The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on glomerulonephritis (GN) is intended to assist the practitioner caring for patients with GN. Two chapters of ...this guideline focus specifically on nephrotic syndrome in children. Guideline development followed a thorough evidence review, and management recommendations and suggestions were based on the best available evidence. Critical appraisal of the quality of evidence and strength of recommendations followed the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach. Chapters 3 and 4 of the guideline focus on the management of nephrotic syndrome in children aged 1–18 years. Guideline recommendations for children who have steroid-sensitive nephrotic syndrome (SNSS), defined by their response to corticosteroid therapy with complete remission, are addressed here. Recommendations for those with steroid-resistant nephrotic syndrome (SRNS) (i.e., do not achieve complete remission) are discussed in the companion article. Limitations of the evidence, including the paucity of large-scale randomized controlled trials, are discussed. This article provides a short description of the KDIGO process, the guideline recommendations for treatment of SSNS in children and a brief review of relevant treatment trials related to each recommendation.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Objective To assess minimally important differences (MIDs) for several pediatrie self-report item banks from the National Institutes of Health Patient-Reported Outcomes Measurement Information ...System® (PROMIS®). Methods We presented vignettes comprising sets of two completed PROMIS questionnaires and asked judges to declare whether the individual completing those questionnaires had an important change or not. We enrolled judges (including adolescents, parents, and clinicians) who responded to 24 vignettes (six for each domain of depression, pain interference, fatigue, and mobility). We used item response theory to model responses to the vignettes across different judges and estimated MID as the point at which 50 % of the judges would declare an important change. Results We enrolled 246 judges (78 adolescents, 85 parents, and 83 clinicians). The MID estimated with clinician data was about 2 points on the PROMIS T-score scale, and the MID estimated with adolescent and parent data was about 3 points on that same scale. Conclusions The MIDs enhance the value of PROMIS pediatric measures in clinical research studies to identify meaningful changes in health status over time.
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BFBNIB, CEKLJ, DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, INZLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NMLJ, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ, ZRSKP
Purpose
Acute kidney injury (AKI) occurs commonly in critically ill children and has been associated with increased mortality of up to 50 %. The Kidney Disease: Improving Global Outcomes (KDIGO) AKI ...working group has proposed a standardized definition of AKI. Utilizing routinely available clinical data, we evaluated the KDIGO AKI criteria and the relationship of AKI with relevant outcomes in a single center tertiary pediatric intensive care (PICU) and cardiac intensive care unit (CICU) population.
Methods
The University of Michigan Pediatric Critical Care Database was probed for all discharges from the pediatric intensive care and cardiac intensive care units between July 2011 and October 2013 (
N
= 4,645). The KDIGO serum creatinine (SCr)-based criteria staged AKI with the modification that a minimum SCr of greater than 0.5 mg/dL was required to be classified as AKI. Exclusion: end-stage renal disease, new renal transplant, missing PRISM III data, or no measured Cr during intensive care unit (ICU) admission (
N
= 1,636).
Results
AKI occurred in 737 (24.5 %, stage 1 = 193, stage 2 = 189, and stage 3 = 355) of 3,009 discharges (PICU
N
= 1,870, CICU
N
= 1,139) that included 2,415 patients. In multivariate analysis AKI was associated with increased ICU length of stay (LOS) in hours (stage I
β
= 42.2,
p
= 0.024, II
β
= 74.1,
p
= 0.003, III
β
= 215.8,
p
< 0.001). Multivariate analysis showed that AKI was associated with increased odds of ICU mortality (OR 3.4, 95 % CI 2.0–6.0) and increased length of mechanical ventilation among those requiring mechanical ventilation (
β
= 2.3 days,
p
< 0.001).
