.0012) and delayed graft function (P =0.0041). Conclusions. During a 10-year period marked by changing recipient demographics, the introduction of MMF and SRL did not result in a significant increase in transplant wound-healing complications. The most significant risk factor associated with transplant wound-healing complications remains body weight, which was the major influence for each of the immunosuppressive drug combinations described.

Should Obese Patients Lose Weight Before Receiving A Kidney Transplant

Background. The results of renal transplantation in obese recipients have been controversial, with some reports finding increased morbidity prohibitive and others finding increased morbidity acceptable. We attempted to determine whether obese patients in extreme excess of their ideal body weight should undergo transplantation. Methods. The study population included 127 obese (body mass index >30 kg/m 2 ) patients who were compared with a matched nonobese control group (body mass index <27 kg/m 2 ) of 127 recipients with similar demographics. There were no significant differences between the groups according to donor source, recipient race or sex, retransplants, transplant percent reactive antibodies, cause of renal failure, or hypertension. However, significantly more obese patients had a pretransplant history of angina (11.2% vs. 3.2%, P=0.02) or a previous myocardial infarction (5.6% vs. 0.8%, P=0.04). Results. The mean follow-up was 58.9±40 (range 3-170) months. Nonobese patients enjoyed a significantly (P=0.0002) greater patient survival (89% vs. 67%) at 5 years and suffered only about half the number of deaths (25 vs. 46) during the period of observation. Cardiac disease was the leading cause of death (39.1%) in the obese group. Patient death had a major impact on graft survival because there were no differences between the groups when death with graft function was censored from the analysis. There were no significant differences between the groups in delayed graft function, acute rejection, chronic rejection, length of hospital stay, operative blood loss, or mean serum creatinine up to 5 years. However, obese patients experienced significantly (P=0.0001) more complications per patient (3.3 vs. 2.2) and a greater incidence (P=0.0003) of posttransplant diabetes (12% vs. 2%). Similar cyclosporine blood levels were observed in obese recipients even though they were receiving 0.75-2 mg/kg/day less cyclosporine than the nonobese recipients. Conclusions. Outcome differences in obese renal transplant patients were primarily due to a higher mortality resulting from cardiac events. Obesity seems to have little effect on immunologic events, long-term graft function, or cyclosporine delivery. Aggressive pretransplant screening for ischemic heart disease is essential to identify an especially high-risk subgroup of obese patients. Although it would seem prudent to recommend weight reduction <30 kg/m 2 to all patients before transplant, these data suggest that obese patients with a history of cardiac disease should not be transplanted until weight reduction has been accomplished.

SUCCESSFUL OUTCOMES IN PHEOCHROMOCYTOMA SURGERY IN THE MODERN ERA

PURPOSE We describe our experience with surgical management, complications and treatment outcome of histologically confirmed pheochromocytoma. MATERIALS AND METHODS The records of 113 patients who underwent surgical excision of pheochromocytoma were reviewed and assessed for preoperative medical treatment, intraoperative findings, postoperative hospitalization and complications. RESULTS There were no surgical mortalities. Average length of stay in the intensive care unit was 1.2 days. There were only 6 major cardiovascular complications all of which occurred in patients who received preoperative medications, including 5 with alpha blockade. Patients receiving no preoperative alpha blockade required an average of 956 cc less in total intraoperative fluids, which approached statistical significance, and 479 cc less fluids on postoperative day 1, which was statistically significant. CONCLUSIONS Preoperative alpha-adrenergic blockade is not essential in pheochromocytoma patients. Calcium channel blockers are just as effective and safer when used as the primary mode of antihypertensive therapy. Surgery for pheochromocytoma is safe in the modern era.

THE IMPACT OF ADJUVANT NEPHRECTOMY ON MULTIMODALITY TREATMENT OF METASTATIC RENAL CELL CARCINOMA

Multimodality treatment of metastatic renal cell carcinoma with biological response modifiers and cytoreductive surgery has produced durable responses. The timing and impact of cytoreductive surgery on the success of immunotherapy require further study. We reviewed the treatment of 62 patients with metastatic renal cell carcinoma and primary tumors in place who qualified for multimodality treatment comprising adjuvant nephrectomy and biological response modifier protocols at our institution between 1987 and 1992. Of the patients 37 were scheduled to undergo initial adjuvant nephrectomy followed by biological response modifier therapy. A total of 25 patients underwent initial biological response modifier therapy with planned delayed adjuvant nephrectomy if a response to treatment was demonstrated. Of the 37 patients undergoing initial adjuvant nephrectomy, 8 (22%) were unable to enter induction of immunotherapy because of perioperative complications (1), medical contraindications (2), tumor progression (4) or death (1). Three patients in the initial adjuvant nephrectomy group (8%) had a partial response and the median survival in this group was 12 months (range 1 to 57). In the initial biological response modifier group 3 patients (12%) with an objective response (2 complete and 1 partial) to biological response modifier therapy underwent nephrectomy. The median survival for the initial biological response modifier group was 14 months (range 1 to 48). These results add to our understanding of the impact of adjuvant nephrectomy on patients with metastatic renal cell carcinoma considered for immunotherapy protocols.

