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This article has reviewed the involvement of the kidney as a target organ of essential hypertension. Since Bright first made the association of renal disease and hypertension in 1836, the nature of this relationship has been debated. Although there is evidence implicating abnormalities of renal function in the pathogenesis of essential hypertension, hypertension frequently precedes histologic evidence of alterations in renal structure. Nephrosclerosis, or hardening of the kidney, is the term used to describe the histologic changes occurring in the kidney as the result of hypertension. It can be though of as an acceleration of the normal aging process of the renal vasculature. Glomerular and tubular changes have been traditionally thought to be ischemic in origin. Experimental evidence supports the notion that, as renal function is lost, intraglomerular hypertension develops and may be responsible for additional nephron loss in hypertension. This idea may have therapeutic implications for hypertensive patients with renal insufficiency in that agents that reduce both systemic and intraglomerular pressure may be preferable. Hemodynamically, early hypertension is often characterized by normal peripheral and renal vascular resistance and an increased cardiac output. In established hypertension, cardiac output is usually normal, and peripheral and renal vascular resistances are increased. Renal blood flow is reduced, glomerular filtration rate is maintained, and the filtration fraction rises. In the absence of an accelerated malignant phase, renal failure is uncommon in essential hypertension. Males and blacks are most sensitive to the vascular damage of essential hypertension. Essential hypertension remains an important cause of end-stage renal disease, especially in blacks. Atherosclerotic obstruction of the renal arteries may be a more common cause of renal failure in patients with essential hypertension than has been previously recognized. There are few sensitive markers of early renal involvement in essential hypertension. Several studies of sensitive markers are promising and may detect patients who are prone to renal injury and deserve more aggressive treatment. Malignant hypertension is characterized pathologically by vascular changes of proliferative endarteritis and fibrinoid necrosis. Fortunately, its frequency is decreasing because of early identification and effective treatment of essential hypertension. Effective treatment of severe and malignant hypertension clearly leads to stabilization (and occasionally improvement) of renal function.(ABSTRACT TRUNCATED AT 400 WORDS)

The necropsy reports and clinical observations of 44 cases of glomerulonephritis occurring in patients over 55 years old were reviewed. Two-thirds of the patients died from a rapidly progressive renal disease with focal necrotizing and fibrosing glomerular lesions; half of these exhibited a granulomatous splenic trabeculitis; an associated vasculitis was found in only a minority of these cases. Another important group consisted of cases of acute diffuse glomerulonephritis which, as a rule, occurred in association with a major infection. There were only four cases of chronic sclerosing glomerulonephritis.

Kidneys from 90 individuals who had died from atherosclerosis, hypertensive disease, or chronic glomerulonephritis were examined following early autopsies. The nephron epithelium and the endothelium of peritubular capillaries were studied for activities and distribution patterns of NADPH2 dehydrogenase, lactate dehydrogenase, succinate dehydrogenase, and acid and alkaline phosphatases, for relative capillary and connective tissue volumes, and for lymphocyte, monocyte, and plasma cell numbers. A mathematical analysis of the histochemical and morphometric data provided information on the nature of changes in the renal microcirculatory bed and on the roles of free stromal cells in various forms of nephrosclerosis as well as on the zonal distribution of the parameters studied. Intercellular and vascular-cellular links were found to be weakest in the most advanced stage of chronic glomerulonephritis involving reduction of peritubular capillaries. In cardiovascular disorders, the morphofunctional characteristics of the microcirculatory bed and of its volume showed reciprocal changes, probably of a compensatory character.

A histometrical study of the distribution pattern of hyalinized glomeruli in diabetic glomerulosclerosis, malignant nephrosclerosis and chronic glomerulonephritis was achieved using the nearest neighbor method. The features of the circulatory dynamics in each disease are discussed based on the results of this study. The glomeruli were hyalinized at random in diabetic glomerulosclerosis. The distribution of hyalinized glomeruli occurred at random in normal kidney, which suggests that glomeruli become hyalinized with no dependency on the vasculature. Malignant nephrosclerosis on the other hand, shows that the glomeruli are hyalinized in clusters, and that suggests that the kidneys react to hypertensive changes in the interlobular artery and more peripheral arteries. The glomeruli supplied by the interlobular arteries will then hyalinize in clusters. If these two renal diseases are used as an end of a spectrum, the distribution pattern of hyalinized glomeruli in chronic glomerulonephritis showed most similarity with that seen in malignant nephrosclerosis. However, the percentage of hyalinized glomeruli was 21% in malignant nephrosclerosis as opposed to 77% in chronic glomerulonephritis. This marked difference suggests that in malignant nephrosclerosis, the percentage of hyalinized glomeruli was low due to participation of arteries larger than the accurate branches. However, the patients became uremic within a short time. Contrary to this finding, in chronic glomerulonephritis, the effect is from the smaller arteries less than that from the interlobular artery. Ordinarily, if an insufficient number of glomeruli become hyalinized, uremia will not develop. Finally, the difference in the genesis and vascular participation of diffuse type and nodular type of diabetic glomerulosclerosis and the relationship between acute glomerulonephritis and chronic glomerulonephritis are discussed.

The condition of a patient with postpartum nephrosclerosis improved during heparin therapy. Review of the literature disclosed 29 other patients with the same histopathologic characteristics, eight of whom also recovered substantial renal function after anticoagulation therapy. Also reported is a patient in whom renal failure occurred while she was taking oral anovulatory agents. Renal biopsy specimen showed the same histopathologic features, which raises the question of similar factors mediating the expression of this disease. We suggest a uniform terminology for this syndrome, either postpartum nephrosclerosis or nephrosclerosis in women taking oral contraceptives.

Analgesic nephropathy, its morphology, development and pathogenesis are described. The earliest analgesic-caused lesion is capillary sclerosis of the urinary tract mucosa. Later focal necroses can be found in the papillae surrounding the collecting ducts. Foci of necrosis progress and become confluent, resulting in complete papillary necrosis. Later renal cortical lesions develop due to retained areas of papillary necrosis. The cortical changes include chronic interstitial nephritis with cortical atrophy in the suprapapillary region as well as hypertrophy of the columnae Bertini with segmental, focal glomerulosclerosis. The analgesic-related lesions are the result of toxic damage to endothelial, tubular and interstitial cells. Analgesic-induced kidney and urinary tract changes are quite specific. Frequent complications include hypertension, pyelonephritis, hydro- or pyonephrosis and urinary tract tumors. The clinical picture is characterized by the consequences of distal tubular damage: impairment of urine concentrating capacity, acidosis, electrolyte loss. Analgesic nephropathy is an example of an absolutely preventable drug induced nephropathy. It is the most important single manifestation of the analgesic syndrome. It is recommended that prescriptions for mixed analgesics (multi-component analgesics) should be made obligatory. Monocomponent analgesics could be sold over-the-counter.

Primary malignant nephrosclerosis shows a haemolytic-uraemic symptomatology and can be differentiated from secondary malignant nephrosclerosis on clinical and histological grounds. The disease was observed in 4 patients: a 25-year-old man and 3 women aged 19, 28 and 49 years. The disease is characterized by a fulminating course, malignant hypertension with progressive retinopathy, and development of progressive renal failure with subsequent irreversible anuria. In addition haemolytic anaemia or posthaemolytic