Hydration for health hypothesis: a narrative review of supporting evidence.

PURPOSE: An increasing body of evidence suggests that excreting a generous volume of diluted urine is associated with short- and long-term beneficial health effects, especially for kidney and metabolic function. However, water intake and hydration remain under-investigated and optimal hydration is poorly and inconsistently defined. This review tests the hypothesis that optimal chronic water intake positively impacts various aspects of health and proposes an evidence-based definition of optimal hydration. METHODS: Search strategy included PubMed and Google Scholar using relevant keywords for each health outcome, complemented by manual search of article reference lists and the expertise of relevant practitioners for each area studied. RESULTS: The available literature suggest the effects of increased water intake on health may be direct, due to increased urine flow or urine dilution, or indirect, mediated by a reduction in osmotically -stimulated vasopressin (AVP). Urine flow affects the formation of kidney stones and recurrence of urinary tract infection, while increased circulating AVP is implicated in metabolic disease, chronic kidney disease, and autosomal dominant polycystic kidney disease. CONCLUSION: In order to ensure optimal hydration, it is proposed that optimal total water intake should approach 2.5 to 3.5 L day-1 to allow for the daily excretion of 2 to 3 L of dilute (< 500 mOsm kg-1) urine. Simple urinary markers of hydration such as urine color or void frequency may be used to monitor and adjust intake.

Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis.

BACKGROUND: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS: Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).

Hydration Status and Kidney Health of Factory Workers Exposed to Heat Stress: A Pilot Feasibility Study.

Dehydration associated with heat stress increases the risk of workplace injury or illness, decreases productivity, and may contribute to the chronic kidney disease epidemic identified in outdoor workers from hot climates. There is limited research on the effects of chronic occupational heat stress among indoor workers. We aimed to test the feasibility of measuring markers of hydration and kidney function in foundry factory workers in Southern Brazil, exposed and not exposed to heat stress. Factory workers exposed to heat stress (wet bulb globe temperature ≥28.9) and not exposed to heat were identified by management and invited to participate. Clinical and biochemical markers of hydration and kidney function were evaluated before and after a single 8.5 h work shift (lunch time not included). Feasibility outcomes included rates of enrolment, % completion of study protocols, and time to complete data collection. This study was deemed feasible with 80% enrolment and 90% completion of the protocol. Among the preselected workers, the enrolment rate was 91%. All subjects completed the physiological measures and blood collection and 95% completed the urine studies. Mean time to complete data collection pre-shift was 19.1 ± 4.2 min and post-shift: 14.3 ± 4.0 min. Workers exposed to heat stress had a greater decline in estimated glomerular filtration rate compared to controls over the work shift (-13 ± 11 vs. -5 ± 7 mL/min; p < 0.01). We demonstrated the feasibility and challenges of conducting future hydration and kidney function research among indoor factory workers. Further study is needed to determine if exposure to indoor heat contributes to a decline in kidney function.

A matched case-control study to assess the association between non-steroidal anti-inflammatory drug use and thrombotic microangiopathy.

Several case reports suggest that non-steroidal anti-inflammatory drug (NSAID) use is associated with development of thrombotic microangiopathy (TMA). We conducted a matched population-based case-control study using linked administrative healthcare data in Ontario, Canada to assess the relationship between TMA hospitalization and recent exposure to prescription NSAIDs versus acetaminophen (acetaminophen was chosen as the referent drug because it has no known association with TMA). Cases and controls were drawn from a source population of adults who filled a prescription for either NSAIDs or acetaminophen between 1991 and 2015 (restricted to adults with prescription drug benefits [n = 3.6 million]). We identified 44 eligible cases with a hospital admission for incident TMA and a recent prescription for NSAIDs or acetaminophen. We successfully matched 38 cases (1:4) to 152 controls without TMA on demographics, risk factors for TMA, and indications for NSAID use. Cases and controls were similar with respect to age (71 years) and sex (63% women); however, on average, cases had more comorbidities than controls (12 vs. 14; p<0.05) and more primary care visits in the year before the index date (19 vs. 12; p<0.05). Cases were significantly less likely than controls to have received a recent prescription for NSAIDs (19/38 [50%] vs. 115/152 [76%], respectively; adjusted odds ratio 0.37, 95% confidence interval: 0.16 to 0.84). Results were similar in several sensitivity analyses. Overall, the results of this study do not support a harmful association between NSAID use and the development of TMA.

