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journal Scan

JOURNAL SCAN

This section has been developed to streamline articles across various national and international Nephrology Journals; to provide a quick update at regular intervals. In today’s times, where journal articles are being published across the globe, it is easy to miss out on clinically relevant important articles which could be pivotal in patient care and beyond. Keeping track of all the published articles may become difficult in busy practice. With this in mind, MKF academy has decided to start this JOURNAL SCAN subsection which will, under the tutelage of senior faculty and Nephrologists, provide regular updates from various journals in concise forms. This, it is hoped, will allow a quick glance in a single document format as a reference point, which can then be accessed thoroughly in the relevant journal online. In collaboration with other sections and subsections in this website, it is an attempt to provide healthcare professionals a single website platform for upgradation of knowledge.

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october 2024

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in Kidney Disease

Aim/Objective: A systemic  review and meta-analysis to evaluate the long-term safety of HIF prolyl hydroxylase inhibitors, which are oral treatments for anemia in chronic kidney disease.

Participant Demographics:

  1. A total of 25 trials were included in the review.
  2. These trials involved 26,478 participants.
  3. The median sample size was 594 participants, with a range from 82 to 3,872 participants.
  4. Out of the 25 trials, 13 trials enrolled 13,230 participants with dialysis-dependent CKD.
  5. The remaining 12 trials included 13,248 participants with nondialysis-dependent CKD

Inclusion Criteria:

  1. Trials included adults with CKD, defined as an estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m².
  2. Participants were either nondialysis-dependent or dialysis-dependent CKD patients.
  3. The trials compared HIF prolyl hydroxylase inhibitors with erythropoiesis-stimulating agents (ESAs) or placebo.
  4.   All trials had a minimum follow-up period of 48 weeks.

Exclusion Criteria:Trials with follow-ups shorter than 48 weeks because they might not reveal safety issues, and some focused mainly on haemoglobin levels rather than cardiovascular safety

 

Intervention:

  1. Databases Searched: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials.
  2. Search Dates: Initial search on October 13, 2021, and updated on March 6, 2023.
  3. Language Restriction: No language restrictions were applied.
  4. Data Extraction: Patient demographics, study design and conduct, and summary estimates of outcome events were collected using a standardized form.
  5. Risk of Bias Assessment: Each trial’s risk of bias was evaluated using the Cochrane RoB assessment tool.

 

 

Statistical  Analysis :

  •         This review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was prospectively registered in PROSPERO under registration number CRD42021278011.
  •         Hazard ratios were used where available; otherwise, log relative risk (RR) and standard errors were estimated from event counts and participant numbers.
  •         Inverse variance–weighted averages of log hazard ratios or log RRs were used to estimate treatment effects.
  •         Summary risk estimates with 95% confidence intervals (CIs) were obtained using random-effects meta-analysis with the restricted maximum likelihood method.
  •         Heterogeneity across trials was estimated using the I² test, with 25%, 50%, and 75% indicating low, moderate, and high heterogeneity, respectively.
  •         Analyses were conducted separately for patients treated with dialysis and those not treated with dialysis at baseline.
  •         Analyses were performed using Stata, version 17.

 

 

 

 

Outcomes:

Primary outcomes:There was no evidence that HIF prolyl hydroxylase inhibitors and ESA or HIF prolyl hydroxylase inhibitors and placebo had different effects on major adverse cardiovascular events (MACE) in people with dialysis-dependent or nondialysis-dependent chronic kidney disease (CKD).

