Dilip S. Kittur

Laparoscopic live donor nephrectomy: the recipient

BACKGROUND Laparoscopic live donor nephrectomy offers advantages to the donor in terms of decreased pain and shorter recuperation. Heretofore no detailed analysis of the recipient of laparoscopically procured kidneys has been performed. The purpose of this study was to determine whether laparoscopic donor nephrectomy had any deleterious effect on the recipient. METHODS A retrospective review was conducted of all live donor renal transplantations performed from January 1995 through April 1998. The control group received kidneys procured via a standard flank approach (Open). Rejection was diagnosed histologically. Creatinine clearance was calculated using the Cockroft-Gault formula. RESULTS A total of 110 patients received kidneys from laparoscopic (Lap) and 48 from open donors. One-year recipient (100% vs. 97.0%) and graft (93.5% vs. 91.1%) survival rates were similar for the Open and Lap groups, respectively. A similar incidence of vascular thrombosis (3.4% vs. 2.1%, P=NS) and ureteral complications (9.1% vs. 6.3%, P=NS) were seen in the Lap and Open groups, respectively. The incidence of acute rejection for the first month was 30.1% for the Lap group and 31.9% for the Open group (P=NS). The rate of decline of serum creatinine level in the early posttransplantation period was initially greater in the Open group, but by postoperative day 4 no significant difference existed. No difference was observed in allograft function long-term. The median length of hospital stay was 7.0 days for both groups. CONCLUSIONS Laparoscopic live donor nephrectomy does not adversely effect recipient outcome. The previously demonstrated benefits to the donor, and the increased willingness of individuals to undergo live kidney donation, coupled with the acceptable outcomes experienced by recipients of laparoscopically procured kidneys justifies the continued development and adoption of this operation.

LAPAROSCOPIC LIVE DONOR NEPHRECTOMY: The Recipient1

Background Laparoscopic live donor nephrectomy offers advantages to the donor in terms of decreased pain and shorter recuperation. Heretofore no detailed analysis of the recipient of laparoscopically procured kidneys has been performed. The purpose of this study was to determine whether laparoscopic donor nephrectomy had any deleterious effect on the recipient. Methods. A retrospective review was conducted of all live donor renal transplantations performed from January 1995 through April 1998. The control group received kidneys procured via a standard flank approach (Open). Rejection was diagnosed histologically. Creatinine clearance was calculated using the Cockroft-Gault formula. Results. A total of 110 patients received kidneys from laparoscopic (Lap) and 48 from open donors. One-year recipient (100% vs. 97.0%) and graft (93.5% vs. 91.1%) survival rates were similar for the Open and Lap groups, respectively. A similar incidence of vascular thrombosis (3.4% vs. 2.1%, P=NS) and ureteral complications (9.1% vs. 6.3%, P=NS) were seen in the Lap and Open groups, respectively. The incidence of acute rejection for the first month was 30.1% for the Lap group and 31.9% for the Open group (P=NS). The rate of decline of serum creatinine level in the early post-transplantation period was initially greater in the Open group, but by postoperative day 4 no significant difference existed. No difference was observed in allograft function long-term. The median length of hospital stay was 7.0 days for both groups. Conclusions. Laparoscopic live donor nephrectomy does not adversely effect recipient outcome. The previously demonstrated benefits to the donor, and the increased willingness of individuals to undergo live kidney donation, coupled with the acceptable outcomes experienced by recipients of laparoscopically procured kidneys justifies the continued development and adoption of this operation.

Intravenous mycophenolate mofetil: safety, tolerability, and pharmacokinetics

An intravenous (i.v.) formulation of mycophenolate mofetil (MMF; CellCept®, Roche Pharmaceuticals, Inc., Palo Alto, CA) that will enable its administration to patients unable to tolerate oral medication is available. Two separate studies, an open‐labeled pharmacokinetic (PK) study and a double‐blind safety study, were performed. Within 24 h after transplant, 153 (safety study) and 45 (PK study) first or second renal transplant recipients were started on i.v. MMF 1 g Q12h or placebo (used in the safety study only, 2:1 MMF:placebo), given over 2 h via a dedicated peripheral venous catheter. In the safety study, per os (p.o.) MMF (1g Q12h) or placebo was administered, starting within 72 h after transplant, whereas in the PK study, p.o. MMF was started on the evening of day 5. Sequential blood samples obtained on study days 5 (i.v. MMF) and 6 (p.o. MMF) before and up to 12 h after the AM dose were analyzed for mycophenolic acid (MPA) and MPA glucuronide (MPAG) concentrations by high‐performance liquid chromatography. The area under the concentration curve (AUC) was calculated using the linear trapezoidal rule. The MPA AUC0–12 was higher for i.v. MMF than p.o. MMF (40.8±11.4 μg·h/mL vs. 32.9±15, p<0.001). There were no other significant PK differences for plasma MPA or MPAG. In the safety study (n=98 i.v. MMF vs. n=55 placebo), 11 patients (11%, i.v. MMF) and 4 patients (7%, placebo) discontinued their use of the drug because of an adverse event (AE). Overall, AEs were similar between i.v. MMF and placebo. Injection site phlebitis (4%) and thrombosis (4%) were observed only with i.v. MMF. MMF i.v. 1 g twice daily (b.i.d.) should provide efficacy at least equivalent to p.o. MMF without increased toxicity, and it provides an acceptable alternative dose form in the immediate period after transplant.

