Hydralazine-induced anti-neutrophil cytoplasmic antibody-positive renal vasculitis presenting with a vasculitic syndrome, acute nephritis and a puzzling skin rash: a case report.

INTRODUCTION: Anti-neutrophil cytoplasmic antibody-associated vasculitis has been associated with many drugs and it is a relatively rare side effect of the antihypertensive drug hydralazine. The diagnosis and management of patients who have anti-neutrophil cytoplasmic antibody-associated vasculitis may be challenging because of its relative infrequency, variability of clinical expression and changing nomenclature. The spectrum of anti-neutrophil cytoplasmic antibody-associated vasculitis is wide and can be fatal. This case documents a 62-year-old woman who presented with hydralazine-induced anti-neutrophil cytoplasmic antibody-positive renal vasculitis with a puzzling cutaneous rash. CASE PRESENTATION: We report a rare case of hydralazine-induced anti-neutrophil cytoplasmic antibody-associated vasculitis in a 62-year-old Caucasian woman who presented with a vasculitic syndrome with a sore throat, mouth ulcers and otalgia after several months of constitutional symptoms. She then proceeded to develop a rash over her right lower limb. Clinically, the rash had features to suggest Sweet's syndrome, but also had some appearances consistent with embolic phenomena and did not have the appearance of palpable purpure usually associated with cutaneous vasculitis. Differential diagnoses were hydralazine-associated Sweet's syndrome, streptococcal-induced cutaneous eruption or an unrelated contact dermatitis. A midstream urine sample detected glomerular blood cells in the setting of anti-neutrophil cytoplasmic antibody-positive renal vasculitis and Streptococcus pyogenes bacteremia. A renal biopsy revealed a pauci-immune, focally necrotizing glomerulonephritis with small crescents. Her skin biopsy revealed a heavy neutrophil infiltrate involving the full thickness of the dermis with no evidence of a leucocytoclastic vasculitis, but was non-specific. She was initially commenced on intravenous lincomycin for her bloodstream infection and subsequently commenced on immunosuppression after cessation of hydralazine. The patient was subsequently discharged from hospital after a rapid clinical improvement. CONCLUSION: Hydralazine-induced anti-neutrophil cytoplasmic antibody-positive renal vasculitis is a rare adverse effect and can present with a severe vasculitic syndrome with multiple organ involvement. Features of this association include the presence of high titres of anti-myeloperoxidase-anti-neutrophil cytoplasmic antibody with multi-antigenicity, positive anti-histone antibodies and the lack of immunoglobulin and complement deposition histopathogically. A rash that is characteristic of Sweet's syndrome has also been described as an association. Prompt cessation of hydralazine may be sufficient to reverse disease activity but immunosuppression may be needed for definite treatment.

A randomized controlled trial of oral heme iron polypeptide versus oral iron supplementation for the treatment of anaemia in peritoneal dialysis patients: HEMATOCRIT trial.

BACKGROUND: Preliminary clinical evidence suggests that heme iron polypeptide (HIP) might represent a promising, novel oral iron supplementation strategy in chronic kidney disease. The aim of this multi-centre randomized controlled trial was to determine the ability of HIP administration to augment iron stores in darbepoetin (DPO)-treated patients compared with conventional oral iron supplementation. METHODS: Adult peritoneal dialysis (PD) patients treated with DPO were randomized 1:1 to receive two capsules daily of either HIP or ferrous sulphate per os for 6 months. The primary outcome measure was transferrin saturation (TSAT). Secondary outcomes comprised serum ferritin, haemoglobin, DPO dose and responsiveness, and adverse events. RESULTS: Sixty-two patients were randomized to HIP (n = 32) or ferrous sulphate (n = 30). On intention-to-treat analysis, the median (inter-quartile range) TSAT was 22% (16-29) in the HIP group compared with 20% (17-26) in controls (P = 0.65). HIP treatment was not significantly associated with TSAT at 6 months on multivariable analysis (P = 0.95). Similar results were found on per-protocol analysis and subgroup analysis in iron-deficient patients. Serum ferritin levels at 6 months were significantly lower in the HIP group (P = 0.003), while the cost of HIP was 7-fold higher than that of ferrous sulphate. No other differences in secondary outcomes were observed. CONCLUSIONS: HIP showed no clear safety or efficacy benefit in PD patients compared with conventional oral iron supplements. The reduction in serum ferritin levels and high costs associated with HIP therapy suggest that this agent is unlikely to have a significant role in iron supplementation in PD patients.