 

Condition

Comparison

Risk Ratio for MACE

95% Confidence Interval (CI)

Certainty of Evidence

Dialysis-Dependent CKD        

HIF-PHIs vs. ESA          

0.99               

0.92 to 1.08               

High

Nondialysis-Dependent CKD     

HIF-PHIs vs. ESA          

1.08               

0.95 to 1.22               

Moderate

Nondialysis-Dependent CKD     

HIF-PHIs vs. Placebo      

1.10               

0.96 to 1.27               

Moderate

 

Secondary outcomes:

DialysisDependent CKD:No evidence of any differencein HIF-PHIs vs ESA except  HIF-PHIs may result in lower risk of atrial fibrillation

Outcome

Comparison

Risk Ratio

95% Confidence Interval (CI)

Certainty of Evidence

All-Cause Death          

HIF-PHIs vs. ESA          

1.00      

0.91 to 1.10               

High

Cardiovascular Death     

HIF-PHIs vs. ESA          

0.98      

0.85 to 1.12               

High

Myocardial Infarction    

HIF-PHIs vs. ESA          

0.91      

0.78 to 1.06               

Moderate  

Stroke

HIF-PHIs vs. ESA          

0.88      

0.69 to 1.11               

Moderate  

Congestive Heart Failure 

HIF-PHIs vs. ESA          

0.98      

0.85 to 1.14               

Moderate  

Dialysis Access Thrombosis

HIF-PHIs vs. ESA          

1.15      

0.94 to 1.42               

Moderate  

Atrial Fibrillation      

HIF-PHIs vs. ESA          

0.69      

0.58 to 0.83                   

Moderate  

Venous Thromboembolism   

HIF-PHIs vs. ESA          

1.02      

0.71 to 1.46               

Low

 

 

Non-dialysisDependent CKD:No evidence of any differencein HIF-PHIs vs ESA

Outcome

Comparison

Risk Ratio

95% Confidence Interval (CI)

Certainty of Evidence

All-Cause Death          

HIF-PHIs vs. ESA          

1.05      

0.95 to 1.18               

High

Cardiovascular Death     

HIF-PHIs vs. ESA          

1.09      

0.91 to 1.31               

Moderate

Myocardial Infarction    

HIF-PHIs vs. ESA          

1.17      

0.94 to 1.46               

Moderate  

Stroke

HIF-PHIs vs. ESA          

1.19      

0.87 to 1.63               

Moderate  

Congestive Heart Failure 

HIF-PHIs vs. ESA          

1.12      

0.94 to 1.35               

Moderate  

Dialysis Access Thrombosis

HIF-PHIs vs. ESA          

0.99      

0.58 to 1.70               

Low

Atrial Fibrillation      

HIF-PHIs vs. ESA          

1.08      

0.80 to 1.46               

Moderate  

Venous Thromboembolism   

HIF-PHIs vs. ESA          

0.92      

0.60 to 1.42               

Low

Composite Kidney Outcome 

HIF-PHIs vs. ESA          

0.99      

0.88 to 1.11               

High 

 

Comparison with placebo:No evidence of any difference in  HIF-PHIs vs Placebo except HIF-PHIs were associated with increased risk of venous  and dialysis access thrombosis( evidence is very uncertain).

Outcome

Comparison

Risk Ratio

95% Confidence Interval (CI)

Certainty of Evidence

All-Cause Death          

HIF-PHIs vs.placebo

1.08      

0.93 to 1.26               

Moderate

Cardiovascular Death     

HIF-PHIs vs. placebo

1.11      

0.86 to 1.44               

Moderate

Myocardial Infarction    

HIF-PHIs vs. placebo

1.29      

0.90 to 1.85               

Low                   

Stroke

HIF-PHIs vs. placebo

1.25      

0.82 to 1.90               

Low

Congestive Heart Failure 

HIF-PHIs vs. placebo

0.93      

0.75 to 1.16               

Moderate  

Dialysis Access Thrombosis

HIF-PHIs vs. placebo

1.86      

1.20 to 2.88               

Very Low              

Atrial Fibrillation      

HIF-PHIs vs. placebo

0.75      

0.36 to 1.57               

Very Low              

Venous Thromboembolism   

HIF-PHIs vs. placebo

3.07      

1.48 to 6.37               

Very Low              

 

 

Adverse Events:

  •         HIF prolyl hydroxylase inhibitors led to more frequent drug discontinuations compared to the control group (moderate-certainty evidence).
  •         Slight reduction in systemic hypertension in non-dialysisdependent CKD compared with baseline.
  •         Increased risk of infection/infestations, and probably increased risks of systemic hypertension and hyperkalemia compared with placebo in non-dialysis Dependent CKD
  •         Oesophageal/Gastric Erosions risk lower  in dialysis-dependent CKD but higher risk in non-dialysisdependent CKD compared with ESA.
  •         Non-dialysisDependent CKDmay increase the risk of seizures compared with placebo, but evidence is very uncertain.

