Pathophysiology and Pathology of Acute Kidney Injury in Patients With COVID-19.

Acute kidney injury (AKI) is common among hospitalized patients with Coronavirus Infectious Disease 2019 (COVID-19), with the occurrence of AKI ranging from 0.5% to 80%. The variability in the occurrence of AKI has been attributed to the difference in geographic locations, race/ethnicity, and severity of illness. AKI among hospitalized patients is associated with increased length of stay and in-hospital deaths. Even patients with AKI who survive to hospital discharge are at risk of developing chronic kidney disease or end-stage kidney disease. An improved knowledge of the pathophysiology of AKI in COVID-19 is crucial to mitigate and manage AKI and to improve the survival of patients who developed AKI during COVID-19. The goal of this article is to provide our current understanding of the etiology and the pathophysiology of AKI in the setting of COVID-19.

Approach to Electrolyte Abnormalities, Prerenal Azotemia, and Fluid Balance.

Volume and electrolyte evaluation and management is seen frequently in primary care practices. Some of the most common abnormalities encountered in outpatient practices are prerenal azotemia, dysnatremias, and altered potassium levels. Perturbations in volume or electrolyte concentrations can lead to serious organ dysfunction as well as hemodynamic collapse. This review focuses on the maintenance and regulation of intravascular volume and electrolytes, specifically sodium and potassium.

Uremia Preventing Osmotic Demyelination Syndrome Despite Rapid Hyponatremia Correction.

Hyponatremia is the most common electrolyte abnormality encountered both in the inpatient and outpatient clinical settings in the United States. Rapid correction leads to a deranged cerebral osmotic gradient causing osmotic demyelination syndrome. Coexisting azotemia is considered to be protective against osmotic demyelination syndrome owing to its counteractive effect on osmolarity change that occurs with rapid hyponatremia correction. In this article, we report the case of a 37-year-old male who presented with altered mentation, acute azotemia, and severe electrolyte derangements, with serum blood urea nitrogen 160 mg/dL, creatinine 8.4 mg/dL, sodium 107 mEq/L, potassium 6.1 mEq/L, bicarbonate 7 mEq/L, and anion gap of 33. Given refractory hyperkalemia with electrocardiogram changes, emergent dialysis was performed. Despite our efforts to avoid rapid correction, serum sodium was corrected to 124 mEq/L and blood urea nitrogen decreased to 87 mg/dL at the end of the 5-hour dialysis session. Fortunately, hospital course and 4-week post-discharge clinic follow-ups were uncomplicated with no neurological sequela confirmed by neurological examination and magnetic resonance imaging.

Use of the Fractional Excretion of Urea in an Azotemic Nonoliguric State: Type 1 Cardiorenal Syndrome.

The fractional excretion of urea is a useful tool to evaluate renal function in oliguric states; however, it remains unexplored in nonoliguric states. We evaluated its use to predict responses in patients with type 1 cardiorenal syndrome. This was a prospective observational study of 116 patients with type 1 cardiorenal syndrome referred over a 4-year period. Fractional excretion of urea and sodium, ejection fraction, mean arterial pressure, age, sex, diabetes, brain natriuretic peptide (BNP), serum sodium and blood urea nitrogen were analyzed for effects upon serum creatinine and survival. Improvement of renal function correlated most significantly with FeUrea (P = 0.00001) followed by the FeNa (P = 0.005) but no other variable studied reached significance. Survival was best predicted by improvement of the serum creatinine at 24 h (P = 0.005) and 7 days after all inotropes were stopped (P = 0.001). A limitation of this study is that it cannot be extrapolated to all cardiorenal syndrome patients other than type 1. Also, the study was not randomized and those with potentially worse disease have had worse outcomes due merely to worse underlying disease. The success of the FeUrea may possibly be related to interference of dobutamine on creatinine levels. Despite being a nonoliguric state, the FeUrea appears to provide insight to those patients with type 1 cardiorenal syndrome whose renal function (as measured by serum creatinine) and survival might improve.

Nephroprotective Effect of EDL Peptide at Acute Injury of Kidneys of Different Genesis.