Conclusions
Using the KDIGO criteria to define AKI, we observed a high prevalence of AKI among critically ill children. Worsening stages of AKI were associated with increased ICU LOS, and AKI was independently associated with prolonged mechanical ventilation and increased mortality. The KDIGO criteria describe clinically relevant AKI in a broad pediatric critical care population.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Kidney Disease: Improving Global Outcomes (KDIGO) recently published the clinical practice guideline on glomerulonephritis (GN) to assist the practitioner caring for patients with GN. Chapter 4 of ...the guideline focuses on managing children aged 1–18 years with steroid-resistant nephrotic syndrome (SRNS), defined by an inability to achieve complete remission with corticosteroid therapy. Guideline development followed a thorough evidence review, and management recommendations and suggestions were based on the best available evidence. Limitations of the evidence, including the paucity of large-scale randomized controlled trials, are discussed. This article provides both the guideline recommendations and a brief review of relevant treatment trials related to each recommendation. This précis serves as a summary of the complete guidelines recently published.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Proteinuria is used as an indicator of FSGS disease activity, but its use as a clinical trial end point is not universally accepted. The goal of this study was to refine proteinuria definitions ...associated with long-term kidney survival.
Data on 466 patients with primary FSGS with proteinuria (urine protein-to-creatinine ratio >1 g/g) were analyzed from five independent cohorts. Proteinuria by months 1, 4, and 8 after study baseline was categorized by conventional definitions of complete (<0.3 g/g) and partial remission (<3.5 g/g and 50% reduction in proteinuria). Novel remission definitions were explored using receiver operating curves. Kaplan-Meier methods were used to estimate the associations of proteinuria with progression to ESRD or a 50% loss in kidney function. Propensity score-adjusted Cox proportional hazards models were used to adjust for baseline proteinuria, eGFR, and therapy.
In the initial derivation cohort, conventional partial remission was not associated with kidney survival. A novel definition of partial remission (40% proteinuria reduction and proteinuria<1.5 g/g) on the basis of receiver operating curve analyses of 89 patients was identified (Sensitivity=0.70; Specificity=0.77). In the validation cohort analyses, complete remission was associated with better prognosis (6 out of 41 patients progressed to kidney failure; 6.6 per 100 patient-years) as was the novel partial remission (13 out of 71 progressed; 8.5 per 100 patient-years), compared with those with no response (51 out of 116 progressed; 20.1 per 100 patient-years). Conventional partial remission at month 8, but not month 4, was also associated with better response (19 out of 85 patients progressed; risk=10.4 per 100 patient-years). Propensity score-adjusted analyses showed the novel partial remission was associated with less progression at months 4 and 8 (month 4: hazard ratio, 0.50;
=0.01; month 8: hazard ratio, 0.30;
=0.002).
Reaching either a complete or partial remission using a novel or conventional definition was associated with better long-term outcomes in patients with FSGS.
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_02_20_CJASNPodcast_18_3_T.mp3.
Idiopathic nephrotic syndrome is the most frequent pediatric glomerular disease, affecting from 1.15 to 16.9 per 100,000 children per year globally. It is characterized by massive proteinuria, ...hypoalbuminemia, and/or concomitant edema. Approximately 85–90% of patients attain complete remission of proteinuria within 4–6 weeks of treatment with glucocorticoids, and therefore, have steroid-sensitive nephrotic syndrome (SSNS). Among those patients who are steroid sensitive, 70–80% will have at least one relapse during follow-up, and up to 50% of these patients will experience frequent relapses or become dependent on glucocorticoids to maintain remission. The dose and duration of steroid treatment to prolong time between relapses remains a subject of much debate, and patients continue to experience a high prevalence of steroid-related morbidity. Various steroid-sparing immunosuppressive drugs have been used in clinical practice; however, there is marked practice variation in the selection of these drugs and timing of their introduction during the course of the disease. Therefore, international evidence-based clinical practice recommendations (CPRs) are needed to guide clinical practice and reduce practice variation. The International Pediatric Nephrology Association (IPNA) convened a team of experts including pediatric nephrologists, an adult nephrologist, and a patient representative to develop comprehensive CPRs on the diagnosis and management of SSNS in children. After performing a systematic literature review on 12 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, recommendations were formulated and formally graded at several virtual consensus meetings. New definitions for treatment outcomes to help guide change of therapy and recommendations for important research questions are given.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
The gut microbiota is altered in patients with chronic kidney disease (CKD), and cardiovascular risk increases with progressive CKD. This study examined the potential link between short chain fatty ...acids (SCFAs), which are produced by the gut microbiota, and cardiovascular outcomes in patients with CKD.
