Major Adverse Kidney Events Are Associated with the Aquaporin 5 -1364A/C Promoter Polymorphism in Sepsis: A Prospective Validation Study

Since the functionally important AQP5 -1364A/C single nucleotide promoter polymorphism alters key mechanisms of inflammation and survival in sepsis, it may affect the risk of an acute kidney injury. Accordingly, we tested the hypothesis in septic patients that this AQP5 polymorphism is associated with major adverse kidney events and also validated its impact on 90-day survival. In this prospective observational monocentric genetic association study 282 septic patients were included and genotyped for the AQP5 –1364A/C polymorphism (rs3759129). The primary endpoint was the development of major adverse kidney events within 30 days. In AC/CC genotypes, major adverse kidney events were less frequent (41.7%) than in AA genotypes (74.3%; OR:0.34; 95%-CI: 0.18–0.62; p < 0.001). Ninety-day survival was also associated with the AQP5 polymorphism (p = 0.004), with 94/167 deaths (56.3%) in AA genotypes, but only 46/115 deaths (40.0%) in C-allele carriers. Multiple proportional hazard analysis revealed AC/CC genotypes to be at significantly lower risk for death within 90 days (HR: 0.60; 95%-CI: 0.42-0.86; p = 0.006). These findings confirm the important role of the AQP5 -1364A/C polymorphism as an independent prognostic factor in sepsis. Furthermore, we demonstrate a strong association between this AQP5 polymorphism and susceptibility for major adverse kidney events suggesting a promising characteristic in terms of precision medicine.

Download Full-text

Aquaporin 5 Gene Promoter −1364A/C Polymorphism Associated with 30-day Survival in Severe Sepsis

Anesthesiology ◽

10.1097/aln.0b013e31820ca911 ◽

2011 ◽

Vol 114 (4) ◽

pp. 912-917 ◽

Cited By ~ 26

Author(s):

Michael Adamzik ◽

Ulrich H. Frey ◽

Stephan Möhlenkamp ◽

André Scherag ◽

Christian Waydhas ◽

...

Keyword(s):

Severe Sepsis ◽

Hazard Analysis ◽

Survival Rates ◽

Gene Promoter ◽

Simplified Acute Physiology Score ◽

Proportional Hazard ◽

Aquaporin 5 ◽

Continuous Hemofiltration ◽

Migration Activity ◽

Multivariate Proportional Hazard

Background Because the aquaporin (AQP) 5 promoter -1364A/C polymorphism is associated with altered AQP5 expression, this association could have an impact on key mechanisms in sepsis, such as cell migration, activity of the rennin-angiotensin- aldosterone system (RAAS), and water transport across biologic membranes. Therefore, we tested the hypothesis that the AQP5 promoter -1364A/C polymorphism is associated with increased 30-day survival in severe sepsis. Methods In a prospective study, adults with severe sepsis (N = 154) were genotyped for the AQP5 promoter -1364A/C polymorphism. The clinical endpoint was 30-day survival. Kaplan-Meier plots and multivariate proportional hazard analyses were used to evaluate the relationship between genotypes and clinical outcomes. Results Thirty-day survival was significantly associated with AQP5 -1364A/C genotypes (P = 0.001). Survival rates were 57% for AA genotypes (n = 90) but 83% for combined AC/CC genotypes (56 vs. 8, respectively). Multivariate proportional hazard analysis including sex, age, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment score, body mass index, necessity for continuous hemofiltration/dialysis, concentrations of plasma angiotensin II, serum aldosterone, C-reactive protein, and interleukin 6 as covariates revealed the AQP5 -1364A/C polymorphism as a strong and independent prognostic factor for 30-day survival. In this analysis, homozygous AA subjects were at high risk for death within 30 days (hazard ratio, 3.59; 95% CI, 1.47-8.80; P = 0.005) compared with AC/CC genotypes. Conclusion The C-allele of the AQP5 -1364A/C polymorphism is associated with increased 30-day survival in patients with severe sepsis. This finding suggests the importance of variations in expression of AQP5 channels in severe sepsis.

Download Full-text

Influence of Genetic Variation in COMT on Cisplatin-Induced Nephrotoxicity in Cancer Patients

Genes ◽

10.3390/genes11040358 ◽

2020 ◽

Vol 11 (4) ◽

pp. 358

Author(s):

Bram C. Agema ◽

Stijn L.W. Koolen ◽

Mirjam de With ◽

Nadia van Doorn ◽

Niels Heersche ◽

...

