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The role of complement in the pathogenesis of IgA nephropathy has been heavily explored over the past 50 years. This has led to the general acceptance that complement plays an important role in the clinical presentation and risk for progression of disease in patients with IgA nephropathy. Herein, we review the evidence for complement activation in IgA nephropathy, focusing on evidence that the lectin and alternate pathways are the main actors. We are entering an era of intense investigation of various inhibitors of complement, which should ultimately be the best indicator of contributions of the lectin, alternate and common complement pathways to disease burden. More importantly, we will see if these efforts result in the discovery of clinically relevant options in managing this important disease. [ABSTRACT FROM AUTHOR]

IgA nephropathy is a chronic immune-mediated kidney disease and a major cause of kidney failure worldwide. The gut mucosal immune system is implicated in its pathogenesis, and Nefecon is a novel, oral, targeted-release formulation of budesonide designed to act at the gut mucosal level. We present findings from the 2-year, phase 3 NefIgArd trial of Nefecon in patients with IgA nephropathy. In this phase 3, multicentre, randomised, double-blind, placebo-controlled trial, adult patients (aged ≥18 years) with primary IgA nephropathy, estimated glomerular filtration rate (eGFR) 35–90 mL/min per 1·73 m2, and persistent proteinuria (urine protein–creatinine ratio ≥0·8 g/g or proteinuria ≥1 g/24 h) despite optimised renin-angiotensin system blockade were enrolled at 132 hospital-based clinical sites in 20 countries worldwide. Patients were randomly assigned (1:1) to receive 16 mg/day oral capsules of Nefecon or matching placebo for 9 months, followed by a 15-month observational follow-up period off study drug. Randomisation via an interactive response technology system was stratified according to baseline proteinuria (<2 or ≥2 g/24 h), baseline eGFR (<60 or ≥60 mL/min per 1·73 m2), and region (Asia-Pacific, Europe, North America, or South America). Patients, investigators, and site staff were masked to treatment assignment throughout the 2-year trial. Optimised supportive care was also continued throughout the trial. The primary efficacy endpoint was time-weighted average of eGFR over 2 years. Efficacy and safety analyses were done in the full analysis set (ie, all randomly assigned patients). The trial was registered on ClinicalTrials.gov , NCT03643965 , and is completed. Patients were recruited to the NefIgArd trial between Sept 5, 2018, and Jan 20, 2021, with 364 patients (182 per treatment group) randomly assigned in the full analysis set. 240 (66%) patients were men and 124 (34%) were women, and 275 (76%) identified as White. The time-weighted average of eGFR over 2 years showed a statistically significant treatment benefit with Nefecon versus placebo (difference 5·05 mL/min per 1·73 m2 [95% CI 3·24 to 7·38], p<0·0001), with a time-weighted average change of –2·47 mL/min per 1·73 m2 (95% CI –3·88 to –1·02) reported with Nefecon and –7·52 mL/min per 1·73 m2 (–8·83 to –6·18) reported with placebo. The most commonly reported treatment-emergent adverse events during treatment with Nefecon were peripheral oedema (31 [17%] patients, vs placebo, seven [4%] patients), hypertension (22 [12%] vs six [3%]), muscle spasms (22 [12%] vs seven [4%]), acne (20 [11%] vs two [1%]), and headache (19 [10%] vs 14 [8%]). No treatment-related deaths were reported. A 9-month treatment period with Nefecon provided a clinically relevant reduction in eGFR decline and a durable reduction in proteinuria versus placebo, providing support for a disease-modifying effect in patients with IgA nephropathy. Nefecon was also well tolerated, with a safety profile as expected for a locally acting oral budesonide product. Calliditas Therapeutics. [ABSTRACT FROM AUTHOR]

The authors discusses the treatment of IgA nephropathy patients through the use of corticosteroids, referencing a study in the issue titled "TESTING Study Group. Effect of oralmethylprednisolone on clinical outcomes in patients with IgA nephropathy: the TESTING randomized clinical trial," by J. Lv, H. Zhang and W.G. Wong. The aforementioned study's use of clinical trials to test the efficacy of corticosteroids to treat IgA nephropathy, including for possible harm, is discussed.

