Introduction to therapeutic plasma exchange.

This review article discusses the history and the evolution of plasmapheresis including its application in certain medical conditions through Evidence-Based Approach.

The vasopressin system: new insights for patients with kidney diseases: Epidemiological evidence and therapeutic perspectives.

People with chronic kidney disease (CKD) are at risk of severe outcomes, such as end-stage renal disease or cardiovascular disease, and CKD is a globally increasing health burden with a high personal and economic cost. Despite major progresses in prevention and therapeutics in last decades, research is still needed to reverse this epidemic trend. The regulation of water balance and the state of activation of the vasopressin system have emerged as factors tightly associated with kidney health, in the general population but also in specific conditions; among them, various stages of CKD, diabetes and autosomal dominant polycystic kidney disease (ADPKD). Basic science findings and also epidemiological evidence have justified important efforts towards interventional studies supporting causality, and opening therapeutic avenues. On the basis of recent clinical data, the blockade of V2 vasopressin receptors using tolvaptan in patients with rapidly progressing ADPKD has been granted in several countries, and a long-term randomized trial evaluating the effect of an increase in water intake in patients with CKD is on-going.

Verotoxigenic Escherichia coli: costs of illness in Canada, including long-term health outcomes.

The main objective of this study was to provide cost estimates of human Escherichia coli O157 infection to facilitate future assessment of the benefits and costs of alternative preventive strategies to reduce illness. We investigated the costs of illness to Canadians from primary human infection by verotoxigenic E. coli O157 (also called Shiga toxin-producing E. coli O157) using data from the National Notifiable Diseases Registry. We used relative risk information from peer-reviewed publications to estimate the burden of illness and associated costs for eight long-term health outcomes. National estimates of the number of cases (mean and 5th and 95th percentiles), associated costs, and a rank correlation test to identify which outcomes were associated with the highest per capita costs were calculated. An estimated 22,344 cases of primary infections occur in Canada annually, costing $26.7 million. There are 37,867 additional on-going long-term health outcomes costing $377.2 million each year. Our analysis indicated that the annual cost for primary and long-term illness is $403.9 million. The analysis supports evaluation of alternative control and prevention measures and the development and implementation of policy and practices aimed at safe food production.

ADAMTS-13 may not predict disease or outcome in patients with Thrombotic Thrombocytopenic Purpura.

BACKGROUND: The pathophysiology of Thrombotic Thrombocytopenia Purpura (TTP) has been questioned since described in 1924. In 1998, Tsai [1] and Furlan [2] demonstrated a relationship of low levels of ADAMTS-13 with an IgG inhibitor in acquired idiopathic TTP. This study reports on a series of TTP patients treated with solvent/detergent plasma (SDP) or cryosupernatant plasma (CSP) and focuses on the correlation of their presentation, clinical response and outcome with the levels of ADAMTS-13, the inhibitor and VWF multimers. METHODS: Plasma exchange was carried out in patients with the clinical diagnosis of acquired idiopathic TTP. ADAMTS-13 enzyme activity and inhibitor levels, VWF multimers and platelet count were analyzed in correlation with patient outcome. This RCT was intended to compare outcome in 280 patients treated either with cryosupernatant or solvent-detergent heated plasmas. The primary end point was survival at six months. RESULTS: Data on 61 TTP patients were obtained from 16 centres across Canada. The study was then closed prematurely due to removal of one of the interventional products from the market. ADAMTS-13 enzyme activity and inhibitor levels varied considerably among study participants. At baseline, only 12/49 (24.5%) had ≤10% enzyme activity and 20/49 (41%) had levels ≥80%; whereas 16/49 had ≥80% inhibitors; 19/49 had ≤10% inhibitors 18/49 (37%) had no inhibitors. No unusually large VWF multimers were identified in any of the patients at presentation. The 6-month, all-cause mortality rates for patients randomized to receive CSP vs. SDP were 3/34 (9%; 95% CI: 3%, 23%) and 1/27 (4%; 95% CI: 1%, 18%), respectively, with a difference of 5% (95% CI: -11%, 20%). CONCLUSION: Although this study was underpowered to compare solvent/detergent vs. cryosupernatant plasma, our data suggest that ADAMTS-13 activity and inhibitor level at baseline cannot differentiate TTP response to plasma exchange therapy.

