Renal involvement is common in children with COVID-19 and can manifest as hematuria, proteinuria, Fanconi syndrome, and acute kidney injury (AKI). AKI occurs in approximately one-fifth of hospitalized children with COVID-19 and is associated with increased mortality and morbidity. The SARS-CoV-2 virus may directly infect kidney cells through binding with ACE2 receptors, which are highly expressed in the kidneys, potentially leading to acute tubular injury. Systemic inflammation and cytokine release can also contribute to renal impairment. Outcomes of AKI in pediatric COVID-19 patients tend to be better than in adults, with lower rates of oliguria and less need for renal replacement therapy.

1. RENAL INVOLVEMENT IN
CHILDREN WITH COVID-19
MOJGAN MAZAHERI.MD
Pediatric nephrologist
Semnan university of medical science

2. KIDNEY DISEASE AMONG PATIENTS WITH COVID-19 CAN MANIFEST AS:
HEMATURIA,
PROTEINURIA,
FANCONI SYNDROME
ACUTE KIDNEY INJURY
AND PORTENDS A HIGHER RISK OF MORTALITY .
IT REMAINS UNCLEAR IF AKI IS LARGELY DUE TO HEMODYNAMIC CHANGES
AND CYTOKINE RELEASE OR IF THE VIRUS ALSO LEADS TO DIRECT
CYTOTOXICITY.

3. In a meta-analysis of approximately 13,000 mostly hospitalized patients,
the incidence of AKI was 17 percent, although the range of AKI
incidence in the included studies was broad (range 0.5 to 80 percent).

4. The reported incidence of AKI among patients with COVID-19, especially
those who are hospitalized, varies depending upon the severity of disease in
the patients who are studied.
In two large observational studies of over 5000 patients hospitalized with
COVID-19, AKI was noted among 32 to 37 percent of patients
Among patients with AKI, approximately one-half had mild disease (1.5- to 2-
fold increase in serum creatinine), and the remaining had moderate or severe
disease (more than doubling of creatinine).

5. FACTORS THAT MAY CONTRIBUTE TO COVID-19- ASSOCIATED ACUTE KIDNEY INJURY
Acute tubular injury
• Regional inflammation
• Direct viral infection
• Renal compartment syndrome
• Tissue hypoxia hypoperfusion leading to hypoxaemia,hypotension, hypovolaemia and
heart failure
• Nephrotoxic- induced injury (potentially associated with the use of antibiotics (vancomycin,
aminoglycosides, colistin) or antivirals (remdesivir, ritonavir))
• Rhabdomyolysis
Vascular injury
• Endotheliitis
• Microthrombi
• Thrombotic microangiopathy
Glomerular injury
• Collapsing glomerulopathy (potentially caused by interferon- associated podocyte injury)
• Glomerulonephritis
Interstitial injury
• Acute interstitial nephritis; infiltration by immune cells
• Interstitial oedema

6. MECHANISM OF RENAL INJURY
Direct effects on the renal tissues of infected patients
Deposition of immune complexes, such as viral antigens and antibodies or
virus-specific T-cell lymphocytes or antibodies in the kidney cells.
Infection-induced cytokines may have indirect effects on the renal tissue and
other organs due to hypoxia, hypoxemia, and shock.
Prerenal azotemia after gastrointestinal involvement usually as diarrhea and
vomiting can lead to AKI
Thrombotic microangiopathy is another cause leading AKI
multiple organ failure, caused by direct viral invasion or acute inflammatory
responses may cause AKI also.
Nephrotoxic drugs

7. .Potential pathophysiological mechanisms behind the development of COVID-19-
associated acute kidney injury.

8. it has been reported that angiotensin converting enzyme 2 (ACE2) is a
cell entry receptor for COVID-19 .
In this regard, Li et al. in a human study revealed that ACE2 expression
in the renal tissue was nearly 100 folds higher than in the lungs.
Accordingly, renal involvement may be caused by coronavirus through
an ACE2-dependent pathway.