Objective: To compare 24-hour urinary protein excretion in twin and singleton pregnancies not complicated by hypertension.Methods: We prospectively evaluated mean 24-hour urinary protein excretion in twin and singleton pregnancies between 24 0/7 weeks and 36 0/7 weeks of gestation. Women with urinary tract infections, chronic hypertension, pregestational diabetes, and renal or autoimmune diseases were excluded. Collection adequacy was assessed by urinary creatinine excretion adjusted for maternal weight.Results: Adequate samples were obtained from 50 twin and 49 singleton pregnancies at a mean gestational age of 30 weeks. At collection, the two groups were similar with regard to maternal age, gestational age, body mass index, and blood pressure. Mean urinary protein excretion was higher in twin compared with singleton pregnancies (269.3±124.1 mg compared with 204.3±92.5 mg, P=.004). Proteinuria (300 mg/day protein or greater) occurred in 38.0% (n=19) of twin and 8.2% (n=4) of singleton pregnancies (P<.001). After adjusting for confounding variables, the difference in mean total protein excretion remained significant (P=.004) and twins were more likely to have proteinuria compared with singleton pregnancies (adjusted odds ratio 9.1, 95% confidence interval 2.1-38.5). Nineteen participants developed a hypertensive disorder at a mean of 7.7 weeks after the urine collection (range 2.6-14.5 weeks). After excluding these women, proteinuria was present in 43% of twin and 7% of singleton pregnancies (P<.001).Conclusion: Mean 24-hour urinary protein excretion in twin pregnancies is greater than in singletons. These data suggest a reevaluation of the diagnostic criteria for preeclampsia in twin pregnancies.Level Of Evidence: II. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare 24-hour urinary protein excretion in twin and singleton pregnancies not complicated by hypertension. METHODS: We prospectively evaluated mean 24-hour urinary protein excretion in twin and singleton pregnancies between 24 0/7 weeks and 36 0/7 weeks of gestation. Women with urinary tract infections, chronic hypertension, pregestational diabetes, and renal or autoimmune diseases were excluded. Collection adequacy was assessed by urinary creatinine excretion adjusted for maternal weight. RESULTS: Adequate samples were obtained from 50 twin and 49 singleton pregnancies at a mean gestational age of 30 weeks. At collection, the two groups were similar with regard to maternal age, gestational age, body mass index, and blood pressure. Mean urinary protein excretion was higher in twin compared with singleton pregnancies (269.3 ±124.1 mg compared with 204.3±92.5 mg, P=.004). Proteinuria (300 mg/day protein or greater) occurred in 38.0% (n=19) of twin and 8.2% (n=4) of singleton pregnancies (P<.001). After adjusting for confounding variables, the difference in mean total protein excretion remained significant (P=.004) and twins were more likely to have proteinuria compared with singleton pregnancies (adjusted odds ratio 9.1, 95% confidence interval 2.1-38.5). Nineteen participants developed a hypertensive disorder at a mean of 7.7 weeks after the urine collection (range 2.-14.5 weeks). After excluding these women, proteinuria was present in 43% of twin and 7% of singleton pregnancies (P<.001). CONCLUSION: Mean 24-hour urinary protein excretion in twin pregnancies is greater than in singletons. These data suggest a reevaluation of the diagnostic criteria for preeclampsia in twin pregnancies. [ABSTRACT FROM AUTHOR]

The article presents a discussion on the kidney preeclampsia. Preeclampsia has been defined as the onset of hypertension with proteinuria and edema. In women with underlying hypertension, preeclampsia generally is identified by elevation of prevailing blood pressure levels and the development of proteinuria. Preeclampsia is characterized by gestational hypertension, a phenomenon that has been attributed to an excess of vasoconstrictor over vasodilator influences in the systemic circulation. A parallel imbalance in the renal circulation would be expected to lower the glomerular perfusion rate.

