New Mexico's COVID-19 Experience.

ABSTRACT: The 2019 novel coronavirus disease (COVID-19) has spread worldwide, infiltrating, infecting, and devastating communities in all locations of varying demographics. An overwhelming majority of published literature on the pathologic findings associated with COVID-19 is either from living clinical cohorts or from autopsy findings of those who died in a medical care setting, which can confound pure disease pathology. A relatively low initial infection rate paired with a high biosafety level enabled the New Mexico Office of the Medical Investigator to conduct full autopsy examinations on suspected COVID-19-related deaths. Full autopsy examination on the first 20 severe acute respiratory syndrome coronavirus 2-positive decedents revealed that some extent of diffuse alveolar damage in every death due to COVID-19 played some role. The average decedent was middle-aged, male, American Indian, and overweight with comorbidities that included diabetes, ethanolism, and atherosclerotic and/or hypertensive cardiovascular disease. Macroscopic thrombotic events were seen in 35% of cases consisting of pulmonary thromboemboli and coronary artery thrombi. In 2 cases, severe bacterial coinfections were seen in the lungs. Those determined to die with but not of severe acute respiratory syndrome coronavirus 2 infection had unremarkable lung findings.

Pathogenic role of angiotensin II and the NF-κB system in a model of malignant hypertensive nephrosclerosis.

We previously reported that rats treated with an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), during lactation developed hypertension in adult life, without apparent functional or structural damage to kidneys, providing a new model of essential hypertension. Here, we investigated whether uninephrectomy associated with salt overload would unveil a latent renal dysfunction in this model, aggravating arterial hypertension and promoting renal injury. Male Munich-Wistar rat pups received PDTC from maternal milk (PDTCLact) from 0 to 20 days after birth. Another group received no treatment during lactation. All offspring underwent uninephrectomy (UNx) at 10 weeks of age and then were subdivided into NS, receiving a normal salt (0.5% Na+) diet, PDTCLact + NS, HS, receiving a high-salt diet (2% Na+ chow + 0.5% saline to drink), and PDTCLact+HS. Twelve weeks later, HS rats were moderately hypertensive with mild albuminuria and renal injury. In contrast, severe hypertension, glomerulosclerosis, and cortical collagen deposition were prominent in PDTCLact + HS animals, along with "onion-skin" arteriolar lesions, evidence of oxidative stress and intense renal infiltration by macrophages, and lymphocytes and angiotensin II-positive cells, contrasting with low circulating renin. The NF-κB pathway was also activated. In a separate set of PDTCLact+HS rats, Losartan treatment prevented NF-κB activation and strongly attenuated glomerular injury, cortical fibrosis, and renal inflammation. NF-κB activity during late nephrogenesis is essential for the kidneys to properly maintain sodium homeostasis in adult life. Paradoxically, this same system contributed to renal injury resembling that caused by malignant hypertension when renal dysfunction caused by its inhibition during lactation was unmasked by uninephrectomy associated with HS.

NF-κB activation mediates crystal translocation and interstitial inflammation in adenine overload nephropathy.

Adenine overload promotes intratubular crystal precipitation and interstitial nephritis. We showed recently that these abnormalities are strongly attenuated in mice knockout for Toll-like receptors-2, -4, MyD88, ASC, or caspase-1. We now investigated whether NF-κB activation also plays a pathogenic role in this model. Adult male Munich-Wistar rats were distributed among three groups: C (n = 17), receiving standard chow; ADE (n = 17), given adenine in the chow at 0.7% for 1 wk and 0.5% for 2 wk; and ADE + pyrrolidine dithiocarbamate (PDTC; n = 14), receiving adenine as above and the NF-κB inhibitor PDTC (120 mg·kg⁻¹·day⁻¹ in the drinking water). After 3 wk, widespread crystal deposition was seen in tubular lumina and in the renal interstitium, along with granuloma formation, collagen accumulation, intense tubulointerstitial proliferation, and increased interstitial expression of inflammatory mediators. Part of the crystals were segregated from tubular lumina by a newly formed cell layer and, at more advanced stages, appeared to be extruded to the interstitium. p65 nuclear translocation and IKK-α increased abundance indicated activation of the NF-κB system. PDTC treatment prevented p65 migration and normalized IKK-α, limited crystal shift to the interstitium, and strongly attenuated interstitial fibrosis/inflammation. These findings indicate that the complex inflammatory phenomena associated with this model depend, at least in part, on NF-κB activation, and suggest that the NF-κB system may become a therapeutic target in the treatment of chronic kidney disease.

Hypertensive nephrosclerosis as a relevant cause of chronic renal failure.

It is currently unclear whether hypertensive nephrosclerosis (HN), usually diagnosed solely on clinical grounds, is a relevant cause of end-stage renal disease. We biopsied 81 hypertensive outpatients (blood pressure >/=160/95 mm Hg) with moderate renal insufficiency, who were referred to our service from 1988 to 1998. Patients with known causes of hypertension, systemic disorders, rheumatic disease, or nephrotic syndrome were excluded. In 65% of patients, HN was the sole histological abnormality associated with renal dysfunction. Benign nephrosclerosis (BN), defined as isolated arteriolar hyalinosis and/or intimal fibrosis, was found in 18 HN patients (22%), whereas malignant nephrosclerosis (MN), denoted mainly by myointimal cell proliferation, appeared in 35 HN patients (43%). Previously undiagnosed primary nephritis (PN) was found in 13 patients (16%), whereas focal and segmental glomerulosclerosis, which might be either primary or secondary to hypertension, appeared in 15 patients (19%). These findings suggest that HN, in both its BN and MN forms, can be a definite cause of chronic renal insufficiency and that a substantial fraction of patients with renal insufficiency and clinical diagnosis of HN may actually have PN.

Intrauterine food restriction as a determinant of nephrosclerosis.

We previously showed that 3-month-old rats subjected to a 50% intrauterine food restriction had a decreased number of nephrons with increased glomerular diameter, which suggests compensatory hypertrophy. Hypertrophy could be the early event of glomerular damage. In this study, we extended our investigation and performed functional, morphological, and immunohistochemical evaluations in 3- and 18-month-old rats that underwent a 50% intrauterine food restriction (RT3 and RT18, respectively) and age-matched control rats (C3 and C18, respectively). Our findings showed that glomerular filtration rate was significant decreased in RT18 rats (2.42 +/- 0.15 mL/min/kg; n = 28; P: < 0.05) compared with C18 control rats (4.19 +/- 0.10 mL/min/kg; P: < 0.05) and the percentage of glomeruli with sclerosis was greater in RT18 rats (13.01% +/- 2.95%; n = 9; P: < 0.01) than in C18 rats (2.71% +/- 0.35%; n = 6). RT18 rats also showed more intense tubulointerstitial lesions and immunohistochemical alterations in the renal cortex. Immunohistochemical studies showed increased fibronectin and desmin expression in glomeruli and tubulointerstitium and increased vimentin and alpha-smooth muscle actin in the tubulointerstitial area from the renal cortex of RT18 rats (P: < 0.05). Desmin was also increased at the edge of glomeruli from RT18 rats, suggesting podocyte injury. Our data show that when food restriction is imposed during pregnancy, permanent damage occurs in the kidney of the offspring. Glomerular lesions were more severe than the tubulointerstitial damage in these animals.

What is 'nephrosclerosis'? lessons from the US, Japan, and Mexico.

BACKGROUND: Selected features of 'nephrosclerosis' can be quantitated morphometrically in renal histology at autopsy. Specimens are available from Japan, Mexico, and the US (blacks and whites). METHODS: Autopsies of men and women aged 15-79 years provided renal samples for paraffin sectioning. These were assembled in New Orleans for objective evaluation after standardized staining with PAS-Alcian blue and interspersion with each other. Obsolescence of glomeruli, interstitial fibrosis, fibroplastic intimal thickenings of arteries, and arteriolar hyalinization, as operationally defined, were measured by objective morphometry. RESULTS: Obsolescence of glomeruli and interstitial fibrosis displayed the expected correlation with arterial intimal fibroplasia, but failed to confirm any direct association with arteriolar hyalinization. Some of the variation of 'nephrosclerosis', within and between populations, cannot be fully explained by microvascular defects. CONCLUSIONS: Arterial intimal fibroplasia appeared to promote 'nephrosclerosis', in the sense of fibrous replacement of atrophied nephrons, but arteriolar hyalinization did not. Hyaline deposits in arterioles may offer little or no threat to the integrity of the affected nephrons. 'Nephrosclerosis' appears to be multifactorial; it may be, in part, a consequence of fibroplasia in microscopic arteries causing ischaemic injury to scattered nephrons, but may also be a confluence of basically separate conditions, only some of which are known.

Nefroesclerose hipertensiva: visäo do patologista / Hypertensive nephrosclerosis: the patologist's approach

A nefroesclerose benigna tem como principais características lesões hialinas de arteríolas aferentes, hipertrofia medial de artéria interlobular, fibrose intersticial, atrofia tubular e glomerulopatia hipertensiva ou isquêmica. Embora o quadro completo seja bastante sugestivo de nefroesclerose benigna, as lesões isoladamente não são patognomônicas e podem estar presentes também na nefropatia diabética, na nefrotoxicidade crônica por ciclosporina e em meio às alterações do parênquima renal dos idosos. O exame da amostra renal à microscopia óptica, imunofluorescência e microscopia eletrônica auxiliam no diagnóstico diferencial. A nefroesclerose maligna caracteriza-se por lesão predominante de arteríolas aferentes e artérias interlobulares, às vezes estendendo-se aos capilares glomerulares com necrose fibrinóide da parede dos vasos, obliteração da luz, focos de edema, necrose e hemorragia interticiais e glomerulopatia isquêmica. O diagnóstico diferencial com o quadro histológico da síndrome hemolítica-urêmica e freqüente.

Renal microvascular features of hypertension in Japan, Guatemala, and the United States.

The finding of benign arteriolar nephrosclerosis at autopsy usually implies the prior existence of essential hypertension. It was found in this study that minor degrees of incipient nephrosclerosis in young people can be shown to correlate with seemingly trivial blood pressure elevations. In this study, autopsy tissues were used to assess the magnitude of early nephrosclerosis in five population groupings. A comparison of males in Tokyo, Japan, Guatemala, and New Orleans, La (blacks and whites); and females in Tokyo revealed significant differences among these populations. Blacks exceeded whites in New Orleans in the magnitude of incipient nephrosclerosis in all 10-year age groups from 15 through 24 years to 45 through 54 years. Guatemalan males were, on average, less affected than New Orleans whites in all age groups. The data for all males (age range, 15 through 54 years) in Tokyo revealed little difference in nephrosclerosis from those in New Orleans whites. Blood pressure data were obtained from reports of cross-sectional surveys in these five populations. Blood pressure in males varied across age x race subgroups in close parallel with nephrosclerosis (r = .90), implying that variation in blood pressure among groups of subjects is strongly nephrosclerosis linked, even at very young ages; findings for Tokyo females were aberrant in this correlation. The results suggest that the lifelong progression toward the hypertensive state begins in childhood, and that these beginnings are measurably in the population averages of both nephrosclerosis and blood pressure elevations. Moreover, population differences in these two commensurate measures of the early precursors of hypertension were found to be well established by the ages of 15 through 24 years and were sustained at least into the ages of 45 through 54 years. The years of adolescence are here brought under suspicion of special importance in setting the lifelong course toward the hypertensive state.

Nephrosclerosis and aortic atherosclerosis from age 6 to 70 years in the United States and Mexico.

With increasing age, the thoracic aorta shows progressive fibroplastic intimal thickening, which is thought to be pre-atheromatous. A similar progressive intimal thickening in the renal cortical arteries is the distinguishing feature of the nephrosclerosis which underlies essential hypertension. Therefore, the earliest detectable youthful precursors of atherosclerosis and hypertension show strong morphological resemblances to each other. In this study, close statistical associations have been shown between the two types of arterial intimal fibroplasia. Both conditions show similar sigmoid growth curves from ages 6 to 70 years, thereby generating correlations across age groups of r = 0.99 in New Orleans and r = 0.95 in Mexico City. Specimens gathered in New Orleans were found to have about 1.4 times greater arterial intimal thickening than specimens from Mexico City, and this excess was seen at all ages in both the aortas and the renal cortical arteries. It seems likely that intimal fibroplasia of arteries is reflecting similar biological principles at all levels of the vascular tree. Whatever etiological factors vary between New Orleans and Mexico City, those factors appear to act directly at a tissue level to promote the early precursors of atherosclerosis and of the nephrosclerosis that underlies hypertension.

Mesangeolise e nefroesclerose maligna / Mesangiolisis and malignant nephosclerosis

Os autores estudaram retrospectivamente 13 casos de nefroesclerose maligna primária em material de necrópsia, correspondendo a pacientes adultos (20-57 anos), na sua maioria masculinos e pretos. A presença de lesöes típicas de mesangeolise foi encontrada em 4 casos. Nenhum destes casos apresentava quadro de microangiopatia trombótica clássica. Aventadas as características clinicopatológicas da doença hipertensiva, somente os sinais de fundoscopia positiva para hipertensäo arterial maligna estiveram freqüentemente associados a mesangeolise. Os autores sugerem a mesangeolise como mais um marcador para a nefroesclerose maligna em estudo histológico

Doença renal terminal pós-gestaçäo / Post pregnancy terminal renal disease

Apresenta-se um caso de paciente jovem que apresentou doença renal terminal pós-gestaçäo e que o estudo necroscópico demonstrou nefroesclerose, com características de degeneraçäo pós-parto. Através da revisäo bibliográfica, discutem-se prováveis diagnósticos diferenciais e salienta-se a relevância do caso

[Focal sclerosing and segmentary nephropathy in children]. / Nefropatía esclerosante focal y segmentaria en niños

The cases of 23 nephrotic children in whom percutaneous renal biopsies or postmortem studies showed focal and segmentary sclerosis were reviewed. It was more common in males and the average age at the onset was 6 years. The main symptoms were edema, hematuria and unspecific general manifestations. On admission, nephrotic syndrome was present in 91% of the cases and in a lesser proportion, edema hematuria and high blood pressure were found. The lesion was diagnosed at the first biopsy in 19 cases and in 4, subsequent biopsies or postmortem studies supported the diagnosis. Only 9 out 21 patients treated showed response to steroids and 5 of the resistant cases were given cyclophosphamide, but only one responded. They were checked at different periods of time ranging from 7 months to 10 years and by the end of the study, 11 patients were still under control showing normal renal function in six of them; 4 other cases showed mild renal insufficiency and in the remaining one, there was moderate renal insufficiency. Two died. A good correlation was evident between response to steroids and conservation of renal function. The findings are compared to those from other authors and emphasis is placed on the need to suspect the entity when a nephrotic syndrome with minimal changes is resistant to steroids, or when persistent hematuria is present; also, in cases showing initial lesions of tubular atrophy or interstitial fibrosis.

The significance of focal sclerotic lesions of glomeruli in children.

To establish the relationship between the type of focal sclerotic lesion of glomeruli and the development of progressive renal disease, the clinical courses of 20 children with focal segmental and 7 with focal global sclerosis were analyzed. Only five patients, all of them with focal segmental sclerosis, did not have the nephrotic syndrome, although all had proteinuria. Results suggest that patients with focal global sclerosis have a course identical to that of children with the minimal lesion form of nephrotic syndrome: onset in early childhood, response to steroid therapy, and a relapsing, nonprogressive course. Focal segmental sclerosis, in constrast, is characterized by older age at onset, high incidence of nephritic symptoms, lack of response to steroid therapy, and a progressive course with histologic and functional deterioration. Since most published reports have not distinguished between these two entities, a more favorable prognosis in focal segmental sclerosis may be inferred than is actually the case.