ABO incompatible renal transplantation without antibody removal using conventional immunosuppression alone.

ABO incompatible living donor renal transplantation (ABOi) can achieve outcomes comparable to ABO compatible transplantation (ABOc). However, with the exception of blood group A2 kidneys transplanted into recipients with low titer anti-A antibody, regimens generally include antibody removal, intensified immunosuppression and splenectomy or rituximab. We now report a series of 20 successful renal transplants across a range of blood group incompatibilities using conventional immunosuppression alone in recipients with low baseline anti-blood group antibody (ABGAb) titers. Incompatibilities were A1 to O (3), A1 to B (2), A2 to O (2), AB to A (2), AB to B (1), B to A1 (9), B to O (1); titers 1:1 to 1:16 by Ortho. At 36 months, patient and graft survival are 100%. Antibody-mediated rejection (AbMR) occurred in one patient with thrombophilia and low level donor-specific anti-HLA antibody. Four patients experienced cellular rejection (two subclinical), which responded to oral prednisolone. This series demonstrates that selected patients with low titer ABGAb can undergo ABOi with standard immunosuppression alone, suggesting baseline titer as a reliable predictor of AbMR. This reduces morbidity and cost of ABOi for patients with low titer ABGAb and increases the possibility of ABOi from deceased donors.

Successful ABO-incompatible kidney transplantation with antibody removal and standard immunosuppression.

ABO-incompatible (ABOi) kidney transplantation is an established therapy, though its implementation to date has been in part limited by the requirement for additional immunosuppression. Here, we describe the outcomes of 37 patients undergoing ABOi kidney transplantation utilizing perioperative antibody depletion and receiving an identical tacrolimus-based immunosuppressive regimen to contemporaneous ABO-compatible (ABOc) recipients, with the exception that mycophenolate was commenced earlier (7-14 days pretransplant). Antibody depletion was scheduled according to baseline anti-ABO antibody titer (tube IAT method: median 1:128, range 1:8 to 1:4096). Patient and graft survival for the 37 ABOi recipients was 100% after a median 26 months (interquartile range [IQR] 18-32). Eight rejection episodes (two antibody-mediated and six cellular) in ABOi recipients were successfully treated with biopsy-proven resolution. Latest median eGFR is 50 mL/min × 1.73 m² (IQR 40-64) for ABOi patients and 54 mL/min × 1.73 m² (IQR 44-66) in the ABOc patients (p = 0.25). We conclude that ABOi transplantation can be performed successfully with perioperative antibody removal and conventional immunosuppression. This suggests that access to ABOi transplantation can include a broader range of end-stage kidney disease patients.

Skin cancer surveillance in renal transplant recipients: re-evaluation of U.K. practice and comparison with Australian experience.

BACKGROUND: Nonmelanoma skin cancer (NMSC) is the most common tumour following solid organ transplantation. In 2000 a survey of U.K. centres managing renal transplant recipients (RTRs) showed that only 21% offered skin cancer surveillance. OBJECTIVES: The survey was repeated in 2006 in the U.K. and Australia. The aims were to determine if U.K. practice had changed since 2000, to define skin cancer surveillance practice in Australian RTRs and to compare this with that in the U.K. METHODS: Questionnaires were sent to 84 U.K. and 45 Australian centres providing long-term RTR follow-up. RESULTS: Fifty-six (67%) U.K. centres caring for 82% (n = 16 349) of the RTR population replied. Sixty-six per cent provided annual skin cancer surveillance and 39% offered full skin examination (FSE) compared with 21% and 20% in 2000. Eighty-one per cent of surveillance was performed by nondermatologists (n = 30), nine (30%) of whom had received formal training for the role. Thirty-one (69%) Australian centres covering 86% (n = 5392) of the RTR population responded. Ninety-seven per cent provided skin cancer surveillance, and 61% offered FSE. Forty per cent (n = 12) of skin cancer surveillance was conducted by nondermatologists. Two nondermatologists had received formal training. CONCLUSIONS: Despite a substantial improvement in the provision of skin cancer surveillance for RTRs in the U.K. between 2000 and 2006, only 39% of units offer FSE. In contrast, virtually all Australian centres offer annual skin cancer surveillance, with more dermatology involvement. Lack of training for nondermatologists involved in skin cancer surveillance is evident in both countries. The availability of dermatologists and the variation in NMSC risk between the populations may explain the different practices observed.