Background. IgA nephropathy is a common form of progressive glomerular disease, associated with proliferation of mesangial cells and mesangial deposition of IgA. The present study was designed to investigate functional and morphological covariates of disease severity in patients with IgA nephropathy. Methods. Glomerular hemodynamics, permselectivity and ultrastructure were studied in 17 adult patients with IgA nephropathy using inulin, para-aminohippuric acid (PAH) and ³H-Ficoll clearances and morphometric methods. A mathematical model of macromolecule permeation through a heteroporous membrane was used to characterize glomerular permselectivity. Controls consisted of 14 healthy living kidney donors and 12 healthy volunteers. Results. The patients were heterogeneous in their disease severity, but as a group had a decreased glomerular filtration rate (GFR) and increased urinary protein excretion compared to controls [63 ± 29 SD vs. 104 ± 23 mL/min/1.73 m², P < 0.001, and (median) 1.34 vs. 0.11 g/day, P < 0.0001, respectively). A multivariate analysis of structural and functional relationships revealed GFR depression to be most strongly correlated with the prevalence of global glomerular sclerosis (t = -4.073, P = 0.002). Those patients with the most severe glomerular dysfunction had a reduced number of glomerular visceral epithelial cells (podocytes) per glomerulus. The degree of podocytopenia was related to the extent of glomerular sclerosis and of impairment of permselectivity and GFR, with worsening injury below an apparent threshold podocyte number of about 250 cells per glomerulus. There were no corresponding correlations between these indices of injury and the number of mesangial and endothelial cells. Conclusions. Our findings show that podocyte loss is a concomitant of increasing disease severity in IgA nephropathy. This suggests that podocyte loss may either cause or contribute to the progressive proteinuria, glomerular sclerosis... [ABSTRACT FROM AUTHOR]

Nature of glomerular dysfunction in pre-eclampsia. Background . Pre-eclampsia is characterized by hypertension, proteinuria and edema. Simultaneous studies of kidney function and structure have not been reported. We wished to explore the degree and nature of glomerular dysfunction in pre-eclampsia. Methods . Physiologic techniques were used to estimate glomerular filtration rate (GFR), renal plasma flow and afferent oncotic pressure immediately after delivery in consecutive patients with pre-eclampsia (PET; N = 13). Healthy mothers completing an uncomplicated pregnancy served as functional controls (N = 12). A morphometric analysis of glomeruli obtained by biopsy and mathematical modeling were used to estimate the glomerular ultrafiltration coefficient (Kf ). Glomeruli from healthy female kidney transplant donors served as structural controls (N = 8). Results . The GFR in PET was depressed below the control level, 91 ± 23 versus 149 ± 34 ml/min/1.73 m2 , respectively (P < 0.0001). In contrast, renal plasma flow and oncotic pressure were similar in the two groups (P = NS). A reduction in the density and size of endothelial fenestrae and subendothelial accumulation of fibrinoid deposits lowered glomerular hydraulic permeability in PET compared to controls, 1.81 versus 2.58 × 10-9 m/sec/PA. Mesangial cell interposition also curtailed effective filtration surface area. Together, these changes lowered the computed single nephron Kf in PET below control, 4.26 versus 6.78 nl/min · mm Hg, respectively. Conclusion . The proportionate (∼40%) depression of Kf for single nephrons and GFR suggests that hypofiltration in PET does not have a hemodynamic basis, but is a consequence of structural changes that lead to impairment of intrinsic glomerular ultrafiltration capacity. [ABSTRACT FROM AUTHOR]

Background: Steroids, the mainstay of treatment for nephrotic syndrome in children, have multiple adverse effects including growth suppression. Methods: Anthropometric measurements in children < 18 years enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were collected. The longitudinal association of medication exposure and nephrotic syndrome characteristics with height z-score and growth velocity was determined using adjusted Generalized Estimating Equation regression and linear regression. Results: A total of 318 children (57.2% males) with a baseline age of 7.64 ± 5.04 years were analyzed. The cumulative steroid dose was 216.4 (IQR 61.5, 652.7) mg/kg (N = 233). Overall, height z-scores were not significantly different at the last follow-up compared to baseline (− 0.13 ± 1.21 vs. − 0.23 ± 1.71, p = 0.21). In models adjusted for age, sex, and eGFR, greater cumulative steroid exposure (β − 7.5 × 10−6, CI − 1.2 × 10−5, − 3 × 10−6, p = 0.001) and incident cases of NS (vs. prevalent) (β − 1.1, CI − 2.22, − 0.11, p = 0.03) were significantly associated with lower height z-scores over time. Rituximab exposure was associated with higher height z-scores (β 0.16, CI 0.04, 0.29, p = 0.01) over time. Conclusion: Steroid dose was associated with lower height z-score, while rituximab use was associated with higher height z-score. [ABSTRACT FROM AUTHOR]