Ustekinumab associated thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder. Plasma exchange therapy has been shown to significantly reduce mortality in patients with TTP. Here, we report a case of TTP associated with ustekinumab therapy after a period of 2-3 years. Ustekinumab, a monoclonal antibody that inhibits interleukin 12 and interleukin 23, is one of the newer treatments for psoriasis. Although our patient experienced a prolonged course of TTP requiring 1 month of daily plasma exchange therapy, he recovered and remains in remission after 6 months.

Plasma exchange for renal disease: evidence and use 2011.

Over the past 37 year the role of plasma exchange in the treatment of patients with renal disease has undergone several changes. The majority of the changes for the use of plasma exchange relied on randomized control trials and delineations of mechanisms that potentially would benefit from the use of plasma exchange. Over the past 11 years plasma exchange indications for renal disease, the absolute numbers have been relatively unchanged but the indications are quite different. The Canadian Apheresis Group indicated in 2010 that TTP/HUS is still the number 1 indication at 63% of the total plasma exchange activity for renal disease but P and C ANCA Vasculitis had risen to 14% followed by renal transplant at 10%, Goodpasture's Syndrome at 6% and transplant FSGS at 5% with Cryoglobulinemia 2% and Myeloma Nephropathy had dropped dramatically to less than 1% with no cases of SLE reported. This report describes the most common indications for plasma exchange in patient's with renal disease and the evidence that supports it's use in 2011.

Clustering and stability of functional lower gastrointestinal symptom after enteric infection.

BACKGROUND: Current diagnostic criteria for functional gut disorder are based on symptom clusters observed after sporadic onset. It remains unclear whether symptoms group similarly in functional disorders of postinfectious etiology. We utilized observational data from the Walkerton Health Study (WHS) to: (i) determine groupings of functional gastrointestinal symptoms among patients exposed to acute gastroenteritis (GE), and (ii) assess the stability of these symptoms grouping over time. METHODS: WHS participants 16 years of age and older at the time of the outbreak were included, if they had completed a modified Talley's Bowel Disease Questionnaire (BDQ) and responded 'yes' to a screening question as to whether they had experienced abdominal pain in the last 2 weeks. Exploratory factor analysis (EFA) using tetrachoric correlations was undertaken to identify symptom constructs. Hierarchical cluster analysis using the k-means method was used to create cluster groupings of patients based on these factors. Confirmatory factors analysis using responses to BDQ questionnaire administered at 4, 6, and 8 years after the outbreak was performed to assess stability of symptom domains over time. KEY RESULTS: A total of 773 participants were eligible for inclusion [62.2% female, mean age 43.1 years (SD = 16.9)]. Eighty-four percent were exposed to acute GE during the outbreak. Two symptom groupings of abdominal pain with either diarrhea or constipation together explained 85.7% of the total variance. Cluster analysis identified four patients groupings based on these factors. These clusters could be qualitatively described as diarrhea- and constipation-predominant, mixed bowel pattern, and no predominance of bowel movements abnormalities. Results of the confirmatory factor analysis validating symptom domains identified in Year 1 showed that the baseline model was acceptable at 4 and 6 years after the outbreak and approached acceptability at 8 years. Values of root mean square error of approximation were 0.071 (90% CI: 0.053, 0.089) at 4 and 0.071 (90% CI: 0.049, 0.092) at 6 years and 0.089 (90% CI: 0.065, 0.114) at 8 years. CONCLUSIONS & INFERENCES: The majority of subjects with postinfectious functional bowel disorders belong to groups with symptoms of abdominal pain and either diarrhea or constipation. These symptom groupings were stable across time.

Plasma exchange for treating cryoglobulinemia: a descriptive analysis.