Constraints on the diameter and albedo of 2060 chiron.

Asteroid 2060 Chiron is the largest known object exhibiting cometary activity. Radiometric observations made in 1983 from a ground-based telescope and the Infrared Astronomical Satellite are used to examine the limits on Chiron's diameter and albedo. It is argued that Chiron's surface temperature distribution at that time is best described by an "isothermal latitude" or "rapid-rotator" model. Consequently, Chiron has a maximum diameter of 372 kilometers and a minimum geometric albedo of 2.7%. This is much bigger and darker than previous estimates, and suggests that gravity may play a significant role in the evolution of gas and dust emissions. It is also found that for large obliquities, surface temperatures can vary dramatically on time scales of a decade, and that such geometry may play a critical role in explaining Chiron's observed photometric behavior since its discovery in 1977.

A Drosophila mechanosensory transduction channel.

Mechanosensory transduction underlies a wide range of senses, including proprioception, touch, balance, and hearing. The pivotal element of these senses is a mechanically gated ion channel that transduces sound, pressure, or movement into changes in excitability of specialized sensory cells. Despite the prevalence of mechanosensory systems, little is known about the molecular nature of the transduction channels. To identify such a channel, we analyzed Drosophila melanogaster mechanoreceptive mutants for defects in mechanosensory physiology. Loss-of-function mutations in the no mechanoreceptor potential C (nompC) gene virtually abolished mechanosensory signaling. nompC encodes a new ion channel that is essential for mechanosensory transduction. As expected for a transduction channel, D. melanogaster NOMPC and a Caenorhabditis elegans homolog were selectively expressed in mechanosensory organs.

A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients.

In a randomized, open-label, multicenter study, de novo renal transplant patients received no steroids (n = 112), steroids to day 7 (n = 115), or standard steroids (n = 109) with cyclosporine microemulsion (CsA-ME), enteric-coated mycophenolate sodium (EC-MPS) and basiliximab. The primary objective, to demonstrate noninferiority of 12-month GFR in the steroid-free or steroid-withdrawal groups versus standard steroids, was not met in the intent-to-treat population. However, investigational groups were not inferior to standard steroids in the observed-case analysis. Median 12-month GFR was not significantly different in the steroid-free or steroid-withdrawal groups (58.6 mL/min/1.73 m(2) and 59.1 mL/min/1.73 m(2)) versus standard steroids (60.8 mL/min/1.73 m(2)). The 12-month incidence of biopsy-proven acute rejection (BPAR), graft loss or death was 36.0% in the steroid-free group (p = 0.007 vs. standard steroids), 29.6% with steroid withdrawal (N.S.) and 19.3% with standard steroids. BPAR was significantly less frequent with standard steroids than either of the other two regimens. Reduced de novo use of antidiabetic and lipid-lowering medication, triglycerides and weight gain were observed in one or both steroid-minimization group versus standard steroids. For standard-risk renal transplant patients receiving CsA-ME, EC-MPS and basiliximab, steroid withdrawal by the end of week 1 achieves similar 1-year renal function to a standard-steroids regimen, and may be more desirable than complete steroid avoidance.

Acute Kidney Injury: It's not just the 'big' burns.