Effect of Coaching to Increase Water Intake on Kidney Function Decline in Adults With Chronic Kidney Disease: The CKD WIT Randomized Clinical Trial.

Importance: In observational studies, increased water intake is associated with better kidney function. Objective: To determine the effect of coaching to increase water intake on kidney function in adults with chronic kidney disease. Design, Setting, and Participants: The CKD WIT (Chronic Kidney Disease Water Intake Trial) randomized clinical trial was conducted in 9 centers in Ontario, Canada, from 2013 until 2017 (last day of follow-up, May 25, 2017). Patients had stage 3 chronic kidney disease (estimated glomerular filtration rate [eGFR] 30-60 mL/min/1.73 m2 and microalbuminuria or macroalbuminuria) and a 24-hour urine volume of less than 3.0 L. Interventions: Patients in the hydration group (n = 316) were coached to drink more water, and those in the control group (n = 315) were coached to maintain usual intake. Main Outcomes and Measures: The primary outcome was change in kidney function (eGFR from baseline to 12 months). Secondary outcomes included 1-year change in plasma copeptin concentration, creatinine clearance, 24-hour urine albumin, and patient-reported overall quality of health (0 [worst possible] to 10 [best possible]). Results: Of 631 randomized patients (mean age, 65.0 years; men, 63.4%; mean eGFR, 43 mL/min/1.73 m2; median urine albumin, 123 mg/d), 12 died (hydration group [n = 5]; control group [n = 7]). Among 590 survivors with 1-year follow-up measurements (95% of 619), the mean change in 24-hour urine volume was 0.6 L per day higher in the hydration group (95% CI, 0.5 to 0.7; P < .001). The mean change in eGFR was -2.2 mL/min/1.73 m2 in the hydration group and -1.9 mL/min/1.73 m2 in the control group (adjusted between-group difference, -0.3 mL/min/1.73 m2 [95% CI, -1.8 to 1.2; P = .74]). The mean between-group differences (hydration vs control) in secondary outcomes were as follows: plasma copeptin, -2.2 pmol/L (95% CI, -3.9 to -0.5; P = .01); creatinine clearance, 3.6 mL/min/1.73 m2 (95% CI, 0.8 to 6.4; P = .01); urine albumin, 7 mg per day (95% CI, -4 to 51; P = .11); and quality of health, 0.2 points (95% CI, -0.3 to 0.3; P = .22). Conclusions and Relevance: Among adults with chronic kidney disease, coaching to increase water intake compared with coaching to maintain the same water intake did not significantly slow the decline in kidney function after 1 year. However, the study may have been underpowered to detect a clinically important difference. Trial Registration: clinicaltrials.gov Identifier: NCT01766687.

Occupational Heat Stress and Kidney Health: From Farms to Factories.

Millions of workers around the world are exposed to high temperatures, intense physical activity, and lax labor practices that do not allow for sufficient rehydration breaks. The extent and consequences of heat exposure in different occupational settings, countries, and cultural contexts is not well studied. We conducted an in-depth review to examine the known effects of occupational heat stress on the kidney. We also examined methods of heat-stress assessment, strategies for prevention and mitigation, and the economic consequences of occupational heat stress. Our descriptive review summarizes emerging evidence that extreme occupational heat stress combined with chronic dehydration may contribute to the development of CKD and ultimately kidney failure. Rising global temperatures, coupled with decreasing access to clean drinking water, may exacerbate the effects of heat exposure in both outdoor and indoor workers who are exposed to chronic heat stress and recurrent dehydration. These changes create an urgent need for health researchers and industry to identify work practices that contribute to heat-stress nephropathy, and to test targeted, robust prevention and mitigation strategies. Preventing occupational heat stress presents a great challenge for a concerted multidisciplinary effort from employers, health authorities, engineers, researchers, and governments.

The Chronic Kidney Disease Water Intake Trial: Protocol of a Randomized Controlled Trial.

