Renal Markers For Monitoring Acute Kidney Injury Transition To Chronic Kidney Disease After COVID-19

Faeq Husain-Syed1,2,3, Gianluca Villa3 , Jochen Wilhelm4,5, Sara Samoni 2 , Ulrich Matt1,5, Istva´n Vada´sz1,5, Khodr Tello1,5, Birgit Jennert1 , Hartmut Dietrich1 , Janina Trauth1 , Shadi Kassoumeh6 , Borros Arneth7 , Harald Renz7,8, Michael Sander9 , Susanne Herold1,5, Werner Seeger1,4,5,10, Stefan J. Schunk11, Thimoteus Speer11,12, Horst-Walter Birk1,* and Claudio Ronco2,13,* 

1 Department of Internal Medicine II, Justus-Liebig-University Giessen, University Hospital Giessen and Marburg, Giessen, Germany, 

2 Department of Nephrology, Dialysis and Transplantation, International Renal Research Institute of Vicenza, San Bortolo Hospital, Vicenza, Italy, 3 Department of Health Science, Section of Anesthesiology and Intensive Care, University of Florence, Florence, Italy, 4 Institute for Lung Health, Justus-Liebig-University Giessen, Giessen, Germany, 5 Member of the German Center for Lung Research, Universities of Giessen and Marburg Lung Center, Giessen, Germany, 6 Justus-Liebig-University Medical School, Giessen, Germany, 7 Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Justus-Liebig-University Giessen, Giessen, Germany, 8 Sechenov First Moscow State Medical University, Moscow, Russia, 9 Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Giessen and Marburg, Justus-Liebig-University Giessen, Giessen, Germany, 10Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany, 11Division of Nephrology and Hypertension, Department of Internal Medicine IV, Saarland University Medical Center, Homburg/Saar, Germany, 12Translational Cardiorenal Medicine, Saarland University, Homburg/Saar, Germany and 13Department of Medicine, University of Padua, Padua, Italy 

*These authors are joint last authors. 

INTRODUCTION 

The association of renal markers with renal recovery after acute kidney injury (AKI) and progression to chronic kidney disease (CKD) after coronavirus disease 2019 (COVID-19) is unexplored. Tubular epithelial cells are the cells most affected by COVID-19-associated AKI, in line with other AKI forms in critical illness [1, 2]. Maladaptive repair of injured tubules post-AKI may trigger persistent profibrotic signaling and delayed resolution of inflammation along multiple pathways that drive renal tubulointerstitial fibrosis and thereby progressive CKD [3]. 

Cistanche deserticola efficacy—tonifying kidney

Click here to view  Cistanche for Kidney disease products

【Ask for more】 Email: xue122522@foxmail.com /  Whats App:  0086 18599088692 /  Wechat:  18599088692

（The modern pharmacological research , Cistanche deserticola  know as desert ginseng,and is cistanche safe.Can excite the pituitary-adrenocortical hormone, improve the immune function and enhance the phagocytic ability of mononuclear macrophages. It has the function of tonifying the kidney and supporting the yang and can resist cold, hypoxia, and fatigue. Cistanche deserticola ma also has the function of regulating endocrine and protecting renal function.

Urinary dickkopf-3 (uDKK3) is a recently described novel CKD progression marker in various causes of CKD [4, 5]. DKK3 is a stress-induced, renal tubular epithelium–derived secreted glycoprotein that induces tubulointerstitial fibrosis through its action on the canonical Wnt–b-catenin signaling pathway [5]. The urinary protein: creatinine ratio, albumin: creatinine ratio (ACR), and a1-microglobulin: creatinine ratio (a1MGCR) are commonly evaluated glomerular dysfunction/ damage and tubule cell dysfunction markers in CKD [6]; higher levels have also been associated with adverse outcomes in COVID-19 [2]. Accordingly, we evaluated the role of renal markers for monitoring subsequent estimated glomerular filtration rate (eGFR) decline in hospitalized COVID-19 patients.

BRIEF METHODS 

This is the second report of an ongoing prospective, observinga national, single-center study investigating the temporal progression of renal markers in hospitalized COVID-19 patients. In the present study, patients were included if they consented to the linkage with administrative data for long-term follow-up. The protocol was approved by the local ethics committee (AZ 58/20) and complied with the Declaration of Helsinki. The participants or their legally authorized representatives provided written informed consent. The study was registered at ClinicalTrials.gov (NCT04353583). 