 

Outcome

Comparison

Risk Ratio (95% CI)

Certainty of Evidence

Adverse Events Leading to Discontinuation

HIF-PHIs vs. Control

Not specified

Moderate

End-Stage Kidney Disease

HIF-PHIs vs. ESA

0.98 (0.91 to 1.07)

High

Acute Kidney Injury

HIF-PHIs vs. ESA

1.15 (0.96 to 1.39)

Moderate

Systemic Hypertension (Dialysis-Dependent CKD)

HIF-PHIs vs. ESA

0.99 (0.87 to 1.12)

High

Systemic Hypertension (Non-dialysis Dependent CKD)

HIF-PHIs vs. ESA

0.90 (0.82 to 0.98)

High

Hyperkalemia

HIF-PHIs vs. Placebo

1.29 (1.06 to 1.56)

Moderate

Oesophageal /Gastric Erosions (Dialysis-Dependent CKD)

HIF-PHIs vs. ESA

0.73 (0.54 to 0.99)

Low

Oesophageal/Gastric Erosions (Non-dialysis Dependent CKD)

HIF-PHIs vs. ESA

1.72 (1.20 to 2.49)

Low

Cancer-Related Adverse Events (Dialysis-Dependent CKD)

HIF-PHIs vs. ESA

0.80 (0.63 to 1.00)

Low

Cancer-Related Adverse Events (Non-dialysis Dependent CKD)

HIF-PHIs vs. ESA

1.03 (0.72 to 1.47)

Low

Seizures

HIF-PHIs vs. Placebo

5.13 (1.79 to 14.68)

Very Uncertain



Limitations :

  1. The study assumes that HIF prolyl hydroxylase inhibitors have a class effect despite variations in their specificity, half-life, and potency.
  2. Intention-to-Treat Analysis
  3. Lack of Subgroup Analyses
  4. No Individual Patient Data

 

Conclusion:

There was no evidence of a difference in long-term cardiovascular safety between HIF prolyl hydroxylase inhibitors and erythropoiesis-stimulating agents in both adults with dialysis-dependent CKD and those with non-dialysis-dependent CKD.

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 – Dr. Pooja Barak

september 2024

Autoantibodies Targeting Nephrin in Podocytopathies

Aims of the Study 

  •  Analysis of anti-nephrin prevalence in adult glomerular diseases and childhood idiopathic nephrotic syndrome
  •  Investigation of anti-nephrin autoantibody association with clinical disease activity
  •  Characterization of anti-nephrin autoantibody course during clinical follow-up
  •  Establishment of an animal model of anti-nephrin–associated podocytopathy

•    Identification of molecular consequences of anti-nephrin autoantibody binding to podocytes

Methodology

  •   Study Design -Multicenter study involving both adults and children.
  •   Patients: 539 (357 adults and 182 children).

•       Controls: 117 healthy individuals (67 adults and 50 children)

Patient eligibility criteria

Adults

  1.       Age of 18 years or older
  2.       Biopsy-proven glomerular disease
  3.       Availability of serum sample

Children

  1.       Age under 18 years
  2.       Clinical diagnosis of idiopathic nephrotic syndrome
  3.       Availability of serum sample
  •       Detection of Autoantibodies

   Immunoprecipitation technique with recombinant human nephrinectodomain to detect                    circulating antinephrin autoantibodies.