BACKGROUND: Cryoglobulinemia is an immune-complex-mediated systemic vasculitis involving small-to-medium-sized vessels. Plasmapheresis transiently removes the circulating cryoglobulins and has been advocated (in conjunction with immunosuppressive therapy) to be effective in reducing morbidities associated with cryoglobulinemia. The goal of this paper was to review over the past 20 years the medical literature for evidence supporting or refuting the reported use of plasmapheresis for cryoglobulinemia (January 1988 through June 2008). METHODS: We included all reported literature of the use of plasma exchange for the treatment of cryoglobulinemia that included at least five patients. Electronic searches were performed using MEDLINE (January 1988 through June 2008) and Cochrane Central Register of Controlled Trials (January 1988 through June 2008). RESULTS: Of the 11 articles included in this review, there were a total of 156 patients studied. Two studies used cryofiltration, one compared plasma exchange to double cascade filtration and the other eight dealt with plasma exchange only. Outcome measures were often not clearly defined. CONCLUSIONS: Although plasma exchange is an accepted treatment for cryoglobulinemia, there are no large multicentre randomized controlled trials of plasma exchange versus placebo or versus immunosuppressive therapy. Of the 11 studies from our literature search, none had a clear report of the apheresis procedures and clearly defined quantitative outcomes. The quality and variability of the evidence precludes a meta-analysis or even a systematic analysis. However, these studies weakly support the use of plasma exchange largely on a mechanistic basis.

Plasma exchange for myeloma kidney: cast(s) away?

Leung et al. (this issue) present a retrospective study of 40 patients. Observations in 14/40 led to the suggestion of restitution of plasma exchange for light-chain responsive, biopsy-proven myeloma kidney until a better randomized control trial (RCT) is constructed. A careful analysis of their study and a recent RCT suggest little difference in outcome between plasma exchange and control groups. The analysis supports restitution of a better RCT of plasma exchange for myeloma kidney rather than off-label use.

Arthritis risk after acute bacterial gastroenteritis.

OBJECTIVES: Reactive arthritis (ReA) may occur from bacterial gastroenteritis. We studied the risk of arthritis after an outbreak of Escherichia coli O157:H7 and Campylobacter species within a regional drinking water supply to examine the relationship between the severity of acute diarrhoea and subsequent symptoms of arthritis. METHODS: Participants with no known history of arthritis before the outbreak participated in a long-term follow-up study. Of the 2299 participants, 788 were asymptomatic during the outbreak, 1034 had moderate symptoms of acute gastroenteritis and 477 had severe symptoms that necessitated medical attention. The outcomes of interest were new arthritis by self-report and a new prescription of medication for arthritis during the follow-up period. RESULTS: After a mean follow-up of 4.5 yrs after the outbreak, arthritis was reported in 15.7% of participants who had been asymptomatic during the outbreak, and in 17.6 and 21.6% of those who had moderate and severe symptoms of acute gastroenteritis, respectively (P-value for trend = 0.009). Compared with the asymptomatic participants, those with moderate and severe symptoms of gastroenteritis had an adjusted relative risk of arthritis of 1.19 [95% confidence interval (CI) 0.99-1.43] and 1.33 (95% CI 1.07-1.66), respectively. No association was observed between gastroenteritis and the subsequent risk of prescription medication for arthritis (P = 0.49). CONCLUSIONS: Acute bacterial gastroenteritis necessitating medical attention was associated with a higher risk of arthritic symptoms, but not arthritic medications, up to 4 yrs afterwards. The nature and chronicity of these arthritic symptoms requires further study.

Absence of renal sequelae after childhood Escherichia coli O157:H7 gastroenteritis.