A randomized controlled trial of intravenous or oral iron for posttransplant anemia in kidney transplantation.

BACKGROUND: Anemia after kidney transplantation has been associated with poor transplant outcomes. We hypothesized that intravenous (IV) iron may more rapidly correct anemia than oral (PO) iron. METHODS: One hundred four kidney transplant recipients were prospectively randomized to IV iron polymaltose (500 mg single dose) or PO ferrous sulfate (210 mg elemental iron daily, continuously). The primary outcome was time to resolution of anemia, defined as hemoglobin more than or equal to 11 g/dL. Secondary outcomes included infections, blood transfusions, gastrointestinal side-effects, and acute rejection. RESULTS: There was no significant difference in the primary outcome comparing IV with PO iron (hazards ratio 1.22; 95% confidence interval 0.82-1.83; P=0.32). The median time to resolution of anemia was 12 days in the IV group versus 21 days in the PO group. There were no differences in infections (20% vs. 24%, P=0.62), acute rejection (8% vs. 6%, P=0.68), blood transfusions (10% vs. 18%, P=0.24), and severe gastrointestinal side-effects (6% vs. 12%, P=0.29) between the IV iron and the PO iron groups. CONCLUSIONS: We conclude that a single dose of IV iron did not result in more rapid resolution of anemia compared with PO iron. Both IV and PO iron are safe and effective in the management of posttransplant anemia.

Cardiac and vascular structure and function parameters do not improve with alternate nightly home hemodialysis: an interventional cohort study.

BACKGROUND: Nightly extended hours hemodialysis may improve left ventricular hypertrophy and function and endothelial function but presents problems of sustainability and increased cost. The effect of alternate nightly home hemodialysis (NHD) on cardiovascular structure and function is not known. METHODS: Sixty-three patients on standard hemodialysis (SHD: 3.5-6 hours/session, 3-5 sessions weekly) converted to NHD (6-10 hours/session overnight for 3-5 sessions weekly). 2Dimensional transthoracic echocardiography and ultrasound measures of brachial artery reactivity (BAR), carotid intima-media thickness (CIMT), total arterial compliance (TAC) and augmentation index (AIX) were performed post dialysis at baseline and 18-24 months following conversion to NHD. In 37 patients, indices of oxidative stress: plasma malonyldialdehyde (MDA) and anti-oxidant enzymes: catalase (CAT), glutathione peroxidase (GPX) and superoxide dismutase (SOD) activity and total antioxidant status (TAS) were measured at baseline, 3 and 6 months. RESULTS: Left ventricular mass index (LVMI) remained stable. Despite significant derangement at baseline, there were no changes in diastolic function measures, CIMT, BAR and TAC. AIX increased. Conversion to NHD improved bone mineral metabolism parameters and blood pressure control. Interdialytic weight gains increased. No definite improvements in measures of oxidative stress were demonstrated. CONCLUSIONS: Despite improvement in uremic toxin levels and some cardiovascular risk factors, conversion to an alternate nightly NHD regimen did not improve cardiovascular structure and function. Continuing suboptimal control of uremic toxins and interdialytic weight gains may be a possible explanation. This study adds to the increasing uncertainty about the nature of improvement in cardiovascular parameters with conversion to intensive hemodialysis regimens. Future randomized controlled trials will be important to determine whether increases in dialysis session duration, frequency or both are most beneficial for improving cardiovascular disease whilst minimizing costs and the impact of dialysis on quality of life.

Do aluminium-based phosphate binders continue to have a role in contemporary nephrology practice?