In Vitro Immunomodulatory Effects of Ten Commonly Used Herbs on Murine Lymphocytes

OBJECTIVES Physicians are increasingly encountering patients who use herbal products. Some of these products are known to modulate the immune system but their scientific basic is not well established. Because these products can affect the host immune system, they could be beneficial in the treatment of immune-related diseases, or alternatively, they could cause inadvertent side-effects. The purpose of this study was to determine which of these common herbal products modulate lymphocyte proliferation in vitro. METHODS Lymphocyte proliferation assays using concanavalin A (mitogen stimulation) and mixed lymphocyte culture (alloantigen stimulation) were used as in vitro tests to investigate the immunomodulatory effects of 10 commonly used herbal products. RESULTS Ginger and tea were consistently immunosuppressive while dong quai, milk thistle, and St. Johns wort were consistently immunostimulatory in vitro. Ginseng enhanced lymphocyte proliferation only in the mitogen-stimulation assay. The magnitude of the enhancement or suppression of the individual herbal products was different in the two assays. CONCLUSION Our study provides a uniform survey of the immunomodulatory properties of 10 commonly used herbal products and paves the way for testing these effects in vivo and in clinical setting.

Baseline glomerular size as a predictor of function in human renal transplantation.

BACKGROUND Nonimmune mechanisms have been implicated in chronic renal allograft injury. In experimental studies, a strong correlation exists between glomerular size and the degree of glomerular sclerosis that develops after subtotal nephrectomy. Therefore, we assessed the impact of glomerular maximal planar area (MPA) in baseline biopsy specimens of human renal allografts on later graft function. METHODS The MPA was measured, by point counting and by computer planimetry, in postperfusion biopsy specimens from 96 allograft kidneys from nonhypertensive donors that had functioned for at least 2 years. Clinical data were analyzed throughout a follow-up period averaging 7.46+/-2.46 years. RESULTS Both methods produced equivalent estimates of MPA. MPA proved to be a strong predictor of late renal allograft function, with a significant correlation (P = 0.02 to P < 0.01) between MPA at baseline and later serum creatinine level and creatinine clearance, beginning at 6 months after transplantation and persisting through follow-up. Creatinine level at discharge and occurrence of rejection were also independent predictors, whereas donor age, gender and race, cold ischemia time, cadaveric versus living donor, delay in initial function, and HLA mismatch did not predict clinical outcome. CONCLUSION Larger glomeruli at baseline, measured by a simple point-counting technique, provide an early predictor of risk for late allograft dysfunction and may identify a subpopulation of patients in whom treatment to prevent/ameliorate glomerular enlargement and/or hypertension may be efficacious.

Morphological and biochemical effects of immunosuppressive drugs in a capillary tube assay for endothelial dysfunction

Abstract: Immunosuppressive drugs common in clinical transplantation are known to have untoward effects on the vascular system. The effects of some drugs, notably cyclosporin A (CyA), have been studied on the vascular system, while those of others have not. In the vascular system, endothelial cells are the predominant cell type exposed to intravascular concentrations of immunosuppressive drugs. We therefore studied the effects of drugs common in clinical transplantation on endothelial cells in a capillary tube assay. The endothelial cells in the capillary tubes are morphologically more similar to those in the microvasculature than endothelial cells in monolayers. We studied the kinetics and extent of capillary tube formation and prostacyclin (PGI2) and endothelin‐1 (ET‐1) release from the in vitro capillaries to determine the morphological and biochemical effects of five immunosuppressive agents on endothelial function. We found a significant difference in the morphological and biochemical effects of the two common calcineurin inhibitors, CyA and tacrolimus (FK506) on capillary morphology in vitro. The former had a pronounced injurious effect on the morphology of the in vitro capillaries, while the latter did not. CyA also significantly increased ET‐1 release by the capillaries, but FK506 did not. Mycophenolate mofetil (MMF) was the only other agent that had a moderately injurious effect on the morphology of the in vitro capillaries. Sirolimus (rapamycin) and dexamethasone, similar to FK506, had no effect on the capillary morphology. All these agents, except dexamethasone, increased PGI2 release. Our data suggest that CyA adversely affects the morphology of the microvasculature and that this is mediated, at least partly, by an increased ET‐1 release by endothelial cells exposed to CyA. These findings describe a novel effect of CyA and MMF on endothelial cells that could be relevant to understanding the mechanisms of immunosuppressive drug‐mediated endothelial injury in clinical transplantation.