BACKGROUND: In observational studies, drinking more water associates with a slower rate of kidney function decline; whether the same is true in a randomized controlled trial is unknown. OBJECTIVE: To examine the 1-year effect of a higher vs usual water intake on estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease. DESIGN: Parallel-group randomized controlled trial. SETTING: Nine centers in Ontario, Canada. Enrollment and randomization occurred between May 2013 and May 2016; follow-up for the primary outcome will continue until June 2017. PARTICIPANTS: Adults (n = 631) with stage 3 chronic kidney disease (eGFR 30-60 mL/min/1.73 m2) and microalbuminuria. INTERVENTION: The high water intake group was coached to increase their oral water intake by 1.0 to 1.5 L/day (depending on sex and weight), over and above usual consumed beverages, for a period of 1 year. The control group was coached to maintain their usual water intake during this time. MEASURES: Participants provided 24-hour urine samples at baseline and at 6 and 12 months after randomization; urine samples were analyzed for volume, creatinine, osmolality, and the albumin-to-creatinine ratio. Blood samples were obtained at baseline and at 3- to 6-month intervals after randomization, and analyzed for creatinine, copeptin, osmolality, and electrolytes. Other measures collected included health-related quality of life, blood pressure, body mass index, and diet. PRIMARY OUTCOME: The between-group change in eGFR from baseline (prerandomization) to 12 months after randomization. SECONDARY OUTCOMES: Change in plasma copeptin concentration, 24-hour urine albumin-to-creatinine ratio, measured creatinine clearance, estimated 5-year risk of kidney failure (using the 4-variable Kidney Failure Risk Equation), and health-related quality of life. PLANNED ANALYSIS: The primary analysis will follow an intention-to-treat approach. The between-group change in eGFR will be compared using linear regression. Supplementary analyses will examine alternative definitions of eGFR change, including annual percentage change, rate of decline, and rapid decline (a P value <0.05 will be interpreted as statistically significant if there is concordance with the primary outcome). TRIAL REGISTRATION: This randomized controlled trial has been registered at www.clinicaltrials.gov; government identifier: NCT01766687.

MISE EN CONTEXTE: Dans les études observationnelles, on a remarqué une association entre un apport hydrique accru et un ralentissement de la détérioration de la fonction rénale. Cependant, nous ignorions si ce phénomène s'observait également lors d'essais contrôlés à répartition aléatoire. OBJECTIFS DE L'ÉTUDE: L'objectif était d'observer, sur une période d'un an, les effets d'un apport hydrique accru sur le débit de filtration glomérulaire estimé (DFGe) de patients atteints d'insuffisance rénale chronique (IRC) par rapport à l'apport hydrique habituel. MODÈLE DE L'ÉTUDE: Essai contrôlé à répartition aléatoire et à groupes parallèles. CADRE DE L'ÉTUDE: L'étude s'est tenue au sein de neuf centres hospitaliers de l'Ontario, au Canada. Le recrutement et la répartition des patients se sont échelonnés sur une période de trois ans, soit de mai 2013 à mai 2016. Le suivi des résultats primaires s'est poursuivi jusqu'en juin 2017. PARTICIPANTS: Un total de 631 adultes atteints d'insuffisance rénale de stade 3 (DFGe entre 30 et 60 mL/min/1,73 m2) et présentant une microalbuminurie. MÉTHODOLOGIE: Sur une période d'un an, nous avons demandé au groupe-test d'augmenter leur apport hydrique de 1 à 1,5 litre par jour, quantité établie selon le sexe et le poids du patient. Le groupe contrôle devait maintenir son apport hydrique au volume habituel. MESURES: Les participants devaient fournir des échantillons d'urine sur une période de 24 heures avant la répartition aléatoire, de même que six mois et douze mois après. Les échantillons d'urine ont été recueillis pour en mesurer le volume, le taux de créatinine et de copeptine, l'osmolarité et les électrolytes. Les autres paramètres analysés incluaient la pression sanguine, l'indice de masse corporelle (IMC), la diète et la qualité de vie générale des patients en considérant leur état de santé. RÉSULTAT PRIMAIRE ESCOMPTÉ: L'observation de variations entre les deux groupes au plan de la mesure de DFGe faite avant la répartition aléatoire et celle faite douze mois après. RÉSULTATS SECONDAIRES: Des variations dans la concentration plasmatique de copeptine, le ratio albumine-créatinine sur une période de 24 heures, la clairance de la créatinine, l'estimation du risque d'insuffisance rénale sur cinq (5) ans (en utilisant l'équation du risque d'insuffisance rénale à quatre variables) et la qualité de vie reliée à l'état de santé. ANALYSE PRÉVUE: L'analyse primaire suivra une approche d'analyse en intention de traiter. Les variations du DFGe entre les deux groupes seront comparées par analyse de covariance. Des analyses subséquentes se pencheront sur les différentes manières de définir les changements observés dans les mesures du DFGe, soit le pourcentage de la variation annuelle, le taux de déclin et le déclin rapide pour lequel une valeur de p plus faible que 0,05 sera interprétée comme étant significative statistiquement si elle concorde avec le résultat primaire. ENREGISTREMENT DE L'ESSAI CLINIQUE: Cet essai contrôlé à répartition aléatoire a été enregistré sur www.clinicaltrials.gov et le code d'identification du gouvernement est le NCT01766687.