BACKGROUND: Aluminium-containing phosphate binders have long been used for treatment of hyperphosphatemia in dialysis patients. Their safety became controversial in the early 1980's after reports of aluminium related neurological and bone disease began to appear. Available historical evidence however, suggests that neurological toxicity may have primarily been caused by excessive exposure to aluminium in dialysis fluid, rather than aluminium-containing oral phosphate binders. Limited evidence suggests that aluminium bone disease may also be on the decline in the era of aluminium removal from dialysis fluid, even with continued use of aluminium binders. DISCUSSION: The K/DOQI and KDIGO guidelines both suggest avoiding aluminium-containing binders. These guidelines will tend to promote the use of the newer, more expensive binders (lanthanum, sevelamer), which have limited evidence for benefit and, like aluminium, limited long-term safety data. Treating hyperphosphatemia in dialysis patients continues to represent a major challenge, and there is a large body of evidence linking serum phosphate concentrations with mortality. Most nephrologists agree that phosphate binders have the potential to meaningfully reduce mortality in dialysis patients. Aluminium is one of the cheapest, most effective and well tolerated of the class, however there are no prospective or randomised trials examining the efficacy and safety of aluminium as a binder. Aluminium continues to be used as a binder in Australia as well as some other countries, despite concern about the potential for toxicity. There are some data from selected case series that aluminium bone disease may be declining in the era of reduced aluminium content in dialysis fluid, due to rigorous water testing. SUMMARY: This paper seeks to revisit the contemporary evidence for the safety record of aluminium-containing binders in dialysis patients. It puts their use into the context of the newer, more expensive binders and increasing concerns about the risks of calcium binders, which continue to be widely used. The paper seeks to answer whether the continued use of aluminium is justifiable in the absence of prospective data establishing its safety, and we call for prospective trials to be conducted comparing the available binders both in terms of efficacy and safety.

The impact of extended-hours home hemodialysis and buttonhole cannulation technique on hospitalization rates for septic events related to dialysis access.

Few studies adequately document adverse events in patients receiving long, slow, and overnight hemodialysis (NHD). Concerns about high rates of dialysis access complications have been raised. This is an observational cohort study comparing hospital admission rates for vascular access complications between alternate nightly NHD (n=63) and conventional hemodialysis (n=172) patients established on chronic hemodialysis for at least 3 months. Overall, hospital admission rates and hospital admission rates for cardiac and all infective events are also reported. The NHD cohort was younger and less likely to be female, diabetic, or have ischemic heart disease than the conventional hemodialysis cohort. When NHD and buttonhole cannulation technique were used simultaneously, there was a demonstrated increased risk of septic dialysis access events: incidence rate ratio 3.0 (95% confidence interval 1.04-8.66) (P=0.04). The majority of blood culture isolates in NHD patients were gram-positive organisms, particularly Staphylococcus aureus. Alternate nightly NHD did not significantly change total hospital admissions or hospital admissions for indications other than dialysis access complications, compared with conventional hemodialysis. Our data suggest that buttonhole cannulation technique should be used with caution in patients performing extended-hours hemodialysis as this combination appears to increase the risk of septic access complications. Randomized-controlled trials are needed to confirm these findings.

Quality of life and alternate nightly nocturnal home hemodialysis.

Hemodialysis has been associated with reduced quality of life (QOL). Small cohort studies of quotidian hemodialysis regimens suggest general QOL and dialysis-related symptoms may improve compared with conventional regimens. An observational cohort study was conducted on 63 patients (age 51.7 +/- 12.9 years; 79.4% male; 33.3% diabetes; duration of renal replacement therapy 1.9 [0.7-6.4] years) converted from conventional home hemodialysis (3-5 sessions weekly, 3-6 h/session) to home nocturnal home hemodialysis (NHD) (3-5 sessions weekly, 6-10 h/session). Kidney Disease Quality of Life (KDQOL) and Assessment of Quality of Life instruments and 6-minute-walk tests were applied at baseline and 6 months. Baseline and 6 month surveys were returned by 70% of patients. On KDQOL, significant improvements in general health (P=0.02) and overall health ratings (P=0.0008), physical function (P=0.003), physical role (P=0.018), and energy and fatigue (P=0.027) were documented. There was a trend toward improvement in burden of kidney disease (P=0.05) and emotional role (P=0.066). There was a significant improvement in distance covered in the 6-minute-walk test from 513 m (420.5-576.4) to 536.5 m (459-609), P=0.007. On Assessment of Quality of Life, there was a trend toward improvement in overall utility score from 0.65 (0.39-0.81) to 0.73 (0.46-0.86), P=0.096. After 86.2 patient-years of observation, 23 patients have discontinued NHD (12 transplanted, 5 deceased, 4 psychosocial problems, 1 dialysis access problem, 1 medically unsuitable). Nocturnal home hemodialysis is a sustainable therapy. In addition to improving general QOL, alternate nightly NHD can significantly improve physical functioning as measured by KDQOL and 6-minute-walk tests.