EDL peptide produced a nephroprotective effect on experimental models gentamycin-induced nephropathy and ischemia/reperfusion kidney injury in rats. The nephroprotective effect of EDL peptide manifested in prevention of oliguria and retention azotemia, a decrease in proteinuria and sodium excretion, prevention of critical decrease in activities of antioxidant enzymes, suppression of LPO, and normalization of energy supply to kidneys cells. Our findings confirm the prospects of further studies of the nephroprotective properties of peptide EDL in various pathologies of the kidneys.

Hepatic vein pressure predicts GFR in cirrhotic patients with hemodynamic kidney dysfunction.

The role of "nephrocongestion" in hemodynamic renal disease is understudied. Intra-abdominal hypertension accompanies liver disease and renal disease. Our hypothesis states that in those patients with liver disease, hepatic vein pressure measured during a transjugular intrahepatic portosystemic shunt (TIPS) procedure reflects intra-abdominal pressure and predicts estimated glomerular filtration rate (eGFR). We gathered data from our clinical database and chart review on a cohort of cirrhotic patients who received TIPS at Montefiore as part of their clinical care between 2004 and 2014. We evaluated association of demographic and measured variables with eGFR in those subjects without end-stage renal disease (ESRD). Using multivariate regression, we examined the relationship between eGFR and hepatic vein pressure while adjusting for age, proteinuria, and ultrasound evidence for parenchymal kidney disease. The mean age of the subjects was 57 years old. Two thirds of the patients were male, 23% were White, and 20% were Black. A higher percentage of patients with chronic kidney disease (CKD), as determined by lower than 60 mL/min/1.73 m2, had proteinuria and ultrasound evidence for parenchymal kidney disease. A multivariate linear regression showed a significant and negative association between hepatic vein pressure and eGFR when adjusting for age, race, and proteinuria. Hepatic vein pressure is negatively and significantly associated with eGFR in those patients with liver failure. This finding has major implications for the way we evaluate hemodynamic renal disease.

Fatal proteinuric kidney disease in a 30-month-old German Fleckvieh heifer caused by unilateral focal segmental glomerulosclerosis subsequent to a non-functional counterpart kidney.

INTRODUCTION: A case of secondary focal segmental glomerulosclerosis (FSGS) in a heifer is presented. A 30-month-old female German Fleckvieh heifer showed deterioration of the general condition, a poor nutritional status, proteinuria, hypoalbuminemia, and renal azotemia. Pathologically, it was diagnosed with unilateral hydronephrosis, and contralateral renal fibrosis with numerous cysts. Histologically, the fibrotic kidney showed FSGS, hyaline reabsorption droplets in proximal tubular epithelial cells, interstitial fibrosis, and tubulointerstitial inflammation. Apart from that, thrombotic microangiopathy (TMA) was seen in few renal arteries and meningeal arterioles. Pathogenesis of FSGS secondary to unilateral renal parenchymal loss (hydronephrosis) and TMA is discussed.

Low T3 syndrome in canine babesiosis associated with increased serum IL-6 concentration and azotaemia.

Low triiodothyronine (T3) syndrome, also named euthyroid sick syndrome or non-thyroidal illness syndrome, has been recognized in canine babesiosis caused by Babesia rossi, where it manifested by lowering of the serum thyrotropin (TSH), total thyroxin (TT4) and free thyroxin (FT4) concentrations. This syndrome has also been observed in critical diseases in humans and animals, and the severity of the disease is considered an important factor in lowering of thyroid hormone concentrations. Interleukin-6 (IL-6) plays a role in the development of low T3 syndrome by causing a decrease in deiodinases 1 and 2 activity and increased activity of deiodinase 3, enzymes involved in the conversion of thyroxin (T4) to T3. The purpose of this study was to compare the concentrations of serum thyroid hormones and TSH between healthy dogs and dogs with babesiosis, and to determine correlations between serum IL-6 concentration and serum total T3 (TT3), TT4, FT4, and TSH concentrations, and the level of azotaemia in dogs with babesiosis. The concentrations of IL-6, TT3, TT4, FT4, TSH, urea and creatinine were determined in 13 dogs with canine babesiosis caused by Babesia canis and in 10 healthy dogs. The results of this study showed decreases in TT3, TT4, FT4, and TSH and increases in IL-6, urea and creatinine concentrations in affected dogs in comparison to healthy dogs. The concentration of IL-6 was negatively correlated with TT3 and TSH concentrations and the TT3 concentration was negatively correlated with serum urea and creatinine concentrations. This study showed low T3 syndrome in canine babesiosis, which was confirmed by the determination of the T3 concentration, and demonstrates that in canine babesiosis the T3 concentration is associated with IL-6 concentration.