Atypical haemolytic uremic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN), different diseases or a spectrum of complement-mediated glomerular diseases?

Historically, patients with kidney diseases caused by genetic or acquired dysregulation of the complement alternative pathway have been grouped into clinical syndromes, C3 glomerulopathy (C3GN/DDD) and thrombotic microangiopathy (TMA), specifically atypical haemolytic uremic syndrome (aHUS). Recent data suggested that these diseases share a common pathophysiology and that patients can transition between glomerulopathies in this spectrum. Histopathologically, the main difference cited is the immunofluorescence (IF) findings, with C3 predominance in C3 glomerulopathy (compared with immunoglobulins and complements in immune complex-mediated membranoproliferative glomerulonephritis (MPGN)) and negative IF in TMA. We report a case in which a patient presented with hypertension, seizures, proteinuria, renal impairment and immune complex-mediated MPGN on kidney biopsy. Months later, she presented with classical TMA. She failed to respond to steroids and plasma exchange therapy but subsequently made a remarkable haematological and renal recovery after eculizumab treatment, thus supporting an underlying complement dysregulation and a diagnosis of aHUS.

How we treat thrombotic thrombocytopenic purpura: Results of a Canadian TTP practice survey.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare disease with 90% mortality if untreated. Since the Canadian Apheresis Group (CAG) trial showed greater survival with therapeutic plasma exchange (TPE) versus plasma infusion, there has been widespread adoption of TPE. Beyond TPE, there is significant practice variation. To characterize this, we developed a survey sent to physicians who might be directly involved in TTP management. METHODS: The survey was sent to CAG members as well as hematologists and nephrologists nationwide and addressed areas of controversy or recognized practice heterogeneity. Descriptive statistics were used to summarize responses, and the χ2 test was used to compare respondents who were and were not CAG physicians. We also compared responses by estimated frequency of TTP cases per year. RESULTS: The CAG response rate was 31% (13 of 42). The survey was sent to 665 non-CAG physicians, of whom 41 responded (6.1%). Though not statistically different, CAG and non-CAG respondents varied regarding use of corticosteroids, aspirin, and venous thromboembolism (VTE) prophylaxis. Significant differences were found between CAG and non-CAG groups regarding cryosupernatant as fluid choice (69.2% vs. 22.5%, P = .004) and the use of TPE tapering (84.6% vs. 51.3%, P = .034), respectively. CONCLUSION: TTP treatment is variable across centres in Canada. Areas of significant variation include the choice of replacement fluid for TPE and whether or not and how to taper TPE. Our survey highlights the practice heterogeneity that exists and identifies areas where more evidence is needed and perhaps where trials should be performed.

Plasmapheresis for the treatment of kidney diseases.

The purpose of this review is to examine the evidence supporting the application of plasma exchange in renal disease. Our review focuses on the following 6 most common renal indications for plasma exchange based on 2014 registry data from the Canadian Apheresis Group: (i) thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome; (ii) renal transplantation, (iii) anti-neutrophil cytoplasm antibodies-associated vasculitis, (iv) cryoglobulinemia, (v) focal segmental glomerulosclerosis, and (vi) Goodpasture syndrome. The rarity of these diseases and their rapid, often fatal course mean that randomized controlled studies of plasma exchange are rarely conducted. Although evidence from an adequately powered randomized controlled trial supports the use of plasma exchange to treat thrombotic thrombocytopenic purpura, the use of plasma exchange to treat other renal diseases is only supported by observational and mechanistic studies. Larger well-designed trials are needed to clarify the potential role of plasma exchange in renal disease. Growing international collaboration will improve the quality of future studies in this area.

The role of plasma exchange in treating post-transplant focal segmental glomerulosclerosis: A systematic review and meta-analysis of 77 case-reports and case-series.