SCFAs were measured using a targeted liquid chromatography-mass spectrometry platform in baseline plasma samples from 214 patients with CKD enrolled in the Clinical Phenotyping Resource and Biobank Core; 81 patients with coronary artery disease (CAD) and 133 without CAD were randomly assigned to training and validation subsets. The primary outcome was a history of CAD and the secondary outcome was a composite history of cardiovascular disease (CVD) at enrollment.
We found significantly higher levels of the SCFA valerate among patients with CAD as compared with patients without CAD in the training set (p < 0.001). The valerate concentrations were also significantly higher among subjects with composite outcomes of CVD compared to those without CVD (p = 0.006). These results were subsequently replicated in the validation set. Logistic regression analysis revealed a strong independent association between plasma valerate levels and CVD in both training and validation sets. When valerate was added to the base clinical model comprising of diabetes, hypertension, urinary protein-creatinine ratio, and estimated glomerular filtration rate, it increased the c-statistics for predicting CVD from 0.68 to 0.79 (p = 0.02) in the training set, an observation which was confirmed in the validation set. -Conclusion: This study provides evidence for alterations in gut-microbiota-derived SCFAs with advancing CKD, demonstrates the association of higher plasma valerate levels with pre-existing CVD, and reveals areas for future exploration of cardiovascular risk in patients with CKD.
We evaluated and compared the effects of sparsentan, a dual endothelin type A (ET
) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist ...irbesartan in patients with primary FSGS.
In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 years with biopsy-proven FSGS, eGFR>30 ml/min per 1.73 m
, and urinary protein-to-creatinine ratio (UP/C) ≥1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: ≤1.5 g/g and >40% reduction secondary).
Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%;
=0.006) or the 400 and 800 mg doses (47% versus 19%;
=0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients (
=0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals.
Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated.
Like many pediatric chronic health conditions, idiopathic childhood onset nephrotic syndrome (iCONS) and late effects of iCONS medical management may continue to impact the affected population in ...adulthood. Approximately 15% of adult survivors of steroid-sensitive iCONS continue to relapse. Long-term kidney health is associated with steroid response patterns as well as pathology findings of FSGS, tubulointerstitial fibrosis, tubular atrophy, and global glomerulosclerosis. Long-term cardiovascular disease burden is largely unknown in adult survivors, but risk factors starting in childhood, including hypertension, dyslipidemia, and obesity, are common in iCONS. Reproductive health concerns, including azo-/oligospermia and successful pregnancies, are largely related to prior exposure to cytotoxic therapies. Additional investigations are needed to complete the assessment and initiate the mitigation of the late effects of treatment-sensitive and treatment-resistant iCONS.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to primary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the ...disease. Here, we analyzed circulating suPAR levels in two cohorts of children and adults with biopsy-proven primary FSGS: 70 patients from the North America-based FSGS clinical trial (CT) and 94 patients from PodoNet, the Europe-based consortium studying steroid-resistant nephrotic syndrome. Circulating suPAR levels were elevated in 84.3% and 55.3% of patients with FSGS patients in the CT and PodoNet cohorts, respectively, compared with 6% of controls (P<0.0001); inflammation did not account for this difference. Multiple regression analysis suggested that lower suPAR levels associated with higher estimated GFR, male sex, and treatment with mycophenolate mofetil. In the CT cohort, there was a positive association between the relative reduction of suPAR after 26 weeks of treatment and reduction of proteinuria, with higher odds for complete remission (P=0.04). In the PodoNet cohort, patients with an NPHS2 mutation had higher suPAR levels than those without a mutation. In conclusion, suPAR levels are elevated in geographically and ethnically diverse patients with FSGS and do not reflect a nonspecific proinflammatory milieu. The associations between a change in circulating suPAR with different therapeutic regimens and with remission support the role of suPAR in the pathogenesis of FSGS.
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