Background: In the current study, longitudinal BP and lipid measurements were examined in a NEPTUNE cohort of children with newly diagnosed nephrotic syndrome (cNEPTUNE). We hypothesized that hypertensive BP and dyslipidemia would persist in children with nephrotic syndrome, regardless of steroid treatment response. Methods: A multi-center longitudinal observational analysis of data obtained from children < 19 years of age with new onset nephrotic syndrome enrolled in the Nephrotic Syndrome Study Network (cNEPTUNE) was conducted. BP and lipid data were examined over time stratified by disease activity and steroid exposure. Generalized estimating equation regressions were used to find determinants of hypertensive BP and dyslipidemia. Results: Among 122 children, the prevalence of hypertensive BP at any visit ranged from 17.4% to 57.4%, while dyslipidemia prevalence ranged from 40.0% to 96.2% over a median of 30 months of follow-up. Hypertensive BP was found in 46.2% (116/251) of study visits during active disease compared with 31.0% (84/271) of visits while in remission. Dyslipidemia was present in 88.2% (120/136) of study visits during active disease and in 66.0% (101/153) while in remission. Neither dyslipidemia nor hypertensive BP were significantly different with/without medication exposure (steroids and/or CNI). In regression analysis, male sex and urine protein:creatinine ratio (UPC) were significant determinants of hypertensive BP over time, while eGFR was found to be a determinant of dyslipidemia over time. Conclusions: Results demonstrate persistent hypertensive BPs and unfavorable lipid profiles in the cNEPTUNE cohort regardless of remission status or concurrent steroid or calcineurin inhibitor treatment. [ABSTRACT FROM AUTHOR]

Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov , NCT03762850. Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White). Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m2 per year versus −3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m2 per year versus −3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. Travere Therapeutics. [ABSTRACT FROM AUTHOR]

Presents a case of a 40-year old white man who was referred for evaluation of an increased serum creatinine concentration. Clinical history; Physical examination findings; Laboratory evaluation; Presentation in the hospital; Treatment; Measurement of renal function; Physiological aspects of creatinine metabolism.

Background. Kidney transplantation is the preferred treatment for end-stage renal disease (ESRD), while peritoneal dialysis affords certain benefits over hemodialysis. Distributions and determinants of first ESRD treatment modality have not been compared across glomerulonephritis (GN) subtypes. Methods. We identified all adult (18-75 years) patients with ESRD attributed to any of sixGNsubtypes [focal segmental glomerulosclerosis (FSGS), IgA nephropathy (IgAN), membranous nephropathy (MN), membranoproliferative GN (MPGN), lupus nephritis (LN) and vasculitis] who were first registered in the US Renal Data System (USRDS) between 1996 and 2011. We used multinomial logistic regression-adjusting for temporal, geographic, demographic, socioeconomic and comorbid factors-to determine odds ratios (ORs) with 95% confidence intervals (CIs) for transplantation versus hemodialysis, and for peritoneal dialysis versus hemodialysis, comparing other GN subtypes to IgAN. Results. Among the 75 278 patients studied, patients with comparator GN subtypes were significantly less likely than those with IgAN to receive either transplantation or peritoneal dialysis. After adjusting for potentially confounding covariates, patients with comparator primary GN subtypes (FSGS, MN, MPGN) were at least as likely to receive transplantation [FSGS OR 0.98 (95% CI 0.93-1.15), MN OR 1.19 (95% CI 1.01-1.39), MPGN OR 1.08 (95% CI 0.93-1.26)] or peritoneal dialysis [FSGS OR 1.05 (95% CI 0.98-1.12), MN OR 1.30 (95% CI 1.18-1.43), MPGN OR 0.95 (95% CI 0.85-1.06)] as patients with IgAN. Conversely, patients with the secondary GN subtypes LN and vasculitis remained significantly less likely to receive either modality [transplantation OR 0.49 (95% CI 0.43- 0.56) for LN and 0.27 (95% CI 0.22-0.34) for vasculitis, peritoneal dialysis OR 0.76 (95% CI 0.70-0.82) for LN and 0.54 (95% CI 0.48-0.60) for vasculitis]. Conclusions. Significant differences in ESRD treatment practice patterns are apparent among GN subtypes. To ensure equitable care for all patients, regardless of GN subtype, reasons for observed disparities should be elucidated and-if appropriate-eliminated. [ABSTRACT FROM AUTHOR]