BACKGROUND: Evidence on the role of plasma exchange for treating recurrent post-transplant focal segmental glomerulosclerosis (FSGS) comes largely from individual cases and uncontrolled series. We conducted a systematic review and meta-analysis to estimate the remission rate after treatment with plasma exchange, and to determine if remission varied with patient or treatment characteristics. METHODS: We searched MEDLINE, EMBASE, Science Citation Index Expanded, and the Conference Proceedings Citation Index (Science and BIOSIS) for studies of patients with post-transplant recurrent FSGS who were treated with plasma exchange after recurrence (1950-2012). Of 678 studies screened, 77 met our inclusion criteria: 34 case reports (45 patients) and 43 case series (378 patients). We extracted patient-level data from each study and used random-effects models to calculate remission, defined as proteinuria <3.5 g/day (partial) or <0.5 g/day (complete). RESULTS: The overall remission rate in 423 patients with outcome data was 71 % (95 % CI: 66 % to 75 %). In 235 patients with data on age, remission was similar for adults and children: 69.1 % (95 % CI: 59.6 % to 77.2 %) and 70.2 % (95 % CI: 61.1 % to 77.9 %). Males were more likely to achieve remission (OR = 2.85; 95 % CI: 1.44 to 5.62) and patients treated within 2 weeks of recurrence showed a trend towards higher likelihood of remission (OR = 2.16; 95 % CI: 0.93 to 5.01). Proteinuria >7 g/day at recurrence was inversely associated with remission (OR = 0.43; 95 % CI: 0.19 to 0.97). Age and type of kidney transplant (living vs. deceased) did not associate with remission. CONCLUSION: In this systematic review of patients with recurrent post-transplant FSGS, 71 % of patients achieved full or partial remission after treatment with plasma exchange; however, extensive missing data and lack of a control group limit any conclusions on causality.

International Society of Nephrology-Hydration and Kidney Health Initiative - Expanding Research and Knowledge.

The purpose of this manuscript is to describe a collaborative research initiative to explore the role of hydration in kidney health. Our understanding of the effects of hydration in health and disease is surprisingly limited, particularly when we consider the vital role of hydration in basic human physiology. Recent initiatives and research outcomes have challenged the global medical community to expand our knowledge about hydration, including the differences between water, sugared beverages and other consumables. Identification of the potential mechanisms contributing to the benefits of hydration has stimulated the global nephrology community to advance research regarding hydration for kidney health. Hydration and kidney health has been a focus of research for several research centers with a rapidly expanding world literature and knowledge. The International Society of Nephrology has collaborated with Danone Nutricia Research to promote development of kidney research initiatives, which focus on the role of hydration in kidney health and the global translation of this new information. This initiative supports the use of existing data in different regions and countries to expand dialogue among experts in the field of hydration and health, and to increase scientific interaction and productivity with the ultimate goal of improving kidney health.

Treatment of severe, refractory and rapidly evolving thrombotic thrombocytopenic purpura.

A 36-year-old man presented to hospital with gross haematuria and evidence of severe, refractory thrombotic thrombocytopenic purpura. Initial treatment with high-volume plasma exchange therapy and early administration of rituximab failed to achieve a sustained clinical response. His clinical course was complicated by left hemianopsia and despite an urgent splenectomy he developed a large right-sided stroke with malignant cerebral oedema that required an emergent decompressive craniotomy. He also had numerous infectious complications as a consequence of an aggressive immunosuppressive strategy. While the patient did not respond to cyclophosphamide, cyclosporine, N-acetylcysteine, and one course of bortezomib, he eventually responded to a second course of bortezomib. One year later, the patient remains in remission and maintains excellent cognitive function. However, he has not completely recovered from his stroke and continues to participate in rehabilitation for his residual physical deficits.

Hydration and Chronic Kidney Disease Progression: A Critical Review of the Evidence.

We performed a comprehensive literature review to examine evidence on the effects of hydration on the kidney. By reducing vasopressin secretion, increasing water intake may have a beneficial effect on renal function in patients with all forms of chronic kidney disease (CKD) and in those at risk of CKD. This potential benefit may be greater when the kidney is still able to concentrate urine (high fluid intake is contraindicated in dialysis-dependent patients). Increasing water intake is a well-accepted method for preventing renal calculi, and current evidence suggests that recurrent dehydration and heat stress from extreme occupational conditions is the most probable cause of an ongoing CKD epidemic in Mesoamerica. In polycystic kidney disease (PKD), increased water intake has been shown to slow renal cyst growth in animals via direct vasopressin suppression, and pharmacologic blockade of renal vasopressin-V2 receptors has been shown to slow cyst growth in patients. However, larger clinical trials are needed to determine if supplemental water can safely slow the loss of kidney function in PKD patients.