Keyword(s):

Acute Kidney Injury ◽

Odds Ratio ◽

Chemotherapeutic Agent ◽

Kidney Injury ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Number Of Patients ◽

Low Incidence ◽

Grade 3

Cisplatin is a chemotherapeutic agent widely used for multiple indications. Unfortunately, in a substantial set of patients treated with cisplatin, dose-limiting acute kidney injury (AKI) occurs. Here, we assessed the association of 3 catechol-O-methyltransferase (COMT) single nucleotide polymorphisms (SNPs) with increased cisplatin-induced nephrotoxicity. In total, 551 patients were genotyped for the 1947 G>A (Val158Met, rs4680), c.615 + 310 C>T (rs4646316), and c.616–367 C>T (rs9332377) polymorphisms. Associations between these variants and AKI grade ≥3 were studied. The presence of a homozygous variant of c.616-367C>T was associated with a decreased occurrence of AKI grade 3 toxicity (p = 0.014, odds ratio (OR) 0.201, 95% confidence interval (CI) (0.047–0.861)). However, we could not exclude the role of dehydration as a potential cause of AKI in 25 of the 27 patients with AKI grade 3, which potentially affected the results substantially. As a result of the low incidence of AKI grade 3 in this dataset, the lack of patients with a COMT variant, and the high number of patients with dehydration, the association between COMT variants and AKI does not seem clinically relevant.

Download Full-text

SNP rs2073618 of the Osteoprotegerin Gene Is Associated with Diabetic Retinopathy in Slovenian Patients with Type 2 Diabetes

BioMed Research International ◽

10.1155/2013/364073 ◽

2013 ◽

Vol 2013 ◽

pp. 1-6 ◽

Cited By ~ 8

Author(s):

Sara Mankoč Ramuš ◽

Tina Kumše ◽

Mojca Globočnik Petrovič ◽

Daniel Petrovič ◽

Ines Cilenšek

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Strong Association ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Regulatory Molecule ◽

Codominant Model ◽

Osteoprotegerin Gene

Recent studies indicate that osteoprotegerin (OPG) acts as an important regulatory molecule in the vasculature. Also, a strong association was observed between circulation OPG and microvascular complication. By considering the possible role of OPG in diabetic retinopathy (DR) we examined two of the most studied polymorphisms of the OPG genes rs2073618 (located in exon I) and rs3134069 (located in the promoter region) and their relation to DR in Slovenian patients with type 2 diabetes. Logistic regression analysis demonstrated that the carriers of the CC genotype had a 2.2 higher risk for DR than those with either the CG genotype or the GG genotype (codominant model for rs2073618). Furthermore, the combined effect of single nucleotide polymorphisms (SNPs) rs2073618 and rs3134069 on the DR was stronger than that of each SNP alone. The odds ratio (OR) for individuals with CC genotype (rs2073618) and AA genotype (rs3134069) compared with carriers of CG/GG (rs2073618) + AA (rs3134069) was 2.54 (95% CI = 1.26–5.13, ). To conclude, these results indicate that SNPs in the OPG gene may be implicated in the pathogenesis of DR.

Download Full-text

Serum klotho as a marker for early diagnosis of acute kidney injury after cardiac surgery

Journal of Medical Biochemistry ◽

10.2478/jomb-2019-0024 ◽

2019 ◽

Vol 0 (0) ◽

Author(s):

Aleš Jerin ◽

Osama F Mosa ◽

Jurij M Kališnik ◽

Janez Žibert ◽

Milan Skitek

Keyword(s):

Acute Kidney Injury ◽

Cardiac Surgery ◽

Early Diagnosis ◽

Lower Risk ◽

Kidney Injury ◽

Tree Model ◽

Significant Difference ◽

Better Than

SummaryBackgroundEarly diagnosis of acute kidney injury (AKI) after cardiac surgery is based on serum creatinine which is neither a specific nor a sensitive biomarker. In our study, we investigated the role of serum Klotho in early prediction of AKI after cardiac surgery using cardiopulmonary bypass (CPB).MethodsThe included patients were classified into three groups according to AKI stages using KDIGO criteria. The measurements of creatinine and Klotho levels in serum were performed before surgery, at the end of CPB, 2 hours after the end of CPB, 24 hours and 48 hours postoperatively.ResultsSeventy-eight patients were included in the study. A significant increase of creatinine levels (p<0.001) was measured on the first day after the surgery in both AKI groups compared to the non-AKI group. However, a significant difference between AKI-2 and AKI-1 groups (p=0.006) was not measured until the second day after the operation. Using decision trees for classification of patients with a higher or lower risk of AKI we found out that Klotho discriminated between the patients at low risk of developing more severe kidney injury in the first hours after surgery and the patients at high risk better than creatinine. Adding also the early measurements of creatinine in the decision tree model further improved the prediction of AKI.ConclusionSerum Klotho may be useful to discriminate between the patients at lower and the patients at higher risk of developing severe kidney injury after cardiac surgery using CPB already in the first hours after surgery.

