Successful simultaneous liver-kidney transplantation for renal failure associated with hereditary complement C3 deficiency.

Hereditary complement C3 deficiency is associated with recurrent bacterial infections and proliferative glomerulonephritis. We describe a case of an adult with complete deficiency of complement C3 due to homozygous mutations in C3 gene: c.1811delT (Val604Glyfs*2), recurrent bacterial infections, crescentic glomerulonephritis, and end-stage renal failure. Following isolated kidney transplantation he would remain C3 deficient with a similar, or increased, risk of infections and glomerulonephritis. As C3 is predominantly synthesized in the liver, with a small proportion of C3 monocyte derived and kidney derived, he proceeded to simultaneous liver-kidney transplantation. The procedure has been successful with restoration of his circulating C3 levels, normal liver and kidney function at 26 months of follow-up. Simultaneous liver-kidney transplant is a viable option to be considered in this rare setting.

Hydroxycloroquine blood concentration in lupus nephritis: a determinant of disease outcome?

Background: Hydroxychloroquine (HCQ) is a recommended drug in systemic lupus erythematosus (SLE). It has a long terminal half-life, making it an attractive target for therapeutic drug monitoring. The aim of this study was to establish a relationship between blood HCQ concentration and lupus nephritis activity. Methods: We conducted a retrospective observational study with data collected from clinical and laboratory records. Inclusion criteria were patients followed in the lupus clinic with biopsy-proven International Society of Nephrology/Renal Pathology Society Classes III, IV or V lupus nephritis on HCQ for at least 3 months (200-400 mg daily) and with HCQ levels measured during treatment. Exclusion criteria were patients on renal replacement therapy at baseline or patients lost to follow-up. Results: In 171 patients, the HCQ level was measured in 1282 samples. The mean HCQ blood level was 0.75±0.54mg/L and it was bimodally distributed. An HCQ level <0.20 mg/L [232 samples (18.1%)] appeared to define a distinct group of abnormally low HCQ levels. For patients in complete or partial remission at baseline compared with those remaining in remission, patients with renal flare during follow-up had a significantly lower average HCQ level (0.59 versus 0.81 mg/L; P= 0.005). Our data suggest an HCQ target level to reduce the likelihood of renal flares >0.6 mg/L (600 ng/mL) in those patients with lupus nephritis. Conclusion: HCQ level monitoring may offer a new approach to identify non-adherent patients and support them appropriately. We propose an HCQ minimum target level of at least 0.6 mg/L to reduce the renal flare rate, but this will require a prospective study for validation.

Long-term outcome of anti-neutrophil cytoplasm antibody-associated glomerulonephritis: evaluation of the international histological classification and other prognostic factors.

BACKGROUND: Anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis with renal involvement requires treatment with potentially toxic drugs to reduce morbidity and mortality, and there is a major challenge to determine clinical and histological features predictive of renal prognosis. The aim of our study was to evaluate the use of the 2010 international histological classification for ANCA-associated glomerulonephritis (AAGN) as a predictor of renal outcome when used in conjunction with other prognostic factors. METHODS: One hundred and four patients with AAGN treated at our centre were included: 23 were classified as focal, 26 as crescentic, 48 as mixed and 7 as sclerotic. Renal outcomes were based on estimated glomerular filtration rate (eGFR) at 1 and 5 years, and on renal survival. RESULTS: By univariate analysis, patients in the focal class had the best renal outcome, those in the sclerotic class the worst outcome, and those in the mixed and crescentic classes had intermediate renal survival. There was no significant difference in outcome between the mixed and crescentic classes. In multivariate models, histological class did not improve model fit or associate with renal outcome after adjusting for established prognostic factors. Lower percentage of normal glomeruli, greater degree of tubular atrophy (TA), MPO-ANCA positivity, increasing age and lower starting eGFR, all correlated with poorer renal outcomes. CONCLUSIONS: We conclude that, in our cohort of patients, the international histological classification is predictive of renal outcome in AAGN, but did not appear to be additionally informative over other established prognostic factors in multivariate analysis. However, it may be of value to combine the current histological classification with other established parameters, such as TA and percentage normal glomeruli.

Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids.

OBJECTIVES: Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE). All current treatment regimens include oral steroids, which are associated with severe adverse events and long-term damage. We have piloted a steroid-avoiding protocol (rituxilup) for the treatment of biopsy-proven active International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III, IV, or class V LN. METHODS: We report the findings from the first 50 consecutive patients, treated with 2 doses of rituximab (1 g) and methyl prednisolone (500 mg) on days 1 and 15, and maintenance treatment of mycophenolate mofetil. Patients on maintenance steroids or with life-threatening SLE or requiring dialysis were excluded. Renal remission was defined as serum creatinine no greater than 15% above baseline; complete biochemical remission (CR) was defined as urine protein : creatinine ratio (PCR)<50 mg/mmol or partial remission (PR) if PCR>50 mg/mmol but non-nephrotic and >50% reduction. RESULTS: A total of 45 (90%) patients achieved CR or PR by a median time of 37 weeks (range 4-200). Overall, 72% (n=36) achieved CR (median time 36 weeks (11-58)) and a further 18% (n=9) achieved persistent PR (median time 32 weeks (19-58)). By 52 weeks, CR and PR had been achieved in 52% (n=26) and 34% (n=17) respectively. In all, 12 relapses occurred in 11 patients, at a median time of 65.1 weeks (20-112) from remission. A total of 6/50 patients had systemic flares. Of the 45 responders, only 2 required >2 weeks of oral steroids. Adverse events were infrequent; 18% were admitted, 10% for an infective episode. CONCLUSIONS: The rituxilup cohort demonstrates that oral steroids can be safely avoided in the treatment of LN. If findings are confirmed, it could mark a step change in the approach to the treatment of LN.