Rationale and design of the oral HEMe iron polypeptide Against Treatment with Oral Controlled Release Iron Tablets trial for the correction of anaemia in peritoneal dialysis patients (HEMATOCRIT trial).

BACKGROUND: The main hypothesis of this study is that oral heme iron polypeptide (HIP; Proferrin ES) administration will more effectively augment iron stores in erythropoietic stimulatory agent (ESA)-treated peritoneal dialysis (PD) patients than conventional oral iron supplementation (Ferrogradumet). METHODS: Inclusion criteria are peritoneal dialysis patients treated with darbepoietin alpha (DPO; Aranesp(R), Amgen) for >or= 1 month. Patients will be randomized 1:1 to receive either slow-release ferrous sulphate (1 tablet twice daily; control) or HIP (1 tablet twice daily) for a period of 6 months. The study will follow an open-label design but outcome assessors will be blinded to study treatment. During the 6-month study period, haemoglobin levels will be measured monthly and iron studies (including transferring saturation [TSAT] measurements) will be performed bi-monthly. The primary outcome measure will be the difference in TSAT levels between the 2 groups at the end of the 6 month study period, adjusted for baseline values using analysis of covariance (ANCOVA). Secondary outcome measures will include serum ferritin concentration, haemoglobin level, DPO dosage, Key's index (DPO dosage divided by haemoglobin concentration), and occurrence of adverse events (especially gastrointestinal adverse events). DISCUSSION: This investigator-initiated multicentre study has been designed to provide evidence to help nephrologists and their peritoneal dialysis patients determine whether HIP administration more effectively augments iron stores in ESP-treated PD patients than conventional oral iron supplementation. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry number ACTRN12609000432213.

Intravenous versus oral iron supplementation for correction of post-transplant anaemia in renal transplant patients.

BACKGROUND: Post-transplant anaemia remains a common problem after kidney transplantation, with an incidence ranging from nearly 80% at day 0 to about 25% at 1 year. It has been associated with poor graft outcome, and recently has also been shown to be associated with increased mortality.Our transplant unit routinely administers oral iron supplements to renal transplant recipients but this is frequently accompanied by side effects, mainly gastrointestinal intolerance. Intravenous iron is frequently administered to dialysis patients and we sought to investigate this mode of administration in transplant recipients after noticing less anaemia in several patients who had received intravenous iron just prior to being called in for transplantation. METHODS: This study is a single-centre, prospective, open-label, randomised, controlled trial of oral versus intravenous iron supplements in renal transplant recipients and aims to recruit approximately 100 patients over a 12-month period. Patients will be randomised to receive a single dose of 500 mg iron polymaltose (intravenous iron group) or 2 ferrous sulphate slow-release tablets daily (oral iron group). The primary outcome is time to normalisation of haemoglobin post-transplant. Prospective power calculations have indicated that a minimum of 48 patients in each group would have to be followed up for 3 months in order to have a 90% probability of detecting a halving of the time to correction of haemoglobin levels to > or =110 g/l in iron-treated patients, assuming an alpha of 0.05. All eligible adult patients undergoing renal transplantation at the Princess Alexandra Hospital will be offered participation in the trial. Exclusion criteria will include iron overload (transferrin saturation >50% or ferritin >800 microg/l), or previous intolerance of either oral or intravenous iron supplements. DISCUSSION: If the trial shows a reduction in the time to correction of anaemia with intravenous iron or less side effects than oral iron, then intravenous iron may become the standard of treatment in this patient group.