9. • ACE2 receptors play a critical role in COVID-19 pathophysiology, due to the high
affinity of the SARS-CoV-2 protein S to membrane-bound ACE2
• Histologic studies have shown that ACE2 expression is about 100 times greater in the
kidneys compared to the lungs, the main pathway for viral infection. Therefore, it is
reasonable to predict that the kidney may be vulnerable to SARS-CoV-2 infection,
resulting in an injury caused by the direct cytopathic effect of the viral infection.
Ultrastructural in-situ hybridization used in some studies has confirmed presence of viral
RNA or viral proteins in kidney tissue.
• A renal post-mortem histopathological analysis of 26 adult patients with COVID-19
showed a prominent proximal acute tubular injury (ATI) associated with the loss of brush
border

10. SARS-COV-2 BINDING WITH ANGIOTENSIN-CONVERTING ENZYME (ACE) 2 AND INTERNALIZATION. FOR
CELLULAR ENTRY, SARS-COV-2 BINDS TO AND INTERNALIZES WITH ACE2 BY THE S1 SUBUNIT. MEMBRANE
FUSION IS MEDIATED VIA ACTIVATION OF SPIKES BY PROTEASES, AND VIRAL RNAS ARE RELEASED INTO THE
CYTOPLASM, FINISHING THE INFECTION WITH AND REPLICATION OF SARS-COV-2.

11. • COVID-19 virus can cause direct injury to podocytes and proximal
tubular cells through attaching to ACE2 receptors and cellular
transmembrane serine protease enzyme activity which may explain
proteinuria in COVID-19 patients.
• They also proposed that the simultaneous expression of ACE 2
receptor genes and cellular transmembrane serine protease in kidney
cells are not less than in other organs, therefore kidney is also a target
organ for the COVID-19

13. • ACE2 is highly expressed in the brush border of tubular cells and some coronavirus-like
particles were found in the renal proximal tubular epithelium supporting the cytopathic
mechanisms of kidney injury.
• As well as this cytopathic mechanism, a systemic condition is another potential mechanism
for kidney injury.
• Cytokine release syndrome (CRS) is being described in pediatric cases of COVID-19 and
might be a cofactor of renal manifestations.
• Hirano and Murakami described the potential role of ACE-AngII-AT1R axis dysregulation of
the RAS during the later phase of infection leading to downregulation of ACE2 that causes
CRS, characterized by high expression of IL-6 and TNF.
• Intrarenal inflammation,increased vascular permeability, volume depletion, and
cardiomyopathy,caused by these cytokines, might also lead to kidney failure.
• Other minor potential mechanisms of kidney injury are being identified, including systemic
effects of septic shock and the deposition of immune-complexes in the kidney.

15. • Vinturache et al. observed greater expression of the AT1R and the AT2R in kidneys and vasculature
in the course of fetal life than at any other time during the lifespan in response to cardiovascular and
renal demands.
• Ang II can bind to both receptors. As previously mentioned, the binding of Ang II to AT1R is
associated to pro-inflammatory activity and cytokine release. In turn, the binding of Ang II to AT2R
triggers vasodilatory effects, anti-inflammatory actions, and natriuresis.
• Hence, AT1R expression leads to inflammatory effects, while AT2R mediates protective effects. This
study has shown that the decline rate of expression of AT2R is greater than that of AT1R, causing a
predominance of AT1R over AT2R with aging.
• Therefore, children might present less severe cases of kidney injury associated with COVID-19 due
to this greater expression of AT2R than adults.
• However, further studies on ACE2 expression and other RAS molecules concentrations in children
are needed.