A decrease in eGFR (using the Chronic Kidney Disease Epidemiology Collaboration equation) 6 months postadmission was defined as an eGFR decline <5 and 5 mL/min/ 1.73 m2 from baseline based on theKidney Disease: Improving Global Outcomes CKD guidelines [6]. Baseline serum creatinine (SCr) was the most recent outpatient SCr taken 7–365 days pre-admission. Other baseline renal parameters beyond SCr were not available. 

Spot urine samples were collected daily on hospital admission [uDKK3 and urinary interleukin (IL)-6 were collected thrice weekly] up to discharge day and at outpatient follow-up 3 and 6 months post-admission. Detailed methods (including the rationale for cut-off values) are described in the Supplementary data. 

Cistanche extract powder—tonifying kidney

KEY RESULTS 

Of 66 patients up to 9 November 2020, renal parameters up to 6 months post-admission (sample size numbers for key time points provided in Supplementary data, Table S1) were available for 55 patients (83.3%; the remaining 11 patients died in the hospital). Patients with an eGFR decline  5 mL/min/1.73 m2 were more likely to be older and to have hypertension, diabetes, CKD, coronary artery disease, and higher disease severity scores at admission (Supplementary data, Table S2). Patients with an eGFR decline 5 mL/min/1.73 m2 were more likely to be admitted to the intensive care unit, develop AKI (63.2% versus 5.6%), require invasive mechanical ventilation during the hospital stay, receive piperacillin/tazobactam or vancomycin and have a longer hospital stay (Supplementary data, Table S3). 

The temporal profile of renal parameters between both groups was markedly different (Table 1). Patients with subsequent higher versus lower eGFR decline had higher admission SCr values compared with baseline, likely owing to a higher proportion of patients presenting with AKI at admission (36.8% versus 2.8%). At Day 31 post-admission, both groups exhibited decreased SCr compared with baseline, likely reflecting decreased muscle mass associated with critical illness, causing eGFR overestimation. Cystatin C is considered a more accurate marker for estimating the GFR, but the relatively high levels observed in comparison with SCr may have been influenced, at least partially, by the high-dose corticosteroid medication on Days 7 and 31 post-admission (Table 1). It should be noted that 40 patients (72.7%) were recruited before the World Health Organization guidance on corticosteroids for COVID- 19 was released, which is reflected in the low overall prescription. Notably, while the higher eGFR decline patients had sustained greater damage and higher functional marker levels, patients with lower eGFR decline showed rapid normalization after Day 7 post-admission. Furthermore, the former group exhibited a distinct biphasic pattern of uDKK3 and urinary IL-6 levels, with greater separation on Day 31 (Figure 1). 

At 6 months post-admission, only the mean a1MGCR and uDKK3 remained elevated in the higher eGFR decline group. Furthermore, while the mean uDKK3 in the lower eGFR decline group was in the lower detection limit range, that in the higher eGFR decline group remained elevated and was comparable to that of other populations with progressive CKD [4]. The spline plots of the renal and inflammatory parameters during the observational period are shown in Supplementary data, Figure S1.

Superman herbs cistanche—tonifying kidney

DISCUSSION 

Among COVID-19 survivors, short-term progression of renal the function was associated with sustained greater damage and higher functional marker levels with a predominantly tubular the pattern in the initial phase (up to 7 days post-admission). However, the uDKK3 and urinary IL-6 biphasic patterns in patients with higher eGFR decline suggest the development of a superimposed ‘second-hit’ injury on unresolved AKI, potentially contributing to sustained and/or progressive tubular stress and renal inflammation, resulting in maladaptive repair and AKI–CKD transition. Sustained uDKK3 elevation at 6 months may indicate the disease chronification of an acute tubular damage; commonly used urinary markers (e.g. a1MGCR, ACR) might be less suitable for distinguishing patients with the progress sive CKD post-COVID-19. 