Themajority of patients withimmunoglobulin light chain amyloidosis (AL) fail to achieve a complete response (CR) to standard light chain suppressive chemotherapy, and almost all patients eventually experience hematologic relapse and progression of organ involvement. Additional well-tolerated treatment options are needed. We present our retrospective experience of 25 consecutive previously treated AL patients who received daratumumab, a CD38-directed monoclonal antibody approved for the treatment of multiple myeloma. Daratumumab was administered at 16 mg/kg weekly for 8 weeks, then every 2 weeks for 8 doses, and then every 4 weeks. Patients had received a median of 3 prior lines of therapy, with a previous hematologic CR in only 5 patients. The overall hematologic response rate to daratumumab was 76%, including CR in 36% and very good partial response in 24%. Median time to response was 1 month. Therapy was well tolerated, even among the 72% of patients with cardiac AL involvement. Grade 1-2 infusion reactions occurred in 15 patients, but no grade 3 or 4 reactions were observed. Daratumumab is a highly effective agent that produced rapid and deep hematologic responses without unexpected toxicity in our cohort of heavily pretreated AL patients. [ABSTRACT FROM AUTHOR]

Background Improvement of proteinuria as a marker for disease activity is associated with a better renal outcome in immunoglobulin A nephropathy (IgAN). Complement is an effector pathway in IgA-mediated kidney injury. Avacopan, a selective C5a receptor inhibitor, has previously shown efficacy in anti-neutrophil cytoplasmic antibody–associated vasculitis. The aim of this study was to evaluate the safety and efficacy of avacopan in patients with IgAN with persistent proteinuria despite a maximally tolerated dose of renin–angiotensin–aldosterone system blockade. The efficacy evaluation was based on the change in proteinuria. Methods This open-label pilot trial enrolled adult patients with biopsy-proven IgAN, urinary protein:creatinine ratio (UPCR) >1 g/g creatinine and an estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2 or >45 mL/min/1.73 m2 if eGFR has not declined >10 mL/min/1.73 m2 over the previous 24 weeks. If the UPCR remained at >1 g/g creatinine after an 8-week run-in period, patients started avacopan 30 mg twice daily. The primary efficacy endpoint was the change in the slope of the UPCR from the 8-week run-in period to the slope in the 12-week avacopan dosing period. Results A total of 10 of 15 screened patients entered the run-in period. Seven patients with a UPCR >1 g/g creatinine received avacopan. Six of seven patients had numerical improvement in the UPCR during the avacopan treatment period, three of whom had a numerical improvement of ∼50% at week 12. At week 24, five of seven patients still showed numerical improvement in the UPCR compared with baseline. The urinary monocyte chemoattractant protein-1:creatinine ratio decreased numerically 30% by week 8, possibly reflecting the anti-inflammatory activity of avacopan. Avacopan was well tolerated. There was one serious adverse event of unstable angina, which was deemed to be unrelated to avacopan. Conclusions This short-term pilot study showed an improvement in the slope of the UPCR, with ∼50% improvement in three of seven patients with IgAN. Longer avacopan treatment duration may be indicated for maximal benefit. [ABSTRACT FROM AUTHOR]

Background There is limited data available on the use of red blood cell (RBC) transfusions in younger chronic kidney disease patients not on dialysis (CKD-ND), for whom the consequences of developing antibodies to foreign antigens (allosensitization) may be particularly relevant. Methods We used the Ingenix medical claims database, comprising data on ∼40 million commercially insured US individuals, to identify annual (2002–08) cohorts of patients 18–64 years of age with newly diagnosed CKD. We followed each cohort for 1 year to estimate RBC transfusion rates and used Cox proportional hazards regression to identify patient characteristics associated with time to first transfusion. Results We identified 120 790 newly diagnosed CKD patients for the years 2002–08; 54% were 50–64 years of age. Overall, the transfusion rate was 2.64/100 person-years (PYs) (95% CI: 2.52–2.77). Rates were higher among those with diagnosed anemia [9.80/100 PYs (95% CI: 9.31–10.3)] and among those who progressed to end-stage renal disease (ESRD) [28.0/100 PYs (95% CI: 23.7–33.0)]. For those progressing to ESRD, transfusion rates more than doubled between 2002 and 2008. Of the factors evaluated, transfusion history and the presence of heart failure and diabetes were most strongly associated with a receipt of a transfusion. Conclusions RBC transfusions are relatively common and on the rise among younger CKD-ND patients who are anemic and progress to ESRD. Efforts to decrease the use of transfusions may be important for potential transplant candidates who progress to ESRD. [ABSTRACT FROM AUTHOR]