BACKGROUND: Acute Kidney Injury (AKI) complicates the management of at least 25% of patients with severe burns and is associated with long term complications. Most research focuses on the patients with more severe burns, and whether the same factors are associated with the development of AKI in patients with burns between 10 and 19% total body surface area (TBSA) is unknown. The aims of this study were to examine the incidence of, and factors associated with, the development of AKI in patients with %TBSA≥10, as well as the relationship with hospital metrics such as length of stay (LOS). METHODS: Retrospective medical record review of consecutive burns patients admitted to The Alfred Hospital, the major adult burns centre in Victoria, Australia. Demographic and injury details were recorded. Factors associated with AKI were determined using multiple logistic regression. RESULTS: Between 2010 and June 2014, 300 patients were admitted with burn injury and data on 267 patients was available for analysis. Median age was 54.5 years with 78% being male. Median %TBSA was 15 (IQR 12, 20). The AKI incidence, as measured by the RIFLE criteria, was 22.5%, including 15% (27/184) in patients with %TBSA 10-19. Factors associated with AKI included increasing age and %TBSA (OR 1.05 p<0.001) as well as increased surgeries (p<0.041) and a cardiac comorbidity (p<0.01). All patients with renal comorbidity developed AKI. In the %TBSA 10-19 cohort, only increasing age (OR 1.05 p<0.001) was associated with AKI. After accounting for confounding factors, the probability of discharge from hospital in Non-AKI group was greater than for the AKI patients at all time points (P<0.001). CONCLUSION: This is the first study to show an association between patients with %TBSA 10-19 and AKI. Given the association between AKI and complications, prospective research is needed to further understand AKI in burns with the aim of risk reduction.

ABO incompatible renal transplantation following lung transplantation.

We present management strategies utilised for the first case of an urgent live-donor ABO incompatible B blood group renal transplant, in a patient with a prior A blood group lung transplant for cystic fibrosis. Three years on, renal function is excellent and stable, whilst lung function has improved.

Impact of acute rejection therapy on infections and malignancies in renal transplant recipients.

BACKGROUND: Infections and malignancies are important causes of mortality and morbidity in renal allograft recipients. Their risk increases with increasing immunosuppression. METHODS: In an attempt to quantitate the increase in the risk of these complications in association with antirejection therapy, we reviewed the records of all renal allograft recipients of our center transplanted during the cyclosporin era. We sub-divided the patients into three groups based on acute rejection episodes during the first 6 months posttransplant, and the treatment for acute rejection: those who did not develop AR--group 1 (n=168); those who had one or more episodes of acute rejection and were treated with high dose corticosteroids --group 2 (n=169); those who in addition to corticosteroids required cytolytics (OKT3) and/or other drugs--group 3 (n=141). RESULTS: 52% patients in group 1, 71% patients in group 2 and 86% patients in group 3 had one or more episodes of infection during the first 6 months posttransplantation. Relative risk for group 2 and 3 were 1.56 (P=0.0002) and 2.98 (P<0.00001), respectively. Infection/patient rates at 6 months were 0.67, 1.23, and 2.79 in groups 1, 2, and 3 respectively. Groups 1 and 2 had a similar number of cases with squamous and basal cell carcinoma, however, there were few cases with these malignancies in group 3. No case of lymphoma was seen in group 1; there were four cases in group 2 and nine in group 3. There was no significant difference in patient survival in group 1 and 2, however, patients in group 3 had a reduced patient survival (1 vs. 3 P<0.001, 2 vs. 3 P=0.067). Graft survival was best in group 1 and worst in group 3 (1 vs. 2 P<0.05; 1 vs. 3 P<0.00001; 2 vs. 3 P<0.01). CONCLUSIONS: In renal transplant recipients the risk of infections and lymphoma increases with increasing immunosuppression and hence mortality and morbidity associated with it. When adding a potent immunosuppressive agent to rescue a kidney one needs to consider the serious and at times fatal side effects given the modest beneficial effect on long-term outcome.

Myofibroblast involvement in chronic transplant rejection.

BACKGROUND: Chronic rejection remains the major cause of late graft failure. We studied the renal tissue of 10 renal transplant patients with chronic rejection in whom biopsies had been performed at various time points over a 15-year posttransplant period to ascertain whether myofibroblasts (MF) have a role in this process. METHODS: Biopsies were grouped into five categories with respect to time after vascular anastomosis: 0 (n=10); 1 day to 3 months (n=7); 6-24 months (n=5); 36-72 months (n=7); and >72 months (n=5). A control group consisted of patients who had undergone routine biopsies at 0 (n=10), 3 (n=10), 12 (n=6), 60 (n=5), and >60 months (n=6) with no rejection. MF were identified by morphology and alpha-smooth muscle actin immunostaining. T cells and macrophages (MF) were identified using an antisera to CD3 and CD68, respectively. Collagen III deposition was similarly quantified by immunohistochemistry. Interstitial fractional area was measured by point counting. RESULTS: At all time points studied beyond time 0, there were significant increases in interstitial fractional area, collagen III staining, MF, and T-cell staining in patients with chronic rejection compared with the controls. Staining for alpha-smooth muscle actin increased with time in conjunction with worsening fibrosis and collagen deposition. CONCLUSIONS: In this study, MF were a major component of the interstitial infiltrate of the 10 patients with chronic transplant rejection. Abnormal persistence of these cells in the interstitium is one of the events that contributes to pathologic scarring of the kidney.