Intradermal versus intramuscular hepatitis B vaccination in hemodialysis patients: a prospective open-label randomized controlled trial in nonresponders to primary vaccination.

BACKGROUND: Primary hepatitis B virus (HBV) vaccination through the intramuscular (IM) route is less efficacious in dialysis patients than in the general population. Previous studies suggest improved seroconversion with intradermal (ID) vaccination. STUDY DESIGN: Prospective open-label randomized controlled trial. SETTING & PARTICIPANTS: Hemodialysis patients nonresponsive to primary HBV vaccination. INTERVENTION: Revaccination with either ID (10 microg of vaccine every week for 8 weeks) [DOSAGE ERROR CORRECTED] or IM (40 microg of vaccine at weeks 1 and 8) HBV vaccine . PRIMARY OUTCOME: proportion of patients achieving HBV surface antibody (anti-HBs) titer of 10 IU/L or greater within 2 months of vaccination course. SECONDARY OUTCOMES: time to seroconversion, predictors of seroconversion, peak antibody titer, duration of seroprotection, and safety and tolerability of vaccine. MEASUREMENTS: Anti-HBs titer to 24 months. RESULTS: 59 patients were analyzed. Seroconversion rates were 79% ID versus 40% IM (P = 0.002). The unadjusted odds ratio for seroconversion for ID versus IM was 5.5 (95% confidence interval [CI], 1.6 to 18.4) and increased with adjustment for baseline differences. The only factor predictive of seroconversion was the ID vaccination route. The geometric mean peak antibody titer was significantly greater in the ID versus IM group: 239 IU/L (95% CI, 131 to 434) versus 78 IU/L (95% CI, 36 to 168; P < 0.001). There was a trend toward longer duration of seroprotection with ID vaccination. ID vaccine was safe and well tolerated. LIMITATIONS: Inability to distinguish whether the mechanism of the greater efficacy of ID vaccination was the cumulative effect of multiple injections or route of administration; use of anti-HBs as a surrogate marker of protection; lack of evidence of long-term protection. CONCLUSIONS: Significantly greater seroconversion rates and peak antibody titers can be achieved with ID compared with IM vaccination in hemodialysis patients nonresponsive to primary vaccination. ID vaccination should become the standard of care in this setting.

Mineral metabolism, bone histomorphometry and vascular calcification in alternate night nocturnal haemodialysis.

BACKGROUND: Poor control of bone mineral metabolism (BMM) is associated with renal osteodystrophy and mortality in dialysis-dependent patients. The authors explored the efficacy of alternate nightly home haemodialysis (ANHHD) in controlling BMM parameters and its effects on bone mineral density and histomorphometry. METHODS: In this prospective observational study, 26 patients on home haemodialysis (3-5 h, 3.5-4 sessions weekly) were converted to ANHHD (6-9 h, 3.5-4 sessions weekly). Biochemical parameters of BMM at baseline, 6 and 12 months, radiological parameters at baseline and 12 months and bone histomorphometry at 12 months are described. RESULTS: Pre-dialysis serum phosphate fell from 2.13+/-0.65 to 1.38+/-0.35 mmol/L; P<0.0001. No binders were required in 77.2% compared with 7.7% at baseline. Calcium-phosphate product fell from 5.28+/-1.64 to 3.42+/-0.88 mmol2/L2; P<0.0001 and parathyroid hormone (PTH) from 301 (110-471) to 127 (47-240) ng/L; P=0.01. Bone mineral density remained stable. Vascular and ectopic calcification improved or stabilized in 87.5%. Bone histomorphometry at 12 months showed high, normal and low bone turnover in 10, 3 and 4 patients, respectively, with 6/17 patients having abnormal mineralization. CONCLUSION: Alternate nightly home haemodialysis effectively manages biochemical parameters of BMM. Patients with very high PTH at baseline (>1000 ng/L) did not significantly improve parathyroid hormone status. Abnormal bone turnover and mineralization were present in a significant proportion of patients at 12 months but low turnover was uncommon. Vascular calcification was stabilized or improved in the majority. ANHHD compares favourably with every night and short daily therapy in relation to BMM management and may offer lifestyle advantages for patients.