Background: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging. Methods: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. Results: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. Conclusions: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes. [ABSTRACT FROM AUTHOR]

The article offers information on the role of Grading cardiac response in Primary light chain amyloidosis (AL). It mentions AL as progressive disorder caused by clonal immunoglobulin light chain tissue deposition; and highlights the poorest prognosis of patients with symptomatic heart failure depending on the presenting N-terminal pro-B type natriuretic peptide cells.

Background: Few data have been reported on anemia management practices in hospital-based dialysis centers (HBDCs), which are uniquely different from other freestanding dialysis centers. Examining data from HBDCs would help determine if HBDCs and the general US dialysis population have similar trends related to how anemia is managed in dialysis patients. Objective: Given recent changes in the prescribing information of erythropoiesis-stimulating agents (ESAs) and in end-stage renal disease-related health policy and reimbursement, this study describes trends in anemia management practices in HBDCs from January 2010 through March 2013. Methods: Electronic medical records of 5404 adult hemodialysis patients in 50 US-based HBDCs were analyzed retrospectively. Patients included in the study cohort were aged ≥18 years and had at least 1 hemoglobin (Hb) measurement and 1 dose of an ESA between January 2010 and March 2013. End points included Hb concentration, darbepoetin alfa dosing, epoetin alfa dosing, and iron biomarkers (transferrin saturation and ferritin) and dosing. Results: From 2010 to 2013, mean monthly Hb levels declined from 11.4 to 10.7 g/dL; the percentage of patients with mean monthly Hb levels < 10 g/dL increased from 11.3% to 24.4%; and the percentage of patients with mean monthly Hb levels >12 g/dL declined from 30.1% to 11.2%. The median darbepoetin alfa cumulative 4-week dose also declined 38.8%, and the weekly epoetin alfa dose declined 24%. From January 2010 to March 2013, the percentage of patients with transferrin saturation >30% increased from 35.8% to 43.6%, the percentage of patients with ferritin levels >500 ng/mL increased from 62.0% to 77.9%, the percentage of patients with ferritin levels ≥800 ng/mL increased from 28.9% to 47.3%, and the median cumulative 4-week intravenous iron dose increased 50%. Conclusions: These study results support growing evidence that meaningful changes have occurred over the last 3 years in how anemia is clinically managed in US hemodialysis patients. Study limitations include that changes in patient clinical/demographic characteristics over time were not controlled for and that study findings may not be applicable to HBDCs that have different patient populations and/or do not use an electronic medical record system. Continuing to evaluate anemia management practices in HBDCs would provide additional information on the risks and benefits of anemia care. Consistent with national data, the findings from this study indicate that from 2010 to 2013, HBDCs modified anemia management practices for dialysis patients, as evidenced by reductions in mean monthly Hb levels and ESA dosing and by increases in iron biomarkers and dosing. [ABSTRACT FROM AUTHOR]

The prevalence and prognostic value of a concomitant diagnosis of symptomatic or asymptomatic multiple myeloma ( MM), as defined by the current International Myeloma Working Group ( IMWG) criteria, in patients with immunoglobulin light chain amyloidosis ( AL), are unknown. We studied 46 consecutive patients with AL who underwent quantification of serum M-protein and clonal bone marrow plasma cells, as well as a comprehensive evaluation for end organ damage by MM. Using standard morphology and CD138 immunohistochemical staining, 57% and 80% of patients were found to have concomitant MM, respectively. Nine patients exhibited end organ damage consistent with a diagnosis of symptomatic MM. While overall survival was similar between AL patients with or without concurrent myeloma (1-year overall survival 68% vs. 87%; P = 0·27), a diagnosis of symptomatic myeloma was associated with inferior outcome (1-year overall survival 39% vs. 81%; P = 0·005). Quantification of bone marrow plasma cells by both standard morphology and CD138 immunohistochemistry identified a much higher prevalence of concurrent MM in patients with AL than previously reported. Evaluation of bone marrow plasma cell infiltration and presence of myeloma associated end organ damage could be clinically useful for prognostication of patients with AL. [ABSTRACT FROM AUTHOR]

Limited data exist regarding screening methods and outcomes for orthotopic heart transplantation (OHT) in cardiac amyloidosis. As a result, uncertainty exists over the best approach to OHT for cardiac amyloidosis and for the timing of critical post-transplant therapies. This article reviews 6 patients who underwent OHT for cardiac amyloidosis at the Stanford University Amyloid Center from 2008 to present. All patients with light-chain amyloidosis received chemotherapy in the interval between OHT and autologous hematopoietic stem cell transplant. Five patients remain alive up to 25 months after OHT, without evidence of recurrent cardiac amyloid deposition. A novel strategy of OHT, followed by light-chain suppressive chemotherapy before autologous hematopoietic stem cell transplant, is feasible for patients with light-chain amyloidosis. [ABSTRACT FROM AUTHOR]

Individual cytokines have been reported to be associated with the pathogenesis and prognosis of immunoglobulin A (IgA) nephropathy (IgAN). We attempted to characterize a broad cytokine matrix in the serum of patients, and investigate its association with renal function. Thirty-two cytokines were simultaneously measured from the serum of IgAN patients (n=22) and healthy controls (n=12). Clinical variables including annual inulin based GFR and 24-h proteinuria were collected on the IgAN patients over a 5-year period. There was a significant difference between serum cytokine signature of IgAN and control values. There was a significant increase in 9 serum cytokines in IgAN patients compared with healthy controls, and these consisted of inflammatory cytokines, growth factors and chemokines. These 9 cytokines demonstrated significant inter-correlation and formed a distinct pattern compared to controls. IgAN appears to be associated with the elevation of multiple serum cytokines in a highly coordinated fashion. The pattern of cytokine changes could serve as a disease biomarker and may provide insights into disease pathogenesis. [ABSTRACT FROM AUTHOR]

Background. Inflammatory markers predict cardiovascular risk and mortality in endstage renal disease. The relationship of chronic infections to inflammation and vascular disease events has not been reported among American dialysis patients. Methods. We performed a cross-sectional and prospective study of a multiracial cohort of 97 chronic hemodialysis patients in California. Anti-Chlamydia pneumoniae IgA and IgG antibodies (Cp-IgA and Cp-IgG), anti-Helicobacter pylori antibodies (Hp-IgG), and highly sensitive C-reactive protein (hsCRP) levels were measured at enrollment. We ascertained the prevalence of atherosclerotic vascular (coronary artery, cerebrovascular, and peripheral vascular) disease (AVD) events, and observed participants for at least 1 year for incident events and mortality. We defined statistical significance as P < 0.01. Results. Elevated hsCRP levels (77%) and seropositivity to C. pneumoniae were common (Cp-IgA, 49%; Cp-IgG, 64%), whereas the seroprevalence of Hp-IgG was relatively low (25%). The hsCRP levels did not vary with infection status. In bivariate analysis, Cp-IgA and Cp-IgG were each associated with approximately fourfold higher odds of prevalent AVD (P < 0.01). Although anti-chlamydial antibodies maintained nearly significant associations with AVD after covariate adjustment (P < 0.05), antibodies did not predict outcomes over the period of observation. However, hsCRP was a nearly significant independent predictor of prevalent AVD (P = 0.02) and of mortality during follow-up (P = 0.01). We did not detect an association of Hp-IgG with any study outcome. Conclusions. Our findings generalize a possible link between C. pneumoniae and prevalent atherosclerosis in American hemodialysis patients and confirm the importance of hsCRP as a prognostic indicator. Our work does not support H. pylori as an important mediator of cardiovascular risk in dialysis patients. [ABSTRACT FROM AUTHOR]

Standard methods for detecting and monitoring of IgA nephropathy (IgAN) have conventionally required kidney biopsies or suffer from poor sensitivity and specificity. The Kidney Injury Test (KIT) Assay of urinary biomarkers has previously been shown to distinguish between various kidney pathologies, including chronic kidney disease, nephrolithiasis, and transplant rejection. This validation study uses the KIT Assay to investigate the clinical utility of the non-invasive detection of IgAN and predicting the progression of renal damage over time. The study design benefits from longitudinally collected urine samples from an investigator-initiated, multicenter, prospective study, evaluating the efficacy of corticosteroids versus Rituximab for preventing progressive IgAN. A total of 131 urine samples were processed for this study; 64 urine samples were collected from 34 IgAN patients, and urine samples from 64 demographically matched healthy controls were also collected; multiple urinary biomarkers consisting of cell-free DNA, methylated cell-free DNA, DMAIMO, MAMIMO, total protein, clusterin, creatinine, and CXCL10 were measured by the microwell-based KIT Assay. An IgA risk score (KIT-IgA) was significantly higher in IgAN patients as compared to healthy control (87.76 vs. 14.03, p < 0.0001) and performed better than proteinuria in discriminating between the two groups. The KIT Assay biomarkers, measured on a spot random urine sample at study entry could distinguish patients likely to have progressive renal dysfunction a year later. These data support the pursuit of larger prospective studies to evaluate the predictive performance of the KIT-IgA score in both screening for non-invasive diagnosis of IgAN, and for predicting risk of progressive renal disease from IgA and utilizing the KIT score for potentially evaluating the efficacy of IgAN-targeted therapies. [ABSTRACT FROM AUTHOR]

Background. Anemia management remains complicated in patients with endstage renal disease on hemodialysis. We wished to evaluate the effect of protocol adherence to EPO and intravenous iron dosing on achieving the desired range of hemoglobin levels. Methods. A cohort of hemodialysis patients was studied to evaluate the rate of adherence to EPO and iron dosing protocols over a 5 month period. A database was completed to evaluate all known comorbidities, demographic factors, and facility issues that might affect hemoglobin levels. A logistic regression model was employed to evaluate the effect of adherence to the anemia protocols on the probability of achieving a hemoglobin level below, within or above the targeted range of 11–12.5g/dl. Results. Among 2114 patients, we found that adherence to both the EPO and iron dosing protocol resulted in the greatest probability of achieving the target hemoglobin range (56 ± 5% in anemia protocol adherent patients versus 42 ± 7% in non adherent patients). This was predominantly due to a lowered risk of having above target hemoglobin levels rather than below. The use of the anemia protocols was associated with lower rates of hospitalization (9 ± 0.7 visits/100 months in adherent group vs 15 ± 2 in non adherent group) and lower utilization of both EPO and intravenous iron. Furthermore, patients in the adherent groups had less variability of their hemoglobin levels month by month, at least as judged by standard deviation. Conclusion. Adherence to anemia protocols, as practiced in the dialysis units included in this cohort, may improve hemodialysis patients ability to achieve target hemoglobin levels, and by avoiding above target hemoglobin values, lower drug utilization and reduce variability of hemoglobin levels. [ABSTRACT FROM AUTHOR]

Background: Atrial natriuretic peptide, a hormone synthesized by the cardiac atria, increases the glomerular filtration rate by dilating afferent arterioles while constricting efferent arterioles. It has been shown to improve glomerular filtration, urinary output, and renal histopathology in laboratory animals with acute renal dysfunction. Anaritide is a 25-amino-acid synthetic form of atrial natriuretic peptide. Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial of anaritide in 504 critically ill patients with acute tubular necrosis. The patients received a 24-hour intravenous infusion of either anaritide (0.2 μg per kilogram of body weight per minute) or placebo. The primary end point was dialysis-free survival for 21 days after treatment. Other end points included the need for dialysis, changes in the serum creatinine concentration, and mortality. Results: The rate of dialysis-free survival was 47 percent in the placebo group and 43 percent in the anaritide group (P = 0.35). In the prospectively defined subgroup of 120 patients with oliguria (urinary output, <400 ml per day), dialysis-free survival was 8 percent in the placebo group (5 of 60 patients) and 27 percent in the anaritide group (16 of 60 patients, P = 0.008). Anaritide-treated patients with oliguria who no longer had oliguria after treatment benefited the most. Conversely, among the 378 patients without oliguria, dialysis-free survival was 59 percent in the placebo group (116 of 195 patients) and 48 percent in the anaritide group (88 of 183 patients, P = 0.03). Conclusions: The administration of anaritide did not improve the overall rate of dialysis-free survival in critically ill patients with acute tubular necrosis. However, anaritide may improve dialysis-free survival in patients with oliguria and may worsen it in patients without oliguria who have acute tubular necrosis. (N Engl J Med 1997;336:828-34.) [ABSTRACT FROM AUTHOR]