Diltiazem in renal allograft recipients receiving cyclosporine.

Of 113 cyclosporine-treated primary renal allograft recipients, 60 were randomized to receive standard therapy without diltiazem (ND) and 53 received standard therapy plus diltiazem (D). There was no difference in CsA blood levels between ND and D at all intervals between 3 and 24 months follow-up, yet the D group required 35% less CsA than the ND group (measured at 12 months). At all intervals to 24 months there was no difference in blood pressure, renal function (as measured by serum creatinine), or in the number of grafts lost between the 2 groups (ND, 4 lost; D, 3 lost). There was no significant difference in the total number of rejection episodes in the 2 groups (ND, 89 episodes; D, 71 episodes). However, the severity of rejection episodes was greater in the ND group as evidenced by a significant difference in the usage of OKT3 (ND, 17 courses; D, 8 courses of OKT3, P < 0.05). Of the biopsy-proven episodes of rejection, there were more episodes of vascular rejection in the ND group (ND, 14 episodes; D, 3 episodes, P = 0.005). The incidence of primary nonfunction was less in the D group (ND, 16 patients; D, 5 patients, P = 0.05). It was concluded that the use of diltiazem was associated with a markedly reduced requirement for CsA without any adverse effect on graft function or graft outcome. Diltiazem with CsA was associated with fewer episodes of primary nonfunction and less-severe rejection episodes and in particular fewer episodes of vascular rejection.

Renal function related changes in lithium kinetics.

The renal clearance of lithium will decrease, and hence the risk of acute lithium toxicity will increase, in any situation leading to dehydration and sodium depletion. Patients on long term lithium therapy with progressively declining urinary concentrating ability may be at special risk in this regard. Chronic histological changes in the kidney attributed to lithium therapy correlate with age rather than with the duration of lithium therapy. Age-related renal histological changes are associated with decreased glomerular filtration rate and therefore reduced renal lithium clearance. Thus, the dose of lithium should be reduced with advancing age.

A screening assay to simultaneously determine the presence and specificity of HLA anti-idiotypic antibodies.

HLA sensitization is generally associated with an increased risk of graft failure. However, in many cases, highly sensitized patients with a negative current serum crossmatch may be successfully transplanted despite the high levels of alloantibodies (Ab1) in their serum. Sensitized patients may be divided into two groups. The group with a high-risk of early graft failure produces a negative current serum crossmatch as a result of antibody attrition, but upon transplantation the reactivation of Ab1 by the donor organ results in graft failure. The low-risk group gives a negative current serum crossmatch due to the abrogation of Ab1 by anti-idiotypic antibodies (Ab2). This specific inhibition results in the protection of the graft and improved graft survival. In this paper we describe a screening method which enables large numbers of patients to be assessed for the presence of Ab2 in pretransplant sera, while simultaneously determining the specificities of these antibodies. The pretransplant assessment of sensitized patients for the presence of Ab2 would enable low-risk patients to be distinguished from high-risk patients, while information regarding Ab2 specificity would enable permissible mismatches to be considered. With this information at hand, the pretransplant waiting time for these patients may be greatly reduced. In our modification of the inhibition assay, selected dilutions of peak sera (P/n) were tested in the presence of either platelet absorbed current serum (P/n + Cabs) or an equal volume of fetal calf serum (P/n + FCS) as a dilution control.(ABSTRACT TRUNCATED AT 250 WORDS)

Lithium nephrotoxicity.