Benefits of cistanche tubulosa—tonifying kidney

Study strengths are the prospective design, including patients post-AKI were assessed for specific kidney damage, and evaluation of a biomarker panel to distinguish progression post-AKI. Study limitations are the single-center design, small sample size and the duration of follow-up. Therefore the results must be considered as hypothesis generating. Another study the limitation is that the number of samples obtained on Day 31 post-admission was significantly lower compared with the other key time points, since >50% of the patients were discharged earlier and were not available for outpatient visits on that day (e.g. due to rehabilitation). The observed uDKK3 and urinary IL-6 biphasic patterns show—in line with previous literature [3]—that a second wave of injury superimposed on unresolved AKI may represent a pathophysiological means of AKI–CKD transition. The etiology of the biphasic pattern is unknown but involves factors beyond systemic inflammation, as high-sensitivity C-reactive protein did not display such a pattern. Wnt–b-catenin signaling activation promotes CKD progression after experimental AKI through renin-angiotensin– aldosterone activation, stress-induced cytokine (e.g. IL-6 and IL-8) expression in tubular epithelial cells, uncontrolled fibroblast activation, and extracellular matrix deposition [7, 8]. 

Desert ginseng—tonifying kidney

Although sustained activation of Wnt–b-catenin signaling is considered detrimental and promotes tubulointerstitial fibrosis, transient activation is thought to be beneficial by mitigating initial injury and accelerating subsequent recovery after AKI [9, 10]. Thus persistently elevated uDKK3 levels may indicate ongoing tubular ‘stress’ leading to progressive kidney fibrosis independent from the type of CKD. Notably, the extent to which the COVID-19-mediated renin–angiotensin–aldosterone system imbalance may contribute to its activation is unknown. Larger studies with long follow-up periods are needed to clarify the role of uDKK3 for monitoring the AKI–CKD transition post-COVID-19.

TRIAL REGISTRATION 

Clinical Trial Registration Information: http://www.clinical trials.gov (NCT04353583). 

SUPPLEMENTARY DATA 

Supplementary data are available at ndt online. 

ACKNOWLEDGEMENTS 

The authors thank the nursing staff of the medical and surgical intensive care units and outpatient departments for their hard work and commitment to patient well-being. Without their support, this work would not have been possible.

FIGURE 1: (A) Albumin:creatinine ratio, (B) a1MGCR, (C) DKK3:creatinine ratio and (D) IL-6 excretion levels in urine stratifified by eGFR decline 6 months after hospital admission. The fifigure illustrates the biomarker levels in patients with COVID-19 on Days 0 (day of hospital admission), 7, 31 and 180 post-admission stratifified by eGFR decline (blue line <5 mL/min/1.73 m2 ; red line  5 mL/min/1.73 m2 ). eGFR decline was defifined as the difference in eGFR values 6 months post-COVID-19 and premorbid ‘baseline’ values. Points are geometric means; error bars show the 95% confifidence intervals. Values up to Day 31 were obtained from the time-course model and values for Day 180 are simple means (not considering values from earlier or later measurements). The dashed horizontal lines indicate the levels of non-physiologic concentrations [4, 6]. Note the use of a logarithmic scale on the y-axis. Due to the log scale, IL-6 values of zero are not displayed.

REFERENCES 

1. Werion A, Belkhir L, Perrot M et al. SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule. Kidney Int 2020; 98: 1296–1307 

2. Nadim MK, Forni LG, Mehta RL et al. COVID-19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup. Nat Rev Nephrol 2020; 16: 747–764 

3. Basile DP, Bonventre JV, Mehta R et al. Progression after AKI: understanding maladaptive repair processes to predict and identify treatments. J Am Soc Nephrol 2016; 27: 687–697 

4. Zewinger S, Rauen T, Rudnicki M et al. Dickkopf-3 (DKK3) in urine identi- fifies patients with short-term risk of eGFR loss. J Am Soc Nephrol 2018; 29: 2722–2733 

5. Roscigno G, Quintavalle C, Biondi-Zoccai G et al. Urinary Dickkopf-3 and contrast-associated kidney damage. J Am Coll Cardiol 2021; 77: 2667–2676 

6. Kidney Disease: Improving Global Outcomes CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013; 3: 1–150 

7. Federico G, Meister M, Mathow D, et al. Tubular Dickkopf-3 promotes the development of renal atrophy and fibrosis. JCI Insight 2016; 1: e84916 

8. Zhou D, Fu H, Xiao L et al. Fibroblast-specific beta-catenin signaling dictates the outcome of AKI. J Am Soc Nephrol 2018; 29: 1257–1271 9. Lin SL, Li B, Rao S, et al. Macrophage Wnt7b is critical for kidney repair and regeneration. Proc Natl Acad Sci USA 2010; 107: 4194–4199 10. Zhou D, Li Y, Lin L, et al. Tubule-specific ablation of endogenous beta-catenin aggravates acute kidney injury in mice. Kidney Int 2012; 82: 537–547