Cardiac survival after pre-emptive coronary angiography in transplant patients and those awaiting transplantation.

BACKGROUND AND OBJECTIVES: Recent interest has focused on wait listing patients without pretreating coronary artery disease to expedite transplantation. Our practice is to offer coronary revascularization before transplantation if indicated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Between 2006 and 2009, 657 patients (427 men, 230 women; ages, 56.5 ± 9.94 years) underwent pretransplant assessment with coronary angiography. 573 of 657 (87.2%) patients were wait listed; 247 of 573 (43.1%) patients were transplanted during the follow-up period, 30.09 ± 11.67 months. RESULTS: Patient survival for those not wait listed was poor, 83.2% and 45.7% at 1 and 3 years, respectively. In wait-listed patients, survival was 98.9% and 95.3% at 1 and 3 years, respectively. 184 of 657 (28.0%) patients were offered revascularization. Survival in patients (n = 16) declining revascularization was poor: 75% survived 1 year and 37.1% survived 3 years. Patients undergoing revascularization followed by transplantation (n = 51) had a 98.0% and 88.4% cardiac event-free survival at 1 and 3 years, respectively. Cardiac event-free survival for patients revascularized and awaiting deceased donor transplantation was similar: 94.0% and 90.0% at 1 and 3 years, respectively. CONCLUSIONS: Our data suggest pre-emptive coronary revascularization is not only associated with excellent survival rates in patients subsequently transplanted, but also in those patients waiting on dialysis for a deceased donor transplant.

Antibody-mediated rejection after alemtuzumab induction: incidence, risk factors, and predictors of poor outcome.

BACKGROUND: Antibody-mediated rejection (AMR) is associated with allograft loss. Identification of factors associated with poor outcome has not been extensively studied. METHODS: We retrospectively studied 469 patients who received a negative crossmatch renal transplant with alemtuzumab induction. Forty-eight of 469 (10.2%) patients were treated for AMR. Thirty of 48 (62.5%) of the cases fulfilled the Banff criteria for definite AMR, whereas 18 of 48 (37.5%) were categorized as suspicious for AMR (tissue injury with C4d staining or donor-specific antibodies [DSAbs]). Sensitization, high human leukocyte antigen, and -DR mismatch were risk factors for the development of AMR (P = 0.0016, 0.001, and 0.012, respectively). RESULTS: Allograft survival was inferior in the AMR group (70.2%) compared with the nonrejector group (97.0%) (P<0.001). Forty-two of 48 (87.5%) of patients with acute AMR had DSAbs. Patients with CII DSAbs at the time of AMR, whether alone or in combination with CI DSAbs had the worst allograft survival (P = 0.014). Both the mean cumulative and immunodominant mean fluorescence index were higher in those patients who subsequently lost their grafts (P<0.001). Patients with diffuse C4d staining had inferior allograft survival than those with focal C4d or no staining (P = 0.02). There was no significant difference in survival by histological grade but a trend to inferior outcomes in those with vascular involvement (P = 0.06). Those patients who met the full Banff criteria had worse survival than those with suspicion for AMR only (P = 0.04). CONCLUSION: This study identifies patients at risk of graft failure from AMR. These patients may benefit from newer therapeutic strategies including the use of eculizumab or bortezomib.

Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin.

Expression of hepcidin, the key hormone governing iron transport, is reduced by anemia in a manner which appears dependent on increased bone marrow activity. The temporal associations between plasma hepcidin and other iron parameters were examined in healthy humans after erythropoietin administration and venesection. Profound hepcidin suppression appeared abruptly 24 hours after subcutaneous erythropoietin (P=0.003), and was near maximal at onset, with peak (mid-afternoon) levels reduced by 73.2%, gradually recovering over the following two weeks. Minor changes in circulating iron, soluble transferrin receptor and growth differentiation factor-15 were observed after the reduction in hepcidin. Similar but more gradual changes in these parameters were observed after reducing hematocrit by removal of 250 mL blood. These human studies confirm the importance of a rapidly responsive marrow-hepcidin axis in regulating iron supply in vivo, and suggest that this axis is regulated by factors other than circulating iron, soluble transferrin receptor or growth differentiation factor-15.

Bacteremia associated with tunneled hemodialysis catheters: outcome after attempted salvage.