Cross-species comparison of gene expression between human and porcine tissue, using single microarray platform--preliminary results.

Abstract:  Introduction:  Xenotransplantation is a potential solution for inadequate supply of donor organs. Pigs are considered the ideal donor for kidney transplantation to human recipients, therefore it is important to understand the gene regulation in the porcine organs. Oligonucleotide array technology has been utilized largely for human, mouse and rat gene expression studies only. Its use with porcine genes has not been reported. We investigated the possibility of studying gene regulation in porcine kidney with a human GeneChip microarray® platform.

Incidence and morbidity of cytomegalovirus disease associated with a seronegative recipient receiving seropositive donor-specific transfusion and living-related donor transplantation: A multicenter evaluation

This retrospective study was conducted to identify the frequency of cytomegalovirus (CMV) disease in seronegative recipients of donor-specific transfusion (DST) and living-related donor (LRD) kidneys from seropositive donors. A total of 151 LRD transplants (TX) were performed at six transplant centers over a 3-year period. A total of 33 patients were identified as having been seronegative (pre-TX) for CMV, yet they had DST and a TX from a seropositive LRD. of these patients, 12 (36.45%) seroconverted within the first 6 months post-TX and developed clinical CMV disease. Additional patients seroconverted, but did not have evidencde of clinical disease and were not tested further. All TX centers, with the exception of one, had seronegative patients that became ill after receiving a seropositive DST/LRD TX. Six patients manifested their disease as a febrile illness with leukopenia and liver enzyme elevations, four had pneumonitis, and two developed CMV ulcerations of the colon (one of whom died from resultant sepsis). Of the 36 seronegative patients who received seronegative DST/LRD TX none became ill with CMV disease. Of the 72 seropositive patients who received DST/LRD TX, only 2 (2.8%) developed CMV illness (one, seropositive into seropositive, the other, seronegative into seropositive). Of the 33 seronegative patients receiving seropositive DST/LRD TX, 17 received antilymphocyte preparations (ALP), and 8 of these became ill (47.1%). Of 16 patients not receiving ALP, 5 (31.3%) developed clinical CMV illness. Of the 33 patients who were identified as having been seronegative for CMV seronegative for CMV yet received seropositive DST/LRD TX, the 12 who did develop CMV illness had two graft losses, one death, and a serum creatinine for the remaining 9 patients of 2.3pL1.6 at last follw-up. the remaining 21 patients who developed no illness had a serum creatining of 1.3pL0.6 with no graft losses at the last follow-up. This evidence suggests that a prospective TX recipient who is seronegative for CMV who received DST/LRD Tx from a seropositive family member has a significant risk for developing morbidity related to clinical CMV illness.

A novel extracorporeal kidney perfusion system: a concept model.

The number of patients awaiting kidney transplantation has more than doubled in the past decade while the number of available donor organs has seen only a modest increase, leading to a critical shortage of organs. In response to this extreme shortage, the criteria for accepting organs have been modified to include marginal donors such as non-heart beating donors (NHBD). In these kidneys, determining viability is important for success of transplantation. Therefore, a study was undertaken to develop a system that would allow the extra-corporeal assessment of function and compatibility of the donor organ before the patient is exposed to the risks associated with surgery. Following bilateral nephrectomy, the kidneys of 10 pigs (~30 kg) were connected to a commercially available hypothermic pulsatile kidney perfusion apparatus. This system was modified to allow for normothermic pulsatile renal perfusion using the potential recipient’s blood, via vascular access. These kidneys were perfused with the animal’s blood for a minimum of two hours while various parameters were monitored. Perfusion pressures were kept between 60 and 90 mmHg, which correlated to flows between 70 and 150 mL/min. A decrease in perfusion pressure with a concomitant rise in flow over the two-hour period served as a good predictor of a viable and compatible graft. The modified kidney preservation system allows the normothermic, pulsatile extracorporeal perfusion of donor kidneys with the ability to monitor resistance to flow and urine production. This model also allows observation of the kidney for signs of hyperacute rejection. Further research needs to be conducted in order to determine if the system represents a methodology to increase the pool of available donor organs.

Does high MHC class II gene expression in normal lungs account for the strong immunogenicity of lung allografts

Abstract Clinical experience has demonstrated that lung allografts are considerably more immunogenic than liver allografts although both organs contain equivalent amounts of lymphoreticular tissue. Northern blot analysis of MHC class II gene expression in various murine organs with I‐AB and I‐EB gene‐specific oligonucleotide probes revealed that MHC class II expression in lungs is semiquantitatively higher than in the liver and other organs with the exception of the spleen. We conclude that this high MHC class II expression strongly suggests that the lymphoreticular tissue in the lungs is in a state of activation. This may be an important reason for the strong immunogenicity of lung allografts.