17. PEDIATR NEPHROL (2021) 36:163–169
BE AWARE OF ACUTE KIDNEY INJURY IN CRITICALLY ILL CHILDREN WITH COVID-19
postmortem renal histopathological analysis of 26 patients with
COVID-19, showed endothelial cell swelling and segmental fibrin
thrombi in glomerular capillary loops were consistent with the
histological features of TMA

18. SARS-COV-2 VIRUS DETECTION IN KIDNEY AND CHARACTERISTIC GLOMERULAR CHANGES. A SARS-COV-2
VIRUS DETECTION IN THE KIDNEY. FLUORESCENCE IN SITU HYBRIDIZATION (FISH) SHOWS RNA EXPRESSION
OF SARS-COV-2 VIRUS (GREEN; ARROWS) AND ITS RECEPTOR ANGIOTENSIN-CONVERTING ENZYME 2
(ACE2; RED) IN THE GLOMERULUS OF THE KIDNEY OF A COVID-19 PATIENT. SCALE BAR = 20 ΜM B RENAL
HISTOLOGY OF A 38-YEAR-OLD PATIENT WITH COVID-19 AND ACUTE RENAL FAILURE. LEFT: MASSON–GOLDNER
STAINING SHOWS FRESH, WALL-BOUND FIBRIN THROMBI (ORANGE) IN THE GLOMERULAR
CAPILLARIES. RIGHT: IMMUNOHISTOCHEMISTRY FOR FIBRINOGEN/FIBRIN SHOWS WALL-ADHERENT
PRECIPITATES (RED) IN NUMEROUS GLOMERULAR CAPILLARIES

19. PEDIATR NEPHROL. 2021 JAN 26 : 1–5. PMCID: PMC7834948
ACUTE NECROTIZING GLOMERULONEPHRITIS ASSOCIATED WITH COVID-19 INFECTION: REPORT
OF TWO PEDIATRIC CASES
Basiratnia et al reported two cases of acute necrotizing
glomerulonephritis (GN) with fibrinoid necrosis in the context of
COVID-19 infection.
The one with more chronic features in the kidney biopsy progressed to
permanent kidney failure but the second one had an excellent
response to glucocorticoid pulse therapy with subsequent normal
kidney function at 2-month follow-up

20. • There is higher C-reactive protein (CRP) and lower thrombocyte count in the severe
form of disease
• This condition probably correlated with the advanced cytokine storm process that
involved in increasing proinflammatory mediators, such as interleukin-6 (IL-6),
transforming growth factor-β (TGF-β), Tumor necroting factor-α (TNF-α), vascular
endothel growth factor (VEGF), platelet derived growth factor (PDGF), IL-10, and soluble
urokinase plasminogen activator receptor (suPAR).
• Those proinflammatory and anti-inflammatory mediators released led to a disturbance
in clotting cascades, while thrombus occurred in the later stages, and plasminogen
stimulation with antithrombin-III activation took place in the fibrinolytic system
• Therefore, fibrinolytic and fibrinogen substances were depleted, while clot formation and
bleeding associated with disseminated intravascular coagulation (DIC) also occurred at
the same time

21. 2020 UPDATE ON THE RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM
IN PEDIATRIC KIDNEY DISEASE AND ITS INTERACTIONS WITH CORONAVIRUS
PEDIATRIC NEPHROLOGY
HTTPS://DOI.ORG/10.1007/S00467-020-04759-1
• A range of immune-related cascades might be activated by the exacerbation of
ACE/Ang II/AT1R, including the synthesis and release of pro-inflammatory
cytokines, including IL-1,IL-6, and TNF-α
• This process, added to viral intrinsic activation of both innate and adaptive immune
systems, may explain the higher levels of IL-6, IL-2R, IL-10, and TNF-α, as well as
lower CD4+ and CD8+ levels in COVID-19 patients
• Pediatric patients, in particular presented increased serum creatine kinase MB,
procalcitonin and C reactive protein, lymphocytopenia, and leukopenia associated
with higher disease severity

22. • A meta-analysis including pediatric patients with SARS-CoV- infection conducted by Zhang et al.
demonstrated that 5% (22/139) had increased urea and 4% (48/184) had increased creatinine.
• A large number of patients had no symptom on admission
• A cohort study by Stewart et al. showed a frequency of increased serum creatinine in 46% (n =
24), and 29% (n = 15) of hospitalised patients that meet the diagnosis criteria for acute kidney
injury.
• Out of these 15 inpatients with AKI, 93% (n = 14) were admitted to the pediatric intensive care unit
(PICU) and 73% (n = 11) were associated with with multisystem inflammatory syndrome in children
(MIS-C) temporarily associated with SARS-CoV-2.
• AKI may be the main cause of critical illness in pediatric patients, requiring PICU admission.
• Patients with AKI are recommended to receive CRRT in order to both protect renal function and
remove inflammatory cytokines, which may accelerate the process of disease recovery.