Long-term outcomes of thrombotic microangiopathy treated with plasma exchange: A systematic review.

With the adoption of plasma exchange as standard treatment for thrombotic microangiopathy (TMA), more patients are surviving and long-term outcomes have greater relevance. We conducted a systematic review to synthesize and evaluate the quality of evidence on long-term outcomes of TMA among adults treated with plasma exchange and to identify factors that may be associated with a worse long-term prognosis. We searched databases from 1980 to 2013 for eligible articles published in any language. We included studies that reported outcomes in at least ten adults with a history of TMA treated with plasma exchange and at least 6 months of follow-up. We abstracted data in duplicate and assessed the methodological quality of each study using an assessment tool developed based on recommended validity criteria. We screened 6672 articles, reviewed 213, and included 34 studies totaling 1182 patients (study median [range], 24 [10-118]). The mean (or median) follow-up ranged from 6 months to 13 years. The cumulative incidence of relapse and mortality was highly variable and ranged from 3 to 84 and 0 to 61%, respectively. The incidence of other outcomes across 10 studies also varied (outcomes included hypertension, kidney disease, preeclampsia, stroke, seizure, severe cognitive impairment, and depression); in three other studies, long-term neurocognitive function and health-related quality of life were significantly lower than in the general population. Patients who survive an episode of TMA may be susceptible to long-term vascular complications, but the magnitude of this risk and how to mitigate it remains unclear. Am. J. Hematol. 91:623-630, 2016. © 2016 Wiley Periodicals, Inc.

Consecutive first-morning urine samples to measure change in the albumin-to-creatinine ratio: a pilot study of a home urine collection protocol.

BACKGROUND: Multiple first-morning urine samples are recommended for measuring the urine albumin-to-creatinine ratio (ACR); however, this can be challenging in community-based research. METHODS: The objectives of the study are to pilot-test a home urine collection protocol and examine how the average and variance of ACR varied with the number of urine collections and time to laboratory analysis. This is a prospective observational pilot study. This study was conducted in London, Ontario, Canada at the London Health Sciences Centre (2012-2013). The patients were adults with chronic kidney disease (mean estimated glomerular filtration rate, 36 mL/min/1.73 m(2)). Participants collected a first-morning 20-mL urine sample on three consecutive days. This process was repeated after 3 months. Samples were picked up by hospital courier and analyzed for ACR on the same day; additional aliquots were analyzed after a delay of 24-48 h (stored at 4 °C) and 3-9 months (stored at -80 °C). The geometric mean of the percentage change in ACR between baseline and 3 months was calculated and compared between single samples and the average of two vs. three consecutive samples. RESULTS: Of 31 patients enrolled, 26 (83.9 %) submitted all six urine samples. The geometric mean of ACR for three consecutive samples at baseline was 87, 83, and 80 mg/mmol, and the corresponding percentage increase from baseline to 3 months was 15 % (95 % confidence interval (CI), -9 to 46 %), 33 % (95 % CI, 10 to 59 %), and 22 % (95 % CI, -6 to 57 %). Compared with single urine collections at baseline and follow-up, averaging ACR values from two consecutive first-morning urine samples improved the sample variance and reduced the required sample size to detect a given treatment effect by approximately 30 %. No further gain in statistical efficiency was achieved with three urine samples. Results were similar when the laboratory analysis was delayed by 24-48 h, but a delay of 3-9 months resulted in systematic overestimation of the ACR. Our study's generalizability is limited by its small sample size and reliance on a clinic-based population from a single urban center. CONCLUSIONS: We successfully used a home urine collection protocol to obtain multiple first-morning urine samples in patients with chronic kidney disease. Statistical efficiency was improved by averaging ACR values from two consecutive first-morning urine samples at baseline and follow-up.

