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Audio Interview: Vaccinology and Covid-19
October 20th, 2020
The continuing spread of SARS-CoV-2 remains a Public Health Emergency of International Concern. What physicians need to know about transmission, diagnosis, and treatment of Covid-19 is the subject of ongoing updates from infectious disease experts at the Journal.
In this audio interview conducted on October 14, 2020, the editors discuss the fundamental concepts behind candidate vaccines against SARS-CoV-2 and the status of ongoing clinical trials.
Click here for the interview: https://www.nejm.org/doi/full/10.1056/NEJMe2031646?query=featured_home
Listen to the Interview
Association between vitamin D metabolites, vitamin D binding protein, and proteinuria in dogs
October 8th, 2020
Chronic kidney disease (CKD) is commonly diagnosed in dogs, with a prevalence of up to 25% of dogs presented to veterinary teaching hospitals. Major consequences of CKD in dogs include development of proteinuria and hypovitaminosis D. In people, proteinuria and hypovitaminosis D, characterized by decreased serum 25-hydroxyvitamin D (25[OH]D) concentrations, are associated with progression of kidney disease and decreased survival, and vitamin D status is inversely associated with magnitude of proteinuria. Proteinuria in people is an independent predictor of vitamin D status in the absence of other causes of vitamin D dysregulation associated with kidney disease.
Similarly in dogs, proteinuria has been shown to be associated with progression of kidney disease and increased morbidity and death. An association between serum vitamin D concentration and proteinuria also has been identified in dogs. In a study of 19 dogs with azotemic CKD, serum 25(OH)D concentrations were inversely related to urine protein:creatinine (UPC) ratios. However, because of the complex pathophysiology of CKD-mineral and bone disorder (CKDMBD), it was not possible to determine whether an independent association between proteinuria and vitamin D status existed separately from other CKD variables (eg, advanced azotemia). As a result, the association between proteinuria and vitamin D status in dogs with minimal to no azotemia remains unknown.
Our primary aim was to evaluate the relationship between vitamin D metabolites (25[OH]D, 1,25[OH]2D, and 24,25[OH]2D) and proteinuria assessed by UPC in dogs with protein-losing nephropathy (PLN) and minimal to no azotemia. Our hypothesis was that, compared to healthy control dogs, vitamin D metabolites would be decreased in dogs with PLN, and vitamin D status (assessed by 25[OH]D) would be correlated with UPC.
Background: Proteinuria has been associated with progression of renal disease and increased morbidity and mortality in dogs and people. In people, proteinuria also has been associated with hypovitaminosis D. Little is known about the relationship between vitamin D metabolism and proteinuria in dogs.
Objectives: To further elucidate vitamin D status in dogs with protein-losing nephropathy (PLN) and minimal to no azotemia. We hypothesized that vitamin D metabolites would be lower in dogs with PLN compared to healthy dogs.
Animals: Twenty-three client-owned adult dogs with PLN and 10 healthy control dogs.
Methods: Serum 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25 [OH]2D), 24,25-dihydroxyvitamin D (24,25[OH]2D), serum vitamin D binding protein (VDBP), and urine 25(OH)D concentrations were measured.
Results: Compared to healthy dogs, dogs with PLN had lower concentrations of all vitamin D metabolites (P < .01). Correlations (rho; 95% confidence interval [CI]) in dogs with PLN are reported. Serum 25(OH)D and 24,25(OH)2D concentrations were positively correlated with albumin (r = 0.47; 0.07-0.74), and 24,25(OH)2D was negatively correlated with urine protein-to-creatinine ratio (UPC; r = −0.54; −0.78 to −0.16). Urine 25(OH)D-to-creatinine ratio was negatively correlated with serum albumin concentration (r = −0.77; −0.91 to −0.50) and positively correlated with UPC (r = 0.79; 0.53-0.91). Serum VDBP concentration was positively correlated with serum albumin concentration (r = 0.53; 0.05-0.81).
Conclusions and Clinical Importance: Dogs with PLN have decreased serum concentrations of vitamin D metabolites. Urine 25(OH)D-to-creatinine ratio and UPC are correlated in PLN dogs. Future studies are needed to assess additional management strategies for dogs with PLN.
Outcome and treatments of dogs with aortic thrombosis: 100 cases (1997-2014)
October 4th, 2020
Aortic thrombosis (ATh) is an uncommon condition in dogs, thought to be associated with a regional prothrombotic environment in the distal aorta. This is in contrast to aortic thromboembolism (ATE) in cats, where thrombi formed in the left atria or auricle embolize to the aorta. Also in contrast with ATE in cats, overwhelmingly because of an underlying cardiomyopathy, a variety of diseases have been implicated in ATh in dogs, including protein-losing diseases, endocrinopathies, and neoplasia. In a previous study, 58% of dogs with ATh have no identified underlying disease, suggesting that ATh with no identifiable cause (or cryptogenic) might be common. Despite an overall guarded prognosis for dogs with ATh, long-term survival occurs in some dogs, suggesting heterogeneity in the clinical presentation of affected dogs.
Consensus guidelines on the optimal strategy for the prevention and treatment of thrombosis in animals have been established, but never studied prospectively. In previous studies, treatment strategies have been clinician-dependent and the variations in cases and treatments make comparison in outcomes difficult. Commonly reported treatment for ATh in dogs typically involves combinations of antiplatelet (eg, clopidogrel, aspirin) alone or in combination with anticoagulant therapies such as heparin, warfarin, direct oral anticoagulants such as rivaroxaban and apixaban with thrombolysis by tissue plasminogen activator (TPA) being attempted with varying clinical outcomes. The efficacy of these therapies in dogs with ATh has been minimally documented.
Available literature on ATh in dogs is limited to case reports, descriptive studies on small numbers of dogs, and a few larger studies without information on outcome or treatments. The aim of our study was to describe the presenting clinical characteristics of dogs with ATh, specifically underlying causes and descriptions of clinical management.
Background: Aortic thrombosis (ATh) is an uncommon condition in dogs, with limited understanding of risks factors, outcomes, and treatments.
Objectives/Hypothesis: To describe potential risk factors, outcome, and treatments in dogs with ATh.
Animals: Client-owned dogs with a diagnosis of ATh based on ultrasonographic or gross necropsy examination.
Method: Multicentric retrospective study from 2 academic institutions.
Results: One hundred dogs were identified. Anti-thrombin diagnosis, 35/100 dogs were nonambulatory. The dogs were classified as acute (n = 27), chronic (n = 72), or unknown (n = 1). Fifty-four dogs had at least one comorbidity thought to predispose to ATh, and 23 others had multiple comorbidities. The remaining 23 dogs with no obvious comorbidities were classified as cryptogenic. Concurrent illnesses potentially related to the development of ATh included protein-losing nephropathy (PLN) (n = 32), neoplasia (n = 22), exogenous corticosteroid administration (n = 16), endocrine disease (n = 13), and infection (n = 9). Dogs with PLN had lower antithrombin activity than those without PLN (64% and 82%, respectively) (P = .04). Sixty-five dog were hospitalized with 41 subsequently discharged. Sixteen were treated as outpatient and 19 euthanized at admission. In-hospital treatments varied, but included thrombolytics (n = 12), alone or in combination with thrombectomy (n = 9). Fifty seven dogs survived to discharge. Sixteen were alive at 180 days. Using regression analysis, ambulation status at the time of presentation was significantly correlated with survival-to-discharge (P < .001).
Conclusions/Clinical Importance: Dogs with ATh have a poor prognosis, with nonambulatory dogs at the time of presentation having worse outcome. Althoug the presence of comorbid conditions associated with hypercoagulability is common, an underlying cause for ATh was not always identified.
Toxicosis with grapes or raisins causing acute kidney injury and neurological signs in dogs
September 11th, 2020
Several reports of dogs developing acute kidney injury (AKI) after ingestion of grapes, raisins, or currants have been published since 1998.1-8 The mechanism of toxicity is still unknown. Hypotheses include contamination of fruits with mycotoxins, heavy metals or pesticides, excess vitamin D, tannin intolerance or excessive ingestion of monosaccharides, hypovolemic shock, and renal ischemia. The exact amount of ingested fruits necessary to cause damage is unknown, and estimations are based on clinical cases. The lowest reported dosage to cause AKI is 19.6 g/kg body weight for grapes, and 2.8 g/kg for raisins.
Reported clinical signs typically include vomiting within 24 (81% of dogs) to 48 (100% of dogs) hours of ingestion, with vomitus or diarrhea fluid possibly containing grapes or swollen raisins. Other signs were compatible with acute uremia and included anorexia, lethargy, diarrhea, and abdominal pain, as well as oliguria or anuria in 49% of dogs. Azotemia developed rapidly within 2 days of ingestion. Less frequent signs reported include dehydration, edema, ptyalism, polyuria, polydipsia, hypothermia, hypertension, trembling, seizures, and ataxia in 23% of dogs. Median onset of ataxia was 2 (range, 0.6-6) days after ingestion of grapes or raisins. It was associated with a negative outcome, and in the only survivor affected, clinical signs of ataxia persisted for 6 days. A case report from Korea describes a Yorkshire Terrier with ataxia that began on the day after grape ingestion. However, the dog died on day 3, and detailed descriptions of neurological signs and associated neuropathology are lacking.
In contrast to previous reports, we observed severe neurological signs in the dogs presented to the Small Animal Clinic of the Vetsuisse Faculty Bern, Switzerland, for AKI after grape or raisin toxicosis (GRT), sometimes dominating the clinical picture and confusing the diagnostic evaluation. Our retrospective study had the following aims: First, to evaluate the clinical, laboratory, pathological, and outcome features of dogs diagnosed with GRT compared to dogs diagnosed with AKI of other origin, with emphasis on renal and neurological manifestations; and second, to investigate potential factors for development of neurological signs by comparing dogs with and without central nervous system deficits.
Background: The ingestion of grapes or raisins has been reported to cause acute kidney injury (AKI) in dogs, with a clinical picture dominated by early gastrointestinal signs and rapidly developing uremia. Ataxia is mentioned in a few reports, but not further characterized.
Objectives: To evaluate the clinical, laboratory, and pathological features of dogs diagnosed with grape or raisin toxicosis (GRT) with emphasis on renal and neurological manifestations, compared to a control group of dogs with AKI from other causes.
Animals: Fifteen client-owned dogs with GRT and 74 control dogs.
Methods: Retrospective study over 17 months.
Results: All dogs with GRT were presented with severe AKI (grade 4, n = 5; grade 5, n = 10). Eleven dogs (73%) had marked forebrain, cerebellar, or vestibular signs. These manifestations dominated the clinical picture in some dogs, but were not associated with the severity of azotemia or the presence of systemic hypertension. Eight dogs (53%) survived, and 5 dogs experienced a complete neurological recovery. Causes of death were unrelated to the neurological manifestations. Neuropathological examination of 4 dogs did not identify any structural central nervous system abnormality. Only 2 control dogs (3%) displayed neurological signs with seizures unrelated to the AKI; 42 control dogs (57%) survived.
Conclusions and Clinical Importance: Severe forebrain, cerebellar, or vestibular signs may be an important feature of GRT and dominate the early clinical picture. The described features suggest a reversible functional brain injury specific to GRT and unrelated to uremia.
Amyloidogenesis of feline amylin and plasma levels in cats with diabetes mellitus or pancreatitis
September 9th, 2020
Amylin is a pancreatic hormone co-secreted along with insulin and involved in pancreatic amyloidosis and b-cell apoptosis in diabetic cats and humans. Amylin is usually elevated in early stages of type 2 diabetes but recently was found to be increased in acute and chronic pancreatitis in humans. Currently, there are little data about feline amylin propensity to fibrillate and no information on circulating levels of this hormone during feline pancreatitis.
We compared 4 amylin analogues and found cat amylin to be more prone to amyloid fibrillation than human amylin, the triple-proline analogue pramlintide and rat amylin. We also measured plasma amylin levels in healthy lean cats, diabetic cats, and cats with pancreatitis. Plasma amylin was higher in diabetic cats compared with healthy lean cats (P < 0.001). Interestingly, amylin levels during pancreatitis were higher than those of both lean cats (P < 0.0001) and diabetic cats without pancreatitis (P < 0.005). These data support evidence of feline amylin being more prone to aggregation than human amylin in vitro, which may influence diabetes mellitus progression and b-cell failure in vivo. Furthermore, our data show an increase in amylin levels during feline pancreatitis and the need for future research on the role of this hormone in the pathogenesis of pancreatic inflammation associated to feline diabetes mellitus.
Pancreatitis and diabetes mellitus appear to occur concurrently in many species, including humans and cats. Although a causal association has not been proven yet in cats, the concurrence of these 2 diseases has clinical implications for case management and clinical control.
Recently, human pancreatitis has been associated with the decrease in b-cell function in a progression rate even higher than in type 2 diabetes mellitus. Previous studies in humans have shown that amylin is increased during acute and chronic pancreatitis. Currently, no study has determined if feline pancreatitis can also induce an increase in amylin levels.
Observational studies prospecting amyloid material in vivo have long suggested that proline residues modulate the propensity for amylin analogues to form amyloid aggregations. However, no comparative assays have been reported to date. In fact, the triple proline analogues rodent amylin and the triple-proline (25,28,29Pro) human amylin analogue pramlintide have long been assumed to be nonamyloidogenic and nontoxic in vitro and in vivo, until recent works revealed their propensity in forming amyloid material.
In the present study, we investigated the amyloid nature of cat amylin compared with other species, exploring the aggregation pattern of cat, human, and murine amylin as well as the amylin analogue pramlintide in vitro. Furthermore, we compared plasma amylin levels between healthy cats, diabetic cats, and cats with pancreatitis.
Prevalence and risk factors associated with systemic hypertension in dogs with spontaneous hyperadrenocorticism
Aug 31st, 2020
Systemic hypertension associated with hypercortisolism is common in people, affecting 70%-85% of the patients. The pathophysiological mechanisms for hypertension in HAC are incompletely understood, but in people a multifactorial model has been proposed with many pathways involved: the renin-angiotensin system, an increased mineralocorticoid activity, the sympathetic nervous system, the vasoregulatory system, metabolic factors, vascular remodeling and sleep apnea. In human medicine, risk factors for hypertension associated with hypercortisolism are reported. In pediatric patients there is a positive correlation between SH and high circulating cortisol concentrations. In addition, SH is more frequent in pediatric patients with ACTH-independent Cushing's syndrome (CS). In adults, this tendency has also been observed in patients with ACTH-independent CS, but the prevalence of SH is similar for ACTH-dependent and independent hypercortisolism. Furthermore, in adults with CS, age, body mass index and duration of hypercortisolism have been associated with the development of SH, but no correlation is observed with circulating cortisol concentrations. Hypertensive human patients with hypercortisolism tend to have lower potassium blood concentrations than normotensive patients, especially those with ectopic CS in which hypokalemia is frequent and strongly associated with hypertension.
Systemic hypertension is also recognized in dogs with HAC with a prevalence between 31% and 86%. Some pathophysiological mechanisms have also been proposed, such as increased mineralocorticoid activity, decreased nitric oxide concentrations or increased renal vascular resistance. There are few studies assessing the risk factors for SH in dogs with HAC; in previous studies, no difference in the prevalence or severity of SH is observed between dogs with PDH or ADH and there is no correlation between systolic blood pressure (SBP) and age, sex, reproductive status or results of the ACTH-stimulation tests. Previous studies have inconsistently identified a relationship between SBP and urinary protein to creatinine ratio (UPC) or baseline cortisol concentrations. A correlation between SBP and UPC but not with baseline cortisol concentrations has been described; however, other authors have found a correlation between SBP and baseline cortisol concentrations but not with UPC.
The objectives of our study were to determine the prevalence and severity of SH in dogs with naturally occurring HAC and to identify potential risks factors for SH in these dogs.
Background: Systemic hypertension (SH) is common in dogs with hyperadrenocorticism (HAC) however there are not many studies assessing its prevalence and risk factors.
Objectives: To determine the prevalence and severity of SH in dogs with HAC and its association with clinical and laboratory findings to identify potential risk factors.
Animals: Sixty-six client owned dogs with spontaneous HAC.
Methods: Retrospective cross-sectional study. Medical records of dogs with HAC were reviewed. Systolic blood pressure (SBP) was measured using Doppler ultrasonography. Clinical signs, physical examination findings and clinicopathologic data (CBC, serum biochemistry and electrolytes, urinalysis and urinary culture, and adrenal function tests) were reviewed for analysis.
Results: Prevalence of SH (≥150 mm Hg) was 82% (54/66) and prevalence of severe SH (≥180 mm Hg) was 46% (30/66). All dogs with thrombocytosis had SH (P = .002), and a platelet count ≥438 x 103/μL was 100% specific and 61.1% sensitive to predict SH (AUC = .802, P = .001). Median potassium levels were lower in hypertensive dogs (4.1 mEq/L, range 3.1-5.4 mEq/L) than in normotensive ones (4.5 mEq/L, range 4.0- 5.0 mEq/L) (P = .007). Dogs with UPC ≥ 0.5 had higher median SBP than those without proteinuria (P = .03). Dogs with concurrent diabetes mellitus seemed to have a reduced risk of SH (OR = .118, 95%CI = .022-.626, P = .02).
Conclusions and Clinical Importance: In conclusion, SH, which is frequently severe, is common in dogs with HAC and blood pressure should be routinely assessed in dogs with a suspicion of HAC. In those cases in which blood pressure cannot be routinely evaluated, the presence of thrombocytosis, low potassium concentrations and proteinuria should raise concerns about possible SH and the risk of TOD and might incite the clinician to perform this procedure. The association between SH and potassium concentrations might suggest a role of MR in the development of hypertension in these dogs; however further studies are needed to investigate the relationship between SH, aldosterone and 11β-HSD activity in dogs with HAC.
These findings might suggest that mineralocorticoid receptors (MR) could be involved in the development of SH in dogs with HAC. The MR has the same affinity to aldosterone and cortisol, but not to cortisone. The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) converts cortisol into cortisone, and it is abundantly expressed in the classical mineralocorticoid target tissues (eg, renal cortex, vascular endothelium and smooth muscle cells), binding the selectivity of MR to aldosterone. Hypercortisolism saturates the 11β-HSD allowing cortisol to bind the MR and resulting in a cortisol induced apparent mineralocorticoid excess. In people with hypercortisolemia, this feature has been associated with sodium retention and potassium excretion, which could contribute to the development of SH.
Finally, dogs with concurrent DM and HAC seemed to have a reduced risk of development of SH; this finding should be further investigated.
Risk factors associated with progressive increases in serum creatinine concentrations in cats with cancer receiving doxorubicin
Aug 13th, 2020
In humans, doxorubicin is not associated with nephrotoxicosis, however, other chemotherapeutic agents, including cisplatin, mitomycin C, gemcitabine and ifosfamide, can be nephrotoxic. Several patient-related factors increase the risk and severity of drug-induced kidney injury. Risk factors nclude age and female sex as both are associated with decreased muscle mass and total body water and therefore likely an underrepresentation of pre-existing kidney dysfunction, as defined by serum creatinine concentration, before administration of chemotherapy. Intravascular volume depletion from vomiting, diarrhea and diuretics also increases the risk of drug-induced nephrotoxicosis.
Cancers such as multiple myeloma, lymphoma and leukemia and diabetes mellitus are associated with increased risk of nephrotoxicosis. While doxorubicin-induced nephrotoxicosis occurs in cats, risk factors for its development have not been thoroughly evaluated. In addition, previous studies have defined decreased kidney function by serum creatinine concentration outside of laboratory reference intervals, which identifies disease late in its course after considerable injury and function loss have occurred. The aims of this retrospective study were to determine the incidence of early loss of kidney function (as defined by ≥0.3 mg/dL increase in serum creatinine concentration) in cats with cancer receiving doxorubicin in single or multiagent chemotherapy protocols and to determine risk factors associated with these progressive elevations in serum creatinine concentration. We hypothesized that pre-existing chronic kidney disease, radiation therapy, recent anesthesia or surgery and cumulative dose of doxorubicin would be risk factors for increasing serum creatinine concentrations in cats receiving doxorubicin.
Background: Azotemia occurs in cats administered doxorubicin, but risk factors have not been explored.
Objective: To determine incidence of progressive increases in serum creatinine concentration in cats with cancer receiving doxorubicin in single or multiagent chemotherapy protocols and associated risk factors.
Animals: Seventy cats with cancer receiving doxorubicin.
Methods: A retrospective study (2007-2017) of cats with indices of kidney function recorded before and after doxorubicin administration was reviewed. Cats diagnosed with kidney injury because of known etiologies other than possible doxorubicin toxicosis were excluded. Variables were compared to identify risk factors.
Results: Mean age (±SD) was 10.9 years (±3.2). Cancer types included lymphoma (n = 36), sarcoma (n = 19) and carcinoma (n = 14). Chronic kidney disease was present in 29/70 (41%) cats before receiving doxorubicin. Of 70 cats, 24 (34%) developed an increase in serum creatinine concentration ≥0.3 mg/dL and 10 (14%) had an increase ≥50% from baseline. Mean time to increases in serum creatinine concentration ≥0.3 mg/dL from first administration of doxorubicin was 119.3 days (±89.7), with mean 2.8 (±1.2) doses administered. Neutropenia or anemia during chemotherapy and number of radiation therapy treatments under general anesthesia were risk factors for increases in serum creatinine concentration (P < .05). Cats receiving single agent doxorubicin had a higher likelihood of an increase in serum creatinine concentration ≥0.3 mg/dL from baseline than cats receiving CHOP-based chemotherapy
protocols (OR 20.0, 95% CI 2.9-100).
Conclusions and Clinical Importance: Progressive increases in serum creatinine concentration from baseline were common in cats receiving doxorubicin and associated risk factors were identified.