Azotemia protects the brain from osmotic demyelination on rapid correction of hyponatremia.

Osmotic demyelination syndrome (ODS) is a dreadful, irreversible and well-recognized clinical entity that classically occurs after rapid correction of hyponatremia. However, it has been observed that when hyponatremia is rapidly corrected in azotemic patients by hemodialysis (HD), patients do not necessarily develop ODS. We studied the effect of inadvertent rapid correction of hyponatremia with HD in patients with azotemia. Fifty-two azotemic patients, who underwent HD at the Sindh Institute of Urology and Transplantation, having pre-HD serum sodium level <125 mEq/L and post-HD serum sodium levels that increased by ≥12 mEq/L from their pre-dialysis level, were studied. Serum sodium was analyzed before and within 24 h after a HD session. HD was performed using bicarbonate solution, with the sodium concentration being 140 meq/L. The duration of the dialysis session was based on the discretion of the treating nephrologist. Patients were examined for any neurological symptoms or signs before and after HD and for up to two weeks. Magnetic resonance imaging was performed in required cases. None of the 52 patients with azotemia, despite inadvertent rapid correction of hyponatremia with HD, developed ODS. This study suggests that patients with azotemia do not develop ODS on rapid correction of hyponatremia by HD, which suggests a possible protective role of azotemia on the brain from osmotic demyelination. However, the mechanism by which azotemia protects the brain from demyelination in humans is largely hypothetical and further studies are needed to answer this question.

Plasma renin activity and aldosterone concentrations in hypertensive cats with and without azotemia and in response to treatment with amlodipine besylate.

BACKGROUND: Role of renin-angiotensin aldosterone system (RAAS) in feline systemic hypertension is poorly understood. OBJECTIVES: Examine plasma renin activity (PRA) and plasma aldosterone concentrations (PAC) in normotensive and hypertensive cats with variable renal function and in response to antihypertensive therapy. ANIMALS: One hundred and ninety-six cats >9 years from first opinion practice. METHODS: PRA, PAC, and aldosterone-to-renin ratio (ARR) were evaluated in cats recruited prospectively and grouped according to systolic blood pressure (SBP) and renal function (nonazotemic normotensive [Non-Azo-NT], nonazotemic hypertensive [Non-Azo-HT], azotemic normotensive [Azo-NT], azotemic hypertensive [Azo-HT]). Changes in PRA and PAC were evaluated with antihypertensive therapy (amlodipine besylate). RESULTS: Plasma renin activity (ng/mL/h; P = .0013), PAC (pg/mL; P < .001), and ARR (P = 0.0062) differed significantly among groups. PRA (ng/mL/h) was significantly lower in hypertensive (Non-Azo-HT; n = 25, median 0.22 [25th percentile 0.09, 75th percentile 0.39], Azo-HT; n = 44, 0.33 [0.15, 0.48]) compared with Non-Azo-NT cats (n = 57, 0.52 [0.28, 1.02]). Azo-HT cats had significantly higher PAC (n = 22, 149.8 [103.1, 228.7]) than normotensive cats (Non-Azo-NT; n = 26, 45.4 [19.6, 65.0], Azo-NT; n = 18, 84.1 [38.6, 137.8]). ARR was significantly higher in Azo-HT (n = 20, 503.8 [298.8, 1511]) than Azo-NT cats (n = 16, 97.8 [77.0, 496.4]). Significant increase in PRA was documented with antihypertensive therapy (pretreatment [n = 20] 0.32 [0.15-0.46], posttreatment 0.54 [0.28, 1.51]), but PAC did not change. CONCLUSIONS AND CLINICAL IMPORTANCE: Hypertensive cats demonstrate significantly increased PAC with decreased PRA. PRA significantly increases with antihypertensive therapy. Additional work is required to determine the role of plasma aldosterone concentration in the pathogenesis of hypertension and whether this relates to autonomous production or activation of RAAS without demonstrable increase in PRA.