MISE EN CONTEXTE: Le prélèvement de la première urine du matin est recommandé pour procéder à l'analyse du ratio albumine/créatinine (RAC) chez les patients atteints d'insuffisance rénale chronique (IRC). Toutefois, cette procédure représente un défi dans le domaine de la recherche communautaire. OBJECTIFS DE L'ÉTUDE: Cette étude constitue un essai pilote qui visait à établir un protocole normalisé pour la collecte d'échantillons d'urine chez les patients atteints d'IRC. Cet essai pilote avait également pour objectif de caractériser les variations dans les valeurs moyennes et les valeurs d'écart à la moyenne des RAC en fonction du nombre de prélèvements effectués et du moment où ceux-ci sont analysés en laboratoire. CADRE ET TYPE D'ÉTUDE: Il s'agit d'une étude pilote prospective réalisée par observation. L'étude s'est tenue au London Health Science Center de London en Ontario, au Canada en 2012 et 2013. MÉTHODE: Les participants, des adultes atteints d'IRC (débit de filtration glomérulaire moyen de 36 mL/min/1,73 m2), ont procédé au prélèvement de 20 mL de la première urine du matin durant trois jours consécutifs. La procédure a été répétée après trois mois. À chaque fois, les échantillons étaient cueillis par un messager envoyé par l'hôpital pour leur analyse du RAC le jour-même. De chacun des échantillons reçus, deux aliquots étaient prélevés pour analyse ultérieure: un premier était conservé à 4 °C pour analyse dans les 24 à 48 heures, et un deuxième était congelé à −80 °C pour analyse du RAC de 3 à 9 mois suivant le prélèvement. La moyenne géométrique des pourcentages de variation du RAC entre les valeurs mesurées le jour-même et les valeurs mesurées après 3 mois a été calculée, on l'a ensuite comparée avec le RAC des échantillons individuels avec les moyennes de RAC obtenues pour deux et trois échantillons consécutifs. RÉSULTATS: Des 31 patients inclus dans l'étude, 83,9 % (n = 26) ont fourni les six échantillons d'urine requis pour analyse. Les moyennes géométriques des RAC pour les échantillons prélevés sur trois jours consécutifs s'élevaient à 87,83 et 80 mg/mmol, et les pourcentages correspondants à la variation entre le RAC au jour 1 et le RAC après 3 mois étaient respectivement de 15 % (95 % IC : −9 % à 46 %), de 33 % (95 % IC : 10 % à 59 %), et de 22 % (95 % IC : −6 % à 57 %). En comparant les RAC des échantillons individuels au jour 1 et après 3 mois avec la moyenne des RAC de deux échantillons prélevés consécutivement, un accroissement de la variance a été observé. De plus, cette comparaison a également permis de conclure qu'il était possible de détecter un effet thérapeutique donné dans un échantillon jusqu'à 30 % moins volumineux. Aucun avantage sur le plan de l'efficacité statistique n'a été amené par l'analyse de trois prélèvements consécutifs. Enfin, les résultats d'analyse du RAC de 24 à 48 heures suivant l'arrivée des échantillons n'a offert que peu de variation en comparaison avec les valeurs obtenues au jour 1. Par contre, dans le cas des échantillons analysés après 3 à 9 mois ceux-ci ont systématiquement entraîné une surévaluation de la mesure du RAC. LIMITES DE L'ÉTUDE: La possibilité de généralisation de la présente étude est limitée par son faible échantillonnage et par le fait qu'elle s'appuie sur une population clinique provenant d'une seule agglomération urbaine. CONCLUSIONS: L'essai pilote mené dans le but d'établir un protocole normalisé permettant aux patients atteints d'IRC de prélever des échantillons d'urine du matin à la maison a été couronné de succès. De plus, les résultats montrent que d'utiliser les moyennes de RAC de deux échantillons prélevés consécutivement permet d'accroître l'efficacité statistique tant pour les échantillons analysés au jour 1 que lors du suivi après 3 mois.

Effect of increased water intake on plasma copeptin in patients with chronic kidney disease: results from a pilot randomised controlled trial.