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.

Determinants of chronic renal allograft rejection in cyclosporine-treated recipients

We analyzed the development of chronic rejection in 511 kidney-only renal transplants in 507 patients between July 1987 and November 1994. A database was established for recipients > or = 18 years old who received cyclosporine-based immunosuppression and demonstrated graft survival for a minimum of 12 months. The 347 recipients of cadaver transplants (67.9%) and 164 recipients of live donor transplants (32.1%) were followed for 12 to 102 months (mean 51 months). Chronic rejection was diagnosed in 124 transplants (24%), with a mean time to diagnosis of 23+/-18 months (range 3-92). Risk factors were identified in a multivariate analysis using the Cox model. The impact of the timing and severity of rejection episodes was analyzed in a univariate model. The presence of chronic rejection resulted in decreased (P=0.0001) 5-year graft survival for both cadaver graft (83.7% vs. 58.2%) and live donor graft (93.2% vs. 53.1%) recipients. Significant variables for the development of chronic rejection included an acute rejection episode (P=0.0001), a black recipient (P=0.0006), donor age > or = 50 years (P=0.006), and a serum creatinine level >2.0 mg/dl by 6 months after transplantation. Severity of rejection measured by peak serum creatinine or posttreatment return to baseline was not related to chronic rejection. However, acute rejection episodes lasting for more that 5 days (P=0.03) or occurring after 6 months (P=0.001) did influence time to chronic rejection. In addition, mismatching for donor-recipient race was a significant (P=0.008) risk factor for recipients of cadaver grafts. We conclude that acute rejection is the most significant risk factor for chronic rejection, and the long-term fate of grafts may be determined as early as the first 6 months. Racial matching of donor-recipient pairs may be useful to minimize chronic rejection risk. Future advances that diminish the incidence and severity of acute rejection may have the greatest impact on long-term survival.

A randomized prospective controlled trial of oral acyclovir versus oral ganciclovir for cytomegalovirus prophylaxis in high-risk kidney transplant recipients.

BACKGROUND Posttransplantation cytomegalovirus (CMV) infection remains a significant cause of morbidity in kidney transplant recipients. We performed a randomized prospective controlled trial of oral acyclovir versus oral ganciclovir for CMV prophylaxis in a group of renal allograft recipients considered at high risk for CMV disease due to the use of OKT3 induction therapy. METHODS A total of 101 recipients of cadaveric (83) and zero haplotype-matched live donor (18) kidney transplants were entered into the trial. A total of 22 D-R- patients received no prophylaxis. Twenty-seven D+R-, 29 D+R+, and 23 D-R+ patients were randomized to receive 3 months of either oral acyclovir (800 mg q.i.d.) or oral ganciclovir (1000 mg t.i.d.). Doses were adjusted according to the level of renal function. The D+R- patients were also given CMV immune globulin biweekly for 16 weeks. Surveillance blood cultures were obtained at transplantation, at months 1, 2, 3, and 6, and when clinically indicated. The primary study end points were time to CMV infection and disease the first 6 months after transplantation. RESULTS The mean follow up was 14.4 months. Both agents were well tolerated, and no drug interruptions for toxicity occurred. CMV was isolated in 14 of 39 (35.9%) acyclovir-treated and 1 of 40 (2.5%) ganciclovir-treated recipients by 6 months (P=0.0001). Symptomatic CMV disease occurred in 9 of 14 (64%) of the acyclovir patients, two with tissue-invasive disease. Infection rates for acyclovir vs. ganciclovir, respectively, stratified by CMV serology were: D+R-, 54 vs. 0%, P=0.0008; D+R+, 43 vs. 6.6%, P=0.01; D-R+, 8.3 vs. 0%, P=NS. No patient developed CMV infection while taking oral ganciclovir, however three delayed infections occurred 2-7 months after finishing therapy. Each patient had been previously treated for acute rejection. CONCLUSIONS Oral acyclovir provides effective CMV prophylaxis only for recipients of seronegative donor kidneys. Oral ganciclovir is a superior agent providing effective CMV prophylaxis for recipients of seropositive donor kidneys. Recipients who are treated for acute rejection are at risk for delayed CMV infection during the first posttransplantation year.