[Cardiorenal syndrome and prerenal azotemia in patients with acute hypertensive encephalopathy].

AIM: To estimate changes in renal function in patients with acute hypertensive encephalopathy (AHE) during standard inpatient antihypertensive therapy. SUBJECTS AND METHODS: Patients were selected for the trial in the cardiology and admission units of a Perm hospital. The group included 60 patients with AHE. The patients received inpatient antihypertensive therapy for 10-14 days. Within the first 2 hours, enalaprilate 1.25 mg was intravenously injected, by monitoring blood pressure. After 6 hours, the patients were given enalaprilate tablets 20 mg b.i.d. plus hydrochlorothiazide 12.5 mg (Subgroup 1) or nifedipine 60 mg plus hydrochlorothiazide 12.5 mg (Subgroup 2). The laboratory parameters of kidney function were measured twice: on admission to and before discharge from hospital. Plasma creatinine and urea concentrations were estimated. Glomerular filtration rate (GFR) and urea/creatinine ratio were calculated. The patients were found to have proteinurea, low GFR, high plasma creatinine concentrations, and increased urea/creatinine ratio. RESULTS: Transient proteinuria was observed in 25% of the patients with AHE within the first 24 hours of the disease. The proportion of patients with lower GFR was unchanged during a 2-week treatment period (20 and 16%, respectively; p = 0.22). There was a rise in the proportion of patients with higher urea/creatinine ratio (83 and 95%, respectively; p = 0.006). CONCLUSION: The course of AHE is complicated by cardiorenal syndrome (CRS) with transient proteinuria and low GFR, as well as by prerenal azotemia (PRA). The number of patients with PRA increased after 2-week conventional inpatient antihypertensive therapy (enalaprilate + hydrochlorothiazide 12.5 mg or nifedipine + hydrochlorothiazide 12.5 mg).

Fibroblast growth factor 23 (FGF-23) concentrations in cats with early nonazotemic chronic kidney disease (CKD) and in healthy geriatric cats.

BACKGROUND: Fibroblast growth factor (FGF-23) has an important role in phosphate regulation. Its clinical relevance in cats with CKD has not been explored previously. HYPOTHESIS/OBJECTIVES: The study objectives were (1) to determine whether FGF-23 concentrations are increased in nonazotemic cats, cats which developed azotemia within 12 months of screening compared with cats that remained non-azotemic, and (2) to evaluate the relationships between FGF-23 and PTH and FGF-23 and glomerular filtration rate (GFR). ANIMALS: Sixty-two healthy client-owned geriatric cats, 14 of which developed azotemia during the 12-month follow-up period. METHODS: Healthy nonazotemic cats were recruited prospectively into the study and followed for 12 months. At the study end-point, cats were categorized into 3 groups according to plasma creatinine concentration. PTH, FGF-23, and additional biochemical variables were evaluated at baseline and after 12 months. GFR was measured by a corrected slope-intercept iohexol clearance method. RESULTS: FGF-23 concentrations at baseline were found to be significantly increased in cats that developed azotemia (P = .001) compared with cats that did not develop azotemia. A significant positive relationship was identified between FGF-23 and PTH, whereas the relationship between FGF-23 and GFR was negative. CONCLUSIONS AND CLINICAL IMPORTANCE: FGF-23 concentrations predicted development of azotemia in geriatric cats. Positive relationships between FGF-23 and PTH suggest an association between FGF-23 and renal secondary hyperparathyroidism.

Histomorphometry of feline chronic kidney disease and correlation with markers of renal dysfunction.

Chronic kidney disease is common in geriatric cats, but most cases have nonspecific renal lesions, and few studies have correlated these lesions with clinicopathological markers of renal dysfunction. The aim of this study was to identify the lesions best correlated with renal function and likely mediators of disease progression in cats with chronic kidney disease. Cats were recruited through 2 first-opinion practices between 1992 and 2010. When postmortem examinations were authorized, renal tissues were preserved in formalin. Sections were evaluated by a pathologist masked to all clinicopathological data. They were scored semiquantitatively for the severity of glomerulosclerosis, interstitial inflammation, and fibrosis. Glomerular volume was measured using image analysis; the percentage of glomeruli that were obsolescent was recorded. Sections were assessed for hyperplastic arteriolosclerosis and tubular mineralization. Kidneys from 80 cats with plasma biochemical data from the last 2 months of life were included in the study. Multivariable linear regression (P < .05) was used to assess the association of lesions with clinicopathological data obtained close to death. Interstitial fibrosis was the lesion best correlated with the severity of azotemia, hyperphosphatemia, and anemia. Proteinuria was associated with interstitial fibrosis and glomerular hypertrophy, whereas higher time-averaged systolic blood pressure was associated with glomerulosclerosis and hyperplastic arteriolosclerosis.

Renal resistive index in 55 dogs with degenerative mitral valve disease.

BACKGROUND: Azotemia occurs frequently in dogs with degenerative mitral valve disease (DMVD). It could indicate changes in renal hemodynamics. HYPOTHESIS/OBJECTIVES: To assess the renal resistive index (RI) in dogs with DMVD, and the statistical link between heart failure class, azotemia, echo-Doppler parameters, several plasma variables, and RI. ANIMALS: Fifty-five dogs with naturally occurring DVMD were used (ISACHC class 1 [n = 28], 2 [n = 19], and 3 [n = 8]). METHODS: Observational, blinded study, performed under standardized conditions. Physical examination, renal ultrasonography, and echo-Doppler examinations were performed in awake dogs. The RI of the renal, interlobar, and arcuate arteries were measured. Plasma creatinine, urea, and N-terminal pro-B-type natriuretic peptide concentrations (NT-proBNP) were determined. Statistical links between variables and RI were tested by means of a general linear model. RESULTS: Although the RI of renal and arcuate arteries were unaffected by ISACHC class, the left interlobar RI increased (P < .001) from 0.62 ± 0.05 (mean ± SD) in class 1 to 0.76 ± 0.08 in class 3. It was also higher (P < .001) in azotemic (0.74 ± 0.08) than in non-azotemic (0.62 ± 0.05) dogs. Similar findings were observed for right interlobar RI. Univariate analysis showed a positive statistical link between NT-proBNP (P = .002), urea (P < .001), creatinine (P = .002), urea-to-creatinine ratio (P < .001), left atrium-to-aorta ratio (P < .001), regurgitation fraction (P < .001), systolic pulmonary arterial pressure (P < .001), shortening fraction (P = .035), and RI. CONCLUSION AND CLINICAL IMPORTANCE: In dogs with DMVD, interlobar RI increases with heart failure severity and azotemia but a cause and effect relationship remains to be established.

The kidney in critically ill small animals.

Critically ill animals may have preexisting renal disease or develop acute kidney injury as a consequence of their presenting complaint. Age, concurrent medical therapy, electrolyte and fluid imbalances, and exposure to potential nephrotoxicants are factors that predispose to acute kidney injury. Many risk factors are correctable or manageable, and these should be addressed whenever possible. Measurement of serum creatinine is insensitive for the detection of acute kidney injury, and clinicians should consider assessment of other parameters such as urine output, urinalysis, and urine chemistry results. A stepwise approach for management of acute kidney injury in small animal patients is outlined.

Toward the optimal clinical use of the fraction excretion of solutes in oliguric azotemia.

While the fractional excretion of solutes have long been considered excellent research tools to investigate tubular physiology, their clinical use has become common over the last 40 years in the diagnoses of many disorders; however, none have reached the clinical utility of the fractional excretion of sodium in the ability to distinguish pre-renal azotemia from acute tubular necrosis. Nevertheless, there are many drugs and medical conditions that interfere with that utility and recently other solutes, including urea, uric acid and lithium, have been recently investigated to improve the diagnostic ability in clinical situations where the fractional excretion of sodium is known to be unreliable. We review the tubular physiology of these solutes and show how the differences in tubular physiology might be exploited to develop a strategy for their optimal clinical use.

The meaning of transient azotemia.

Acute kidney injury (AKI) is common in hospitalized patients and its associated mortality is high. The causes of AKI are commonly divided into 3 groups: pre-renal, intra-renal, and post-renal. According to this paradigm, pre-renal azotemia (PRA) represents a separate entity characterized by a rapidly reversible increase in serum creatinine and urea concentration. This rapid reversibility is believed to reflect a functional reduction in glomerular filtration rate as opposed to established structural kidney injury, which leads to acute tubular necrosis (ATN). This PRA vs. ATN paradigm is well established in the medical and renal literature and widely discussed in textbooks. However, there is no consensus definition for PRA or ATN. The typical description for PRA in the literature is 'reversible increase in serum creatinine and urea concentrations', 'characterized by intact renal parenchymal function but renal hypoperfusion'. Therefore, although the term PRA implies that it is defined histopathologically, it also contains a functional aspect (transient azotemia, TA). Early recognition of PRA or ATN is considered important because PRA can be reversed with fluid resuscitation, but such treatment causes edema in lungs as well as other tissues and therefore can be harmful in ATN. However, evidence suggests that PRA cannot be diagnosed prospectively and is clinically the same as TA, that urinary analysis and biochemistries cannot distinguish PRA and ATN in septic AKI, and that ATN is histologically uncommon in septic AKI. Recent observational studies also found that TA cannot be distinguished from ATN epidemiologically and that the existence of TA is related to high hospital mortality. These findings suggest the need for specific and focused investigations directed at identifying effective treatments to decrease the incidence of TA in hospitalized patients.

Prerenal azotemia in congestive heart failure.

Prerenal failure is used to designate a reversible form of acute renal dysfunction. However, the terminology encompasses different conditions that vary considerably. The Acute Kidney Injury Network group has recently standardized the acute kidney injury (AKI) definition and classification system; however, these criteria have not determined specific diagnostic criteria to classify prerenal conditions. The difference in the pathophysiology and manifestations of prerenal failure suggests that our current approach needs to be revaluated. Several mechanisms are recognized as contributory to development of a prerenal state associated with cardiac failure. Because of the broad differences in patients' reserve capacity and functional status, prerenal states may be triggered at different time points during the course of the disease. Prerenal state needs to be classified depending on the underlying capacity for compensation, the nature, timing of the insult and the adaptation to chronic comorbidities. Current diagnosis of prerenal conditions is relatively insensitive and would benefit from additional research to define and classify the condition. Identification of high-risk states and high-risk processes associated with the use of new biomarkers for AKI will provide new tools to distinguish between the prerenal and established AKI. Achieving a consensus definition for prerenal syndrome will allow physicians to describe treatments and interventions as well as conduct and compare epidemiological studies in order to better describe the implications of this syndrome.

Effect of azotemia on serum N-terminal proBNP concentration in dogs with normal cardiac function: a pilot study.

OBJECTIVES: To evaluate amino-terminal pro-B type natriuretic peptide (NT-proBNP) concentration in dogs with renal dysfunction and normal cardiac structure and function. ANIMALS: Eight dogs with renal disease, 23 healthy control dogs. METHODS: Serum NT-proBNP concentration was measured in healthy dogs and dogs with renal disease using an ELISA validated for use in dogs. Affected dogs were eligible for inclusion if renal dysfunction was diagnosed based on urinalysis and serum chemistry, and if they were free of cardiovascular disease based on physical exam, systolic blood pressure, and echocardiography. RESULTS: The geometric mean serum NT-proBNP concentration was significantly higher in dogs with renal disease (617 pmol/L; 95% CI, 260-1467 pmol/L) than in healthy control dogs (261 pmol/L; 95% CI, 225-303 pmol/L; P=0.0014). There was a modest positive correlation between NT-proBNP and BUN and creatinine. Median NT-proBNP concentration was not significantly different between groups when indexed to BUN (median NT-proBNP:BUN ratio; renal, 14.2, IQR, 3.93-17.7 vs. control, 16.3, IQR, 9.94-21.2; P=0.29) or creatinine (median NT-proBNP:creatinine ratio; renal, 204, IQR, 72.6-448 vs. control, 227, IQR, 179-308; P=0.67). CONCLUSION: Dogs with renal disease had significantly higher mean serum concentration of NT-proBNP than control dogs. Renal function should be considered when interpreting NT-proBNP results as concentrations may be falsely elevated in dogs with renal dysfunction and normal cardiac function. The effect of renal disease was lessened by indexing NT-proBNP to BUN or creatinine. Future studies in dogs with both renal and heart disease are warranted.