After nearly two decades of concern and controversy surrounding the long-term effects of lithium on the kidney, the fact that lithium is capable of causing a major disturbance in water balance, manifest as polyuria and secondary polydipsia, remains undisputed. A decreased urinary concentrating ability (nephrogenic diabetes insipidus) with a disturbed responsiveness of the distal nephron to the action of ADH (vasopressin) is demonstrable, and the symptoms are largely reversible on cessation of lithium or reduction of the dose. An acute histological lesion of the distal nephron, corresponding to the site of lithium inhibition of the action of ADH, and consisting of epithelial cellular swelling and glycogen deposition, also appears to be readily reversible. Of greater concern is the development of a progressive impairment of urinary concentrating ability in patients on long-term maintenance therapy--especially those with a history of acute lithium toxicity and those additionally treated with neuroleptics. This functional lesion is not always reversible, and the underlying renal histology is a chronic focal interstitial nephropathy. Interestingly, some psychiatric patients never exposed to lithium have demonstrated similar renal histology. There is very little evidence that stable maintenance lithium therapy, without episodes of acute intoxication, is associated with a reduction of glomerular filtration rate. Episodes of acute lithium intoxication are largely predictable, and therefore avoidable, provided appropriate precautions are taken. Patients with polyuria and impaired urinary concentrating ability are at increased risk of acute lithium toxicity because of excessive renal losses of fluid, and these symptoms should be treated in the first instance with dosage reduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Structural and functional effects of long-term lithium therapy.

To determine the effects of long-term lithium therapy, we have studied the renal histology and the renal function of 47 patients with affective disorders who were either currently receiving or had previously received maintenance lithium therapy (lithium patients), and we have compared the results with those of 32 other psychiatric patients with similar affective illnesses who had never taken lithium (prelithium patients). The renal biopsy samples, analyzed by a point-counting technique for interstitial fibrosis, were not different in degree between the lithium and the prelithium patients. Interstitial fibrosis was also not different between prelithium patients and age-matched transplant donor kidney controls, but it was greater in lithium patients when compared with the donor kidney controls (P less than 0.01). The specific distal tubular lesion associated with lithium therapy was present in all the biopsy samples of the patients who were currently receiving lithium therapy. Marked distal nephron dysfunction, as measured by urinary concentrating ability (P less than 0.0001) and urinary acidification (P less than 0.0001), was evident in lithium patients compared with the prelithium patients. These defects were correlated with the duration of lithium therapy. Serum creatinine estimations (P less than 0.01), serum beta-2 microglobulins (P less than 0.01), and 51Cr-EDTA clearances (P less than 0.01) suggested some impairment of GFR in lithium patients compared with prelithium patients. These defects did not correlate with the duration of lithium therapy. From these studies we concluded that the marked distal nephron dysfunction induced by lithium might produce prerenal impairment of GFR because the renal function abnormalities have no structural basis when the degree of interstitial fibrosis of other psychiatric patients is used as a control. Prospective studies are needed to answer the controversial question of whether stable maintenance lithium therapy produces chronic nephrotoxicity.

Renal pathology associated with lithium therapy.

Renal biopsies have been examined in patients either currently (50 patients) or previously (5 patients) on maintenance lithium therapy for severe affective disorders. In patients currently taking lithium, a distinctive lesion of the distal convoluted tubules and collecting ducts was identified. This lesion consisted of vacuolation and swelling of the cytoplasm with accumulations of PAS positive material; this material was confirmed to be particulate glycogen by light and ultrastructural techniques. This 'lithium-associated' lesion was not present in patients who had discontinued lithium therapy. Prospective studies showed that the accumulation of glycogen occurs in distal tubules and collecting ducts within days of commencing lithium treatment. The relationship of this distinctive lesion to the patchy focal cortical interstitial fibrosis seen in these biopsies remains to be elucidated.

Morphology of renal parenchymal culture in collagen gels.