Although a quarter of children who survive diarrhea-associated hemolytic uremic syndrome develop long-term renal sequelae, the prognosis of acute, self-limited Escherichia coli O157:H7 gastroenteritis has never been previously studied. Four years after a drinking water outbreak of E. coli O157:H7, we examined the risk of high blood pressure (>95th percentile expected for age, sex, and height), reduced kidney function, and microalbuminuria among previously healthy children and adolescents. Of the 951 participants, 313 were asymptomatic during the outbreak, 305 had moderate symptoms of acute gastroenteritis, and 333 had severe symptoms that necessitated medical attention. An additional 23 children who developed hemolytic uremic syndrome during the outbreak were excluded from this analysis. There were no differences in mean systolic blood pressure between those who had no, moderate, or severe symptoms of acute gastroenteritis during the outbreak (109, 110, and 107 mm Hg). Similarly, there were no group differences in diastolic blood pressure, estimated glomerular filtration rate, or random urine albumin to creatinine ratio (P ranged from 0.14 to 0.52), or in the adjusted relative risk of high blood pressure, a glomerular filtration rate <80 ml/min per 1.73 m(2), or microalbuminuria (P ranged from 0.23 to 0.89). Patients who presented to medical attention with gastroenteritis during this E. coli O157:H7 outbreak had an absence of renal sequelae 4 years later. With no existing data to support screening after self-limited E. coli O157:H7 gastroenteritis, we recommend that only those children who develop recognized features of hemolytic uremic syndrome be followed for long-term renal health.

Thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome: a new index predicting response to plasma exchange.

Despite the favourable response of thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome (TTP/HUS) to plasma exchange, an early level of mortality persists. Non-response has been associated with a low frequency of exchange. The Rose index of TTP/HUS severity, occasionally used to predict the response of TTP/HUS to plasma exchange, remains unsatisfactory. The purpose of this study was to develop a new index predicting response of TTP/HUS to plasma exchange and to compare it with the Rose index. Retrospective analysis of 171 cases of TTP/HUS from 39 apheresis units across Canada between 1980 and 2001 was conducted. Logistic regression analysis was used to derive a model predicting 6-month mortality from presenting characteristics. The reduced model contained age >40 years, haemoglobin <9.0 g/dl and the presence of a fever at presentation. Gender, platelet count, creatinine and neurological signs were not part of the final model. This model predicted 13.4% of outcome variance. Predictive scores of 0, 2, 4 and 6 correlated with 6-month mortality rates of 12.5%, 14.0%, 31.3% and 61.5% respectively in our source population. This simple model may help identify those patients who would benefit from higher treatment intensity.

Association between renal insufficiency and malnutrition in older adults: results from the NHANES III.

BACKGROUND: The extent to which relevant confounding variables influence the recognized association between renal insufficiency and malnutrition is not known. This study examined whether renal insufficiency was associated with malnutrition, independent of relevant demographic, social, and medical conditions in noninstitutionalized adults 60 years of age and older. METHODS: Participants (5248) in the United States Third National Health and Nutrition Examination Survey (NHANES III, 1988 to 1994), a cross-sectional study, were examined in a multivariate logistic regression model. Participants were stratified into three groups of glomerular filtration rate (GFR) by serum creatinine. Dietary and nutritional factors were estimated from 24-hour dietary recall, biochemistry measurements, anthropometry, and bioelectrical impedance. Participants were malnourished if they demonstrated at least three of the following five criteria: (1) serum albumin < or =37 g/L, (2) male weight < or =63.9 kg, female weight < or =51.8 kg, (3) serum cholesterol <4.1 mmol/L, (4) energy intake <15 kcal/kg/day, and (5) protein intake <0.5 g/kg/day. RESULTS: A GFR <30 mL/min/1.73 m(2) was present in 2.3% of men and 2.6% of women; these participants demonstrated low energy and protein intake and higher serum markers of inflammation. Thirty-one percent of individuals with malnutrition demonstrated a GFR <60 mL/min/1.73 m(2). In multivariate analysis, a GFR <30 mL/min/1.73 m(2) was independently associated with malnutrition [odds ratio 3.6 (2.0 to 6.6)] after adjustment for relevant demographic, social and medical conditions. CONCLUSIONS: It is probable that renal insufficiency is an important independent risk factor for malnutrition in older adults. Malnutrition should be considered, prevented, and treated as possible in persons with clinically important renal insufficiency. These results should be confirmed in a prospective longitudinal cohort study.

Frequently relapsing thrombotic thrombocytopenic purpura treated with cytotoxic immunosuppressive therapy.