BACKGROUND AND OBJECTIVES: Treatment without catheter replacement (catheter salvage) has been described for bacteremia associated with tunneled venous catheters in hemodialysis patients, but few data are available on which to base an estimation of the likelihood of treatment success. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a prospective cohort study, all cases of catheter-associated bacteremia that occurred in a large dialysis center were identified during a 12-mo period. Catheter salvage was attempted according to a standard protocol in all cases in which a favorable early response to antibiotic therapy was seen, and patients were followed for at least 6 mo. Bacteremias, catheter changes, and all major clinical events were recorded. RESULTS: During a period covering 252,986 catheter days, 208 episodes were identified involving 133 patients, 74% of which were selected for attempted salvage. Salvage was successful in 66.1% of incident bacteremias with a very low complication risk (0.9%). Some bacteremias, however, recurred as late as 6 mo after the initial infection; salvage was less likely to be successful in treating recurrences. CONCLUSIONS: Appropriately used catheter salvage can be successful in approximately two thirds of cases; however, recurrences continue to occur up to 6 mo later and are unlikely to be cured without catheter replacement.

Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease.

Hepcidin is a critical inhibitor of iron export from macrophages, enterocytes, and hepatocytes. Given that it is filtered and degraded by the kidney, its elevated levels in renal failure have been suggested to play a role in the disordered iron metabolism of uremia, including erythropoietin resistance. Here, we used a novel radioimmunoassay for hepcidin-25, the active form of the hormone, to measure its levels in renal disease. There was a significant diurnal variation of hepcidin and a strong correlation to ferritin levels in normal volunteers. In 44 patients with mild to moderate kidney disease, hepcidin levels were significantly elevated, positively correlated with ferritin but inversely correlated with the estimated glomerular filtration rate. In 94 stable hemodialysis patients, hepcidin levels were also significantly elevated, but this did not correlate with interleukin-6 levels, suggesting that increased hepcidin was not due to a general inflammatory state. Elevated hepcidin was associated with anemia, but, intriguingly, the erythropoietin dose was negatively correlated with hepcidin, suggesting that erythropoietin suppresses hepcidin levels. This was confirmed in 7 patients when hepcidin levels significantly decreased after initiation of erythropoietin treatment. Our results show that hepcidin is elevated in renal disease and suggest that higher hepcidin levels do not predict increased erythropoietin requirements.

Ethnicity and survival on dialysis in west London.

BACKGROUND: Indo-Asian and Afro-Caribbean patients have higher rates of renal failure and requirement for renal replacement therapy than the general population in the UK. Despite this, information regarding survival on dialysis is limited. METHODS: The incident hemodialysis population of a large west London renal service was reviewed from 1996 to 2001 (N = 465). RESULTS: The cohort's ethnic background was Indo-Asian (30.8%), Caucasian (49%), Afro-Caribbean (18.3%), and other (1.9%). Indo-Asians and Afro-Caribbeans were younger than Caucasian patients, with a higher rate of diabetes mellitus. Survival on hemodialysis for Indo-Asians was 97.5% and 81.6% at 1 and 3 years, respectively, compared with 92.7% and 75.2% for Caucasians, and 97.5% and 85.3% for Afro-Caribbeans (P = nonsignificant). Dialysis adequacy was observed to be associated with survival. Patients with mean single pool Kt/V of over 1.4 had survival of 90.6% and 74.8% at 2 and 5 years, respectively, compared with 74.0% and 42.9% for those with Kt/V less than 1.4 (P < 0.001). There were significantly more patients in the Indo-Asian cohort with a mean Kt/V of 1.4 or over (87.4%) compared with Caucasians (57.6%) and Afro-Caribbeans (52.4%), and the benefit of higher Kt/V was seen in all ethnic groups. In a multivariate analysis of factors including Kt/V over 1.4, age, diabetic status, gender, and ethnicity, Indo-Asian or Afro-Caribbean ethnicity did not confer a survival disadvantage. The strongest predictors of survival were age and dialysis adequacy. CONCLUSION: Indo-Asian and Afro-Caribbean hemodialysis patients have survival comparable to Caucasians despite a higher burden of diabetes.

Outcome of renal transplantation in South Asian recipients is similar to that in non-Asians.

BACKGROUND: The United Kingdom has a large South Asian population, in which there is a high rate of renal disease and which forms a significant percentage of the renal transplant waiting list. Information about short- and long-term transplant outcomes in this ethnic group is limited, although it has been suggested that graft survival is poorer in this population compared with non-Asians. METHODS: The authors examined the outcome and determinants of medium-term (5-year) survival in 245 renal transplants, 53 of which were performed in South Asian patients between 1995 and 2002. RESULTS: Three-year survival with a functioning graft was 89% for the non-Asians and 85% for the South Asians. At 5 years, this deviated to 83% and 70%, respectively, for the two groups, but this did not reach statistical significance. Acute rejection rates were similar in the two groups. South Asian ethnicity was not a significant predictor of medium-term graft loss in the authors' study. CONCLUSIONS: In this cohort of patients, South Asian ethnic background did not confer a survival disadvantage after renal transplantation.