Explants of rabbit renal parenchyma have been grown in primary tissue culture suspended within hydrated collagen gels. Light and phase contrast microscopic analysis of the first 17 days in culture is described. Pieces of NZW rabbit renal parenchyma were suspended in collagen gels and bathed in supplemented RPMI 1640 medium and incubated at 37 degrees C in 5% CO2 in air. Tubules demonstrated a fine granularity by phase contrast microscopy and glomeruli appeared as red spheres. Blebs formed at the sides and ends of the explant and a monolayer outgrowth of tightly packed polygonal cells occurred from day 4. Histologically an immediate phase of necrosis was followed by regeneration whereby tubules became lined with a confluent epithelium composed of a single layer of flat to cuboidal-shaped cells sitting on an intact tubular basement membrane (TBM). Intraluminal casts of organized cellular debris as well as material presumed to be Tamm Horsfall protein were present. Glomeruli demonstrated collapsed capillary loops. The interstitium became widened by eosinophilic material. The tissue surface contained epithelial cells arranged in places into sac-like structures enclosing a space.

Treatment of IgA nephropathy with eicosapentanoic acid (EPA): a two-year prospective trial.

Thirty-seven patients with biopsy proven mesangial IgA nephropathy were prospectively allocated to either two years of treatment with eicosapentanoic acid (EPA) 10 g per day or no treatment. At entry treated and untreated patients with renal dysfunction (Group A) or patients with normal serum creatinine less than 0.12 mmol/l (Group B) did not differ in serum creatinine, creatinine clearance, urinary protein excretion, or quantitative urinary red cell counts. Compliance with EPA therapy was excellent as assessed by plasma fatty acid profiles. At the end of the trial creatinine clearance in treated patients had gone from 80 +/- 16 to 57 +/- 17 ml/min (p less than 0.05) and in untreated patients from 76 +/- 18 to 55 +/- 14 (p less than 0.05). There were no beneficial effects in either Group A or Group B patients. The only two patients who had improvement in renal function were in the EPA treatment group. Although no side effects of treatment were noted, EPA does not alter the course of established mesangial IgA nephropathy.

Low red cell arachidonic acid in cyclosporine-treated patients.

Red blood cell phospholipid arachidonic acid concentration was determined in 38 renal transplant recipients on cyclosporine-azathioprine-prednisolone therapy and in a comparable group of 20 patients on azathioprine-prednisolone alone. Samples also were obtained from 18 normal controls and 30 patients with "classical" hemolytic uremic syndrome (HUS). The arachidonic acid content was estimated as the percentage relative to the five principal fatty acids in red blood cell phospholipids (C16:0, C18:0, C18:1 omega 9, C18:2 omega 6, C18:3 omega 6) and quoted as mean value +/- standard deviation. There was a highly significant difference between patients on cyclosporine (14.7 +/- 2.9) and non-cyclosporine-treated transplant recipients (17.1 +/- 2.5; p less than 0.002). This difference was even more significant when patients who had been on cyclosporine for less than 3 months were excluded (14.1 +/- 2.7; p less than 0.001). The mean arachidonic acid content in non-cyclosporine recipients also was significantly less than that in normal controls (19.2 +/- 1.5; p less than 0.005) whilst the HUS patients (11.2 +/- 3.6) had significantly reduced values when compared with all the other groups. Cyclosporine often causes nephrotoxicity and in some cases HUS may develop in cyclosporine-treated transplant recipients. We have found a significant negative correlation between serum creatinine levels and red blood cell phospholipid arachidonic acid levels (r = -0.45; p less than 0.01). We propose that the decreased concentration of arachidonic acid in the cyclosporine-treated group may be related to the development of nephrotoxicity in the long term and may be a useful marker in predicting the early development of nephrotoxicity in these patients.

Cadmium telluride detectors in the external measurement of glomerular filtration rate using 99mTc-DTPA (Sn): comparison with 51Cr-EDTA and 99mTc-DTPA (Sn) plasma sample methods.

GFR was determined in 16 patients using an external detector to monitor disappearance of a single injected dose of 99mTc-DTPA (Sn) simultaneously with determinations of GFR using plasma sample methods for 99mTc-DTPA (Sn) and 51Cr-EDTA. Values of GFR were correlated closely between the external determinations of GFR and the plasma sample methods of 51Cr-EDTA and 99mTc-DTPA (Sn) with correlation coefficients of 0.97 and 0.99, respectively. Although the external detector method is apparently accurate, its advantages are as yet insufficient to warrant its adoption as the method of choice for determination of GFR.