Download Full-text

Acute Kidney Injury in COVID-19

International Journal of Molecular Sciences ◽

10.3390/ijms22158081 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8081

Author(s):

Marta Głowacka ◽

Sara Lipka ◽

Ewelina Młynarska ◽

Beata Franczyk ◽

Jacek Rysz

Keyword(s):

Acute Kidney Injury ◽

Strong Association ◽

Kidney Injury ◽

Respiratory Illness ◽

Angiotensin Converting Enzyme 2 ◽

Tubular Cells ◽

Collapsing Glomerulopathy ◽

Proximal Tubular ◽

Insight Into

COVID-19 is mainly considered a respiratory illness, but since SARS-CoV-2 uses the angiotensin converting enzyme 2 receptor (ACE2) to enter human cells, the kidney is also a target of the viral infection. Acute kidney injury (AKI) is the most alarming condition in COVID-19 patients. Recent studies have confirmed the direct entry of SARS-CoV-2 into the renal cells, namely podocytes and proximal tubular cells, but this is not the only pathomechanism of kidney damage. Hypovolemia, cytokine storm and collapsing glomerulopathy also play an important role. An increasing number of papers suggest a strong association between AKI development and higher mortality in COVID-19 patients, hence our interest in the matter. Although knowledge about the role of kidneys in SARS-CoV-2 infection is changing dynamically and is yet to be fully investigated, we present an insight into the possible pathomechanisms of AKI in COVID-19, its clinical features, risk factors, impact on hospitalization and possible ways for its management via renal replacement therapy.

Download Full-text

The aquaporin 5 -1364A/C promoter polymorphism impacts on resolution of acute kidney injury in pneumonia evoked ARDS

PLoS ONE ◽

10.1371/journal.pone.0208582 ◽

2018 ◽

Vol 13 (12) ◽

pp. e0208582 ◽

Cited By ~ 5

Author(s):

Tim Rahmel ◽

Hartmuth Nowak ◽

Katharina Rump ◽

Winfried Siffert ◽

Jürgen Peters ◽

...

Keyword(s):

Acute Kidney Injury ◽

Kidney Injury ◽

Promoter Polymorphism ◽

Aquaporin 5

Download Full-text

Niacinamide may be Associated with Improved Outcomes in COVID-19-Related Acute Kidney Injury: An Observational Study

Kidney360 ◽

10.34067/kid.0006452020 ◽

2020 ◽

pp. 10.34067/KID.0006452020

Author(s):

Nathan Hutzel Raines ◽

Sarju Ganatra ◽

Pitchaphon Nissaisorakarn ◽

Amar Pandit ◽

Alexander Morales ◽

...

Keyword(s):

Acute Kidney Injury ◽

Lower Risk ◽

Primary Outcome ◽

Total Mortality ◽

Kidney Injury ◽

Proportional Hazard ◽

Vitamin B3 ◽

Cox Proportional Hazard ◽

Improved Outcomes ◽

Quasi Experimental

Background: Acute kidney injury (AKI) is a significant complication of Coronavirus Disease 2019 (COVID-19), with no effective therapy. Niacinamide, a vitamin B3 analog, has some evidence of efficacy in non-COVID-19-related AKI. The objective of this study is to evaluate the association between niacinamide therapy and outcomes in patients with COVID-19-related AKI. Methods: We implemented a quasi-experimental design with non-random, prospective allocation of niacinamide in 201 hospitalized adult patients, excluding those with baseline estimated glomerular filtration rate <15 ml/min/1.73m2 on or off dialysis, with COVID-19-related AKI by Kidney Disease Improving Global Outcomes (KDIGO) criteria, in two hospitals with identical COVID-19 care algorithms, one of which additionally implemented treatment with niacinamide for COVID-19-related AKI. Patients on the niacinamide protocol (B3 patients) were compared against patients at the same institution before protocol commencement and contemporaneous patients at the non-niacinamide hospital (collectively, non-B3 patients). The primary outcome was a composite of death or renal replacement therapy (RRT). Results: 38/90 B3 patients and 62/111 non-B3 patients died or received RRT. Using multivariable Cox proportional hazard modeling, niacinamide was associated with a lower risk of RRT or death (HR 0.64, 95% CI 0.40 to 1.00, p=0.05), an association driven by patients with KDIGO stage 2/3 AKI (HR 0.29, 95% CI 0.13 to 0.65, p=0.03; p interaction with KDIGO stage 0.03). Total mortality also followed this pattern (HR 0.17, 95% CI 0.05-0.52 in KDIGO 2/3 patients, p=0.002). Serum creatinine following AKI increased by 0.20 (SE 0.08) mg/dL/day among non-B3 patients with KDIGO 2/3 AKI but was stable among comparable B3 patients (+0.01 (SE 0.06) mg/dL/day; p interaction 0.03). Conclusions: Niacinamide was associated with lower risk of RRT/death and improved creatinine trajectory among patients with severe COVID-19-related AKI. Larger randomized studies are necessary to establish a causal relationship.

Download Full-text