23. ACUTE KIDNEY INJURY IN CHILDREN WITH COVID-19
KING ABDULAZIZ UNIVERSITY ,RESEARCH SQUARE
▪ in the setting of COVID-19, AKI occurred in approximately one-fifth of our
hospitalized children, and more than one-third of those required PICU admission.
▪ AKI is more commonly found in younger children and in those with comorbid
conditions.
• AKI is associated with increased mortality and morbidity.
• A small proportion of children with AKI can develop residual renal impairment at the
time of discharge.
• Nonetheless, it tends to be milder than in adults, with a lower incidence of oliguria
and less need for RRT.

24. CRIT.CARE.MED 2020 DEC;48(12):1809-1818.
ACUTE KIDNEY INJURY IN PEDIATRIC INFLAMMATORY MULTISYSTEM SYNDROME TEMPORALLY
ASSOCIATED WITH SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS-2 PANDEMIC:
EXPERIENCE FROM PICUS ACROSS UNITED KINGDOM
.
• Severe acute kidney injury occurred in just over a quarter of children
admitted to United Kingdom PICUs with pediatric inflammatory multisystem
syndrome temporally associated with severe acute respiratory syndrome
coronavirus-2.
• Hyperferritinemia was significantly associated with severe acute kidney
injury.
• Severe acute kidney injury was associated with increased duration of stay
and ventilation.
• Although short-term outcomes for acute kidney injury in pediatric
inflammatory multisystem syndrome temporally associated with severe
acute respiratory syndrome coronavirus-2 appear good, long-term outcomes
are unknown.

25. ARCH PEDIATR INFECT DIS. 2021 JANUARY; 9(1):E106597.
RENAL INVOLVEMENT IN COVID-19 AMONG IRANIAN CHILDREN
• In total of 71 patients , 10% of the patients had oliguria, 7.7% had edema, and 3% had
hypertension. No patients showed signs of hypotension. The first urinalysis showed
proteinuria,leukocyturia, and hematuria in 46%, 24%, and 23% of the patients, respectively.
Overall, 40.7% of the patients showed some degree of renal involvement.
• During hospitalization the peak serum creatinine level was 9.6 mg/dL(range: 0.4 - 9.6 mg/dL;
mean: 1.31 mg/dL), and the prevalence of AKI was 34.5%.
• Based on the pRIFLE classification stage I (risk group) was found in 20% of the patients,
stageII (injury group) in 25% of the patients, and stage III (failure group) in 55% of the patients
with AKI.
• Compared to patients with normal renal function those with elevated serum creatinine levels
on admission were predominantly older and more severely ill.
• The total mortality rate of the patients was 12.67%. The rate of inhospital death among
patients with AKI was estimated at 30%.

26. • Independent predictors of AKI included;
• being older
• Black American
• male
• obesity
• diabetes
• hypertension
• cardiovascular disease
• low baseline estimated glomerular filtration rate (eGFR)
• higher interleukin-6 level
• requiring mechanical ventilation
• vasopressor medications

27. •
Key points
•
• Over a quarter of patients hospitalized with coronavirus disease 2019 (COVID-19)
•
have been reported to develop acute kidney injury (AKI).
•
• Low molecular weight proteinuria, Fanconi syndrome and histological findings point
•
towards tubular injury.
•
• Analyses of kidney biopsy samples from patients with COVID-19 and AKI have
•
inconsistently reported viral infection of kidney cells.
•
• Collapsing glomerulopathy has been identified in patients with high- risk APOL1
•
genotypes, mostly in those without severe respiratory symptoms.
•
• Regional inflammation, endothelial injury and renal microthrombi have been
reported
•
• Anti- inflammatory drugs (for example, steroids and IL-6 receptor blockers) seem to
•
limit the development of severe AKI in patients with COVID-19.