  •       Experimental Animal Model -actively immunizing mice with recombinant murine nephrin

Statistical analysis

  •       Differences in clinical parameters between anti-nephrin antibody positive and negative patients were shown as scatter dot plots with bars indicating medians and their unadjusted 95% confidence intervals. 
  •       Associaton of anti-nephrin antibodies measured by immunoprecipitation with disease activity was assessed by fitting linear repeated measures models to ln-transformed proteinuria data for children and adults, who tested positivefor anti-nephrin antibody at least once and had available follow-up samples/data. 
  •       Time points within patients were treated as repeated measures while anti-nephrin positivity, sex, as well as their interaction term (anti-nephrin positivity x sex) as fixed effects. 

 Results

ü  In adults, antinephrin autoantibodies were found in 46 of the 105 patients (44%) with minimal change disease, 7 of 74 (9%) with primary focal segmental glomerulosclerosis

ü  In 182 children with idiopathic nephrotic syndrome, 94 (52%) had detectable antinephrin autoantibodies.

ü  In the subgroup of patients with active minimal change disease or idiopathic nephrotic syndrome who were not receiving immunosuppressive treatment, the prevalence of antinephrin autoantibodies was as high as 69% and 90%, respectively.

ü  At study inclusion and during follow-up, antinephrin autoantibody levels were correlated with disease activity.

ü  Experimental immunization induced a nephrotic syndrome, a minimal change disease–like phenotype, IgG localization to the podocyte slit diaphragm, nephrin phosphorylation, and severe cytoskeletal changes in mice.

Limitations

  • Sample Size and Population
  • Cross-Sectional Design
  • Assay Sensitivity
  • Lack of Mechanistic Insights
  • Immunosuppressive Treatment Influence 

Conclusion

  • This study research highlights the significant role of antinephrin autoantibodies in podocytopathies like MCD and INS.
  • findings suggest these autoantibodies are not just markers of disease activity but also active players in disease progression.
  •  Understanding their role could pave the way for more targeted and effective treatments, ultimately improving patient care in nephrotic syndrome.
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 – Dr. Pooja Barak

august 2024

SPRINT Trial Analysis

Aim/Objective:SPRINT trial aimed to evaluate the Legacy Effect of Intensive versus Standard Blood Pressure Control on the Incidence of initiation of Dialysis therapy or  Kidney Transplantation and all cause mortality. 

Participant Demographics:

 Total Participants:Out of 9,361 randomized trial participants9,279 (99%) were included in the analysis and 8,882 (95%) were linked to the US Renal Data Systemwhich assessed kidney failure( initiation of dialysis therapy or transplantation) and all-cause mortality through 2020.

Location: 102 Clinic sites in the unitedstates and Puerto Rico
● Age:50 years and older
Inclusion Criteria:Participants were aged 50 years or older with hypertension and increased cardiovascular risk

Exclusion Criteria: 

  • Diabetes mellitus,
  • History of stroke,
  • Heart failure or reduced ejection fraction (<35%),
  • Proteinuria > 1 gram per day
  • Polycystic kidney disease
  • Persons with a diagnosis of dementia

Intervention: 

Design: Secondary analysis of a randomized, open-label clinical trial with observational follow-up.

Linkage: Participants from SPRINT were linked to the US Renal Data System (USRDS) for follow-up through 2020.

Randomization Groups:

Intensive treatment: Systolic BP goal <120 mm Hg (n=4,678)

Standard treatment: Systolic BP goal <140 mm Hg (n=4,683)

  • Period: November 2010 to March 2013.
  •         Trial Phase: November 8, 2010 – June 30, 2016.
  •         Observational Follow-Up: July 1, 2016 – December 31, 2020.

Outcomes Achieved:

  •     Over a median follow-up of 8.6 years, 101 cases of kidney failure ( initiation of dialysis therapy or renal transplantation) were recorded.
  •     Most kidney failures (73.3%) occurred in participants with baseline eGFR <45 ml/min/1.73m².
  •     The cumulative incidence of kidney failure at 8.6 years was 10.6% for the intensive treatment group and 7.8% for the standard treatment group.
  •     Additionally, 1,596 participants died before developing kidney failure by December 31, 2020.

Statistical  Analysis :

  •         Comparisons of kidney failure incidence between treatment groups accounted for the risk of all-cause mortality using cause-specific Cox proportional hazards models, with stratification by clinic site.
  •         The models separately analysed the first occurrence of serious adverse events (SAEs) related to acute kidney injury (AKI) and other causes, adjusting for age, sex, race/ethnicity, baseline eGFR, UACR, and treatment group.
  •         Due to the low incidence of kidney failure in participants with a baseline eGFR ≥60 ml/min/1.73 m², analyses were limited to those with a baseline eGFR <60 ml/min/1.73 m².

Limitations :

  •         Trial focused on high-quality matches from USRDS and NDI, but there could be misclassification between sources.
  •         USRDS omits cases where conservative management for kidney failure (eGFR <15 ml/min/1.73 m²) is chosen, leading to possible underestimation of end-stage kidney disease incidence in SPRINT.
  •         Passive follow-up limits exploration of factors like BP measurements, medication regimens, hospitalizations, and consistent kidney function monitoring.
  •         Inability to assess the impact of medication changes or BP control on trial results.
  •         Low number of kidney failure events limits ability to evaluate non-linear associations, interactions, or confounding variables between AKI and subsequent kidney failure risk

Conclusion:

With approximately 5 years of observational follow-up and linkage to USRDS for kidney failure events, SPRINT participants randomized to more intensive treatment for systolic BP lowering as compared to standard treatment had higher rates of kidney failure overall and in those with eGFR <45 mL/min/1.73 m², but these differences were not statistically significant.

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 – Dr. Yogesh Khandagale

july 2024

SELECT Trial Analysis

Aim/Objective: The SELECT trial aimed to evaluate the long-term cardiovascular and renal outcomes of semaglutide in non-diabetic patients with overweight or obesity and established cardiovascular disease . Specifically, the study sought to determine whether semaglutide could reduce major adverse cardiovascular events (MACE) and improve kidney function in this high-risk population.

Participant Demographics:

  •       Total Participants: 17,604
  •       All participants had established CVD and were classified as overweight or obese with a BMI ≥ 27 kg/m².

●        Age: Participants were aged 45 years or older.

Inclusion Criteria:

  • Age ≥ 45 years
  • BMI ≥ 27 kg/m²
  • Established Cardiovascular disease (history of myocardial infarction, ischemic or hemorrhagic stroke, or symptomatic peripheral artery disease)

Exclusion Criteria:

  • History of type 1 or type 2 diabetes
  • HbA1c ≥ 6.5% (48 mmol/mol)
  • Presence of end-stage kidney disease or need for dialysis
  • Recent (within 60 days) myocardial infarction, stroke, hospitalization for unstable angina, or transient ischemic attack
  • New York Heart Association Class IV heart failure

Intervention:

  • Dosage: Participants were randomized 1:1 to receive escalating doses of once-weekly subcutaneous semaglutide over 16 weeks, reaching a target dose of 2.4 mg.
  • Duration: The median follow-up time was 182 weeks. 

Outcomes Achieved:

  1. Cardiovascular Outcomes:
  • 20% reduction in MACE compared to placebo
  •  This benefit was observed across a wide range of weight changes, including minimal weight loss
  1. Renal Outcomes
  • Significant reduction in the main 5-component kidney composite endpoint. (death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent eGFR < 15 ml/min/1.73 m², persistent ≥ 50% reduction in eGFR, or onset of persistent macroalbuminuria) in the semaglutide group (1.8%) compared to the placebo group (2.2%)
  • Improvement in eGFR at 104 weeks was observed, with a treatment benefit of 0.75 ml/min/1.73 m² in the overall population and 2.19 ml/min/1.73 m² in patients with baseline eGFR < 60 ml/min/1.73 m²

Mediation Analysis Findings:

  • Mediation analysis was used to explore whether the cardiovascular and renal benefits of semaglutide were independent of weight loss, blood pressure and glycated hemoglobin

Challenges with Mediation Analysis in SELECT:

  • The number of events for the main composite endpoint and the study power was too low to support a robust formal mediation analysis.
  • Exploratory analyses indicated that there was little correlation between the within-person change in eGFR and the within-person changes in body weight, systolic blood pressure or glycated hemoglobin (HbA1c) in the semaglutide or placebo arms
  • However, a mediation analysis suggested that 81% (95% CI 41.30, 120) of the change in eGFR was attributable to change in body weight with considerable imprecision in the estimate
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June 2024

FLOW Trial Analysis

Aim/Objective: The FLOW trial aimed to evaluate whether semaglutide can reduce major kidney disease events, cardiovascular events, and death in patients with type 2 diabetes and CKD.

Participant Demographics:

  •       Total Participants: 3,533
  •    Geographic Distribution: Participants were from Asia, Europe, and North America.
  •       Ethnic Diversity: Very few Black participants were included.
  •       BMI Statistics: Mean BMI was around 31, with 10% having a BMI > 40 and 10% having a BMI < 25.

Inclusion Criteria:

  •       Type 2 diabetes (HbA1c < 10%)
  •       GFR 50-75 with UACR 300-5000 mg/g OR GFR 25-50 with UACR 100-5000 mg/g
  •       Use of RAS inhibitors (mainly ACE inhibitors or ARBs)

Exclusion Criteria:

  •       Patients with glomerulonephritis, polycystic kidney disease , or post-transplant
  •       No specific weight/BMI eligibility criteria

Intervention:

  •       Dosage: Participants were randomized 1:1 to receive subcutaneous semaglutide at a dose of 1.0 mg weekly or placebo. An 8-week dose-escalation regimen was used, starting from 0.25 mg per week for 4 weeks and 0.5 mg per week for another 4 weeks, followed by a maintenance dose of 1.0 mg per week.
  •       Duration: The median follow-up time was 3.4 years.

Outcomes Achieved:

The risk of a primary-outcome event was 24% lower in the semaglutide group than in the placebo group

  1. Cardiovascular Outcomes:
  •       Reduced the risk of major renal events
  •       Lowered the risk of death from cardiovascular causes
  •       Decreased the overall mortality rate
  •       Reduced the incidence of major cardiovascular events
  1. Renal Outcomes:
  •       Slowed the decline in renal function
  •       Reduced the incidence of the main composite kidney endpoint (death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent eGFR < 15 ml/min/1.73 m², persistent ≥ 50% reduction in eGFR, or onset of persistent macroalbuminuria) in the semaglutide group compared to the placebo group
  •       Improvement in eGFR at 104 weeks, with a treatment benefit confirmed by Cystatin C measurements, indicating that the results were not influenced by loss of muscle mass
  1. Intermediate Outcomes:
  •       Significantly reduced urinary albumin levels
  •       Achieved greater weight reduction
  •       Improved blood glucose control
  •       Reduced both systolic and diastolic blood pressure, primarily driven by weight loss
  1. Safety Outcomes:
  •       Reduced incidence of cardiac failure
  •       No significant difference in rates of acute kidney injury (AKI) or gastrointestinal effects
  •       Slight increase in pancreatitis cases (only 3), but overall rates were low

Mediation Analysis Findings:

The mediation analysis identified hematocrit as the strongest mediator in the protective effects of semaglutide, with hemoglobin, uric acid, and urine albumin-to-creatinine ratio also contributing but to a lesser extent. These factors highlight the potential of semaglutide in managing glycemic control and offering renal protection for patients with T2D and CKD.

Weight loss was not identified as a significant mediator.

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– Dr. Sakti Selvakumar

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