BACKGROUND AND OBJECTIVES: Treatment of thrombotic thrombocytopenic purpura (TTP) with plasma exchange has reduced mortality rates from 90% in untreated cases to less than 20%. Despite plasma exchange, relapses may occur in as many as 40% of cases. Multiple relapses occur in a minority but pose a significant therapeutic challenge. Recent evidence supports the presence of an autoantibody which inhibits proteolysis of von Willebrand factor (vWF) in active TTP, allowing large multimers of vWF to form and promote platelet aggregation. Additional evidence suggests autoantibodies activate capillary endothelium and promote platelet aggregation in the microcirculation. Immunosuppression, thus, has a biologically plausible role in TTP. We describe three consecutive cases of relapsing TTP treated with cytotoxic therapy to highlight the potential role of immunosuppression. DESIGN AND METHODS: Cytotoxic immunosuppressive therapy with either cyclophosphamide or azathioprine was used in three consecutive patients with frequently relapsing TTP. RESULTS: All three patients have maintained remissions of 8 to 10 months without recurrence. INTERPRETATION AND CONCLUSIONS: Cytotoxic immunosuppressive therapy may have a role in inducing long-term remissions in recurrent TTP.

Flaxseed in lupus nephritis: a two-year nonplacebo-controlled crossover study.

OBJECTIVE: The objective of this study was to determine the renoprotective effects of ground flaxseed in patients with lupus nephritis. METHODS: Forty patients with lupus nephritis were asked to participate in a randomized crossover trial of flaxseed. Twenty-three agreed and were randomized to receive 30 grams of ground flaxseed daily or control (no placebo) for one year, followed by a twelve-week washout period and the reverse treatment for one year. At baseline and six month intervals, serum phospholipids, flaxseed sachet counts, serum creatinine, 12-hour urine albumin excretion and urine albumin to creatinine ratios, serum viscosity and plasma lipids were measured. RESULTS: There were eight drop-outs and of the 15 remaining subjects flaxseed sachet count and serum phospholipid levels indicated only nine were adherent to the flaxseed diet. Plasma lipids and serum viscosity were unaltered by the flaxseed supplementation whereas serum creatinine in the compliant patients during flaxseed administration declined from a mean of 0.97+/-0.31 mg/dL to a mean of 0.94+/-0.30 mg/dL and rose in the control phase to a mean of 1.03+/-0.28 mg/dL [p value <0.08]. Of the fifteen patients who completed the study, similar changes were noted [p value <0.1]. The nine compliant patients had lower serum creatinines at the end of the two-year study than the 17 patients who refused to participate [p<0.05]. Microalbumin at baseline declined in both control and flaxseed time periods, but there was a trend for a greater decline during flaxseed administration [p<0.2]. CONCLUSIONS: Flaxseed appears to be renoprotective in lupus nephritis, but this interpretation is affected by under powering due to poor adherence and potential Hawthorne effects.

Pauci-immune renal vasculitis: natural history, prognostic factors, and impact of therapy.

The purpose of this study is to describe the clinical presentation and natural history of pauci-immune renal vasculitis and determine whether particular presenting features or administered therapies predict outcome. We reviewed our experience since 1984 with such vasculitides, and 94 cases of pauci-immune vasculitis were identified. Presenting features were as follows: men, 63%; mean age at biopsy, 59 years; and mean serum creatinine level, 5.0 mg/dL. Patients with no extrarenal involvement had a tendency to present with a greater serum creatinine level. Since the antineutrophil cytoplasmic autoantibody (ANCA) assay became available, 77% of the patients tested were ANCA positive. In terms of natural history, 27 patients required dialysis immediately, there were 22 renal relapses, 28 patients progressed to dialysis, 10 patients died before requiring dialysis, 19 patients were lost to follow-up, and 37 patients remain active, not on dialysis. Overall, half the patients recovered some renal function, one third remained stable, and one sixth deteriorated. Female sex and angiotensin-converting enzyme inhibitor use predicted favorable outcome (P < 0.05). Advanced age, male sex, respiratory tract involvement, and a greater relapse rate predicted unfavorable outcome (P < 0.05). The incidence of pauci-immune renal vasculitis appears to be increasing, likely related to the emergence of the ANCA assay. Attempts to classify patients based on existing schemes may result in delayed diagnosis and therapy, with subsequent poorer outcomes. Also, given the increased mortality of patients with respiratory tract involvement, we speculate that respiratory tract disease therapeutic and monitoring regimens are ineffective. In general, we conclude that pauci-immune renal vasculitis is a heterogeneous disorder with an unfavorable prognosis.