OBJECTIVES: Increased water intake may have a beneficial effect on the kidney through suppression of plasma vasopressin. We examined the effect of increased water intake on plasma copeptin (a marker of vasopressin) over 6 weeks in patients with chronic kidney disease. DESIGN: Secondary analysis of a randomised controlled parallel-group pilot trial. SETTING: Canada, 2012-2013. PARTICIPANTS: 28 patients with stage 3 chronic kidney disease randomised (2:1) to a hydration (n=17) or control group (n=11). INTERVENTION: The hydration group was coached to increase water intake by up to 1.5 L/day for 6 weeks. The control group was asked to maintain regular water intake. MEASURES AND OUTCOMES: Participants provided blood and 24 h urine samples at baseline and 6 weeks. Change in plasma copeptin was compared within and between study groups. RESULTS: Participants were 64% male with a mean age of 62 years and an estimated glomerular filtration rate of 40 mL/min/1.73 m(2). Between baseline and 6 weeks, 24 h urine volume increased by 0.7 L/day in the hydration group, rising from 2.3 to 3.0 L/day (p=0.01), while decreasing by 0.3 L/day among controls, from 2.0 to 1.7 L/day (p=0.07); between-group difference: 0.9 L/day (95% CI 0.37 to 1.46; p=0.002). In the hydration group, median copeptin decreased by 3.6 pmol/L, from 15.0 to 10.8 pmol/L (p=0.005), while remaining stable among controls at 19 pmol/L (p=0.76; p=0.19 for the between-group difference in median change); the between-group difference in mean change was 5.4 pmol/L (95% CI -1.2 to 12.0; p=0.11). CONCLUSIONS: Adults with stage 3 chronic kidney disease can be successfully randomised to drink approximately 1 L more per day than controls. This increased water intake caused a significant decrease in plasma copeptin concentration. Our larger 12-month trial will examine whether increased water intake can slow renal decline in patients with chronic kidney disease. TRIAL REGISTRATION NUMBER: NCT01753466.

Primary and Secondary Thrombotic Microangiopathy Referred to a Single Plasma Exchange Center for Suspected Thrombotic Thrombocytopenic Purpura: 2000-2011.

BACKGROUND: Patients who present with unexplained thrombocytopenia, that is, hemolytic anemia with end-organ dysfunction with a normal coagulation profile are suspected to have thrombotic thrombocytopenic purpura (TTP) and are usually referred to a plasma exchange (PE) center for immediate treatment to prevent mortality. Here, we describe the distribution and outcomes of patients with suspected TTP referred to a single center for PE therapy. METHODS: In this retrospective cohort study, we reviewed the data of all consecutive patients who were treated with PE for suspected TTP at our center between January 2000 and December 2011 (Canada). Patients were followed for a median of 73 months. RESULTS: Of 137 patients, 70 (51%) were determined to have primary (idiopathic) TTP and 67 (49%) secondary TTP or hemolytic uremic syndrome (HUS). Patients with primary TTP were twice as likely to be refractory than those with secondary TTP or HUS: 27 vs. 12%; p = 0.03. Patients with primary TTP were more likely to experience remission (61/70 (87%) vs. 45/67 (67%); p = 0.01); however, the relapse rate was higher in patients with primary versus secondary TTP-HUS: 11 vs. 1.5%, respectively (p = 0.03). The overall mortality rate was 23% (13 vs. 33% in those with primary vs. secondary TTP-HUS; p = 0.007). After excluding deaths from scleroderma renal crisis (100% mortality), malignancy (75% mortality) and stem cell transplant (50% mortality), the survival rate for secondary TTP was 85%. CONCLUSIONS: In contrast to patients with secondary TTP or HUS, those with primary TTP have a higher refractory and relapse rate, but are also more likely to achieve remission and survive.

Increasing Water Intake in Chronic Kidney Disease: Why? Safe? Possible?

Increased water intake may slow the progression of chronic kidney disease by lowering vasopressin levels. Prior to initiating a large randomized controlled trial on the effect of increased water intake on renal decline, we conducted a six-week pilot study to examine the safety and feasibility of asking adults with chronic kidney disease to increase their water intake. We randomly assigned 29 patients to either a hydration or a control group. The hydration group was asked to increase water intake by 1 to 1.5 l/day relative to their weight, gender, and 24 h urine osmolality, in addition to usual consumed beverages; the control group was asked to continue with usual fluid intake. After six weeks, the change in urine volume was significantly different between groups (0.9 l/day; p = 0.002) with no change in serum sodium and no serious adverse effects. Similarly, preliminary results of our large clinical trial of the same intervention (489 patients enrolled to date) demonstrated a significant separation between groups on 24 h urine volume (at 12 months the mean difference between groups was 1.2 l/day; p < 0.001) with no serious adverse effects. Serum sodium has remained stable in both groups over follow-up. To our knowledge, this trial is currently the largest of its kind to date; the significant separation between groups with respect to urine volume indicates that we will have scientifically reliable data on the effect of increased fluid intake on renal decline. The analysis of primary and secondary outcomes will be conducted at the conclusion of follow-up in July 2016.