A novel treatment for lupus nephritis: lignan precursor derived from flax.

BACKGROUND: Flaxseed has renoprotective effects in animal and human lupus nephritis. We have recently extracted the lignan precursor (secoisolariresinol diglucoside) (SDG) to determine if this more palatable derivative of flaxseed would exert renoprotection similar to the whole flaxseed in the aggressive MRL/lpr lupus mouse model. METHODS: 131 MRL/lpr mice were randomly assigned to saline gavage, 600, 1,200 and 4,800 microg lignan gavage groups. At 7 weeks, 6 animals underwent platelet aggregating factor (PAF) lethal challenge and 40 were studied with urine collection to determine the levels of secoisolariresinol, enterodiol and enterolactone in the gavaged animals. A baseline study of 10 saline gavaged animals took place at 6 weeks. 25 animals in the saline gavage, 600 and 1200 microg lignan groups were studied at 14 and 22 weeks for GFR, spleen lymphocyte S-phase and organ weight studies. RESULTS: Metabolic studies indicated that secoisolariresinol is the major metabolite absorbed and the lowest lignan dose provides a lengthening in survival for the PAF lethal challenge. Body weight, fluid and water intake studies demonstrated that the lignan was well tolerated. Changes in proteinuria, GFR and renal size showed a time- and dose-dependent protection for the lignan precursor. Cervical lymph node size and spleen lymphocyte cells in the S-phase demonstrated modest dose-dependent reductions in the lignan gavaged groups. CONCLUSION: SDG was converted in the gut to secoisolariresinol, which was absorbed and well tolerated by the MRL/lpr mice. Renoprotection was evidenced, in a dose-dependent fashion, by a significant delay in the onset of proteinuria with preservation in GFR and renal size. This study suggests that SDG may have a therapeutic role in lupus nephritis.

To pay or not to pay? A decision and cost-utility analysis of angiotensin-converting-enzyme inhibitor therapy for diabetic nephropathy.

BACKGROUND: Angiotensin-converting-enzyme (ACE) inhibitor therapy can significantly delay the progression of diabetic nephropathy to end-stage renal failure (ESRF). The main obstacle to successful compliance with this therapy is the cost to the patients. The authors performed a cost-utility analysis from the government's perspective to see whether the province or territory should pay for ACE inhibitors for type I diabetic nephropathy on the assumption that cost is a major barrier to compliance with this important therapy. METHODS: A decision analysis tree was created to demonstrate the progression of type I diabetes with macroproteinuria from the point of prescription of ACE inhibitor therapy through to ESRF management, with a 21-year follow-up. Drug compliance, cost of ESRF treatment, utilities and survival data were taken from Canadian sources and used in the cost-utility analysis. One-way and two-way sensitivity analyses were performed to test the robustness of the findings. RESULTS: Compared with a no-payment strategy, provincial payment of ACE inhibitor therapy was found to be highly cost-effective: it resulted in an increase of 0.147 in the number of quality-adjusted life-years (QALYs) and an annual cost savings of $849 per patient. The sensitivity analyses indicated that the cost-effectiveness depends on compliance, effect of benefit and the cost of drug therapy. Changes in the compliance rate from 67% to 51% could result in a swing in cost-effectiveness from a savings of $899 to an expenditure of more than $1 million per additional QALY. A 50% reduction in the cost of ACE inhibitors would result in a cost savings of $299 per additional QALY with compliance rates as low as 58% in the provincial payment strategy. INTERPRETATION: Provincial coverage of ACE inhibitor therapy for type I diabetes with macroproteinuria improves patient outcomes, with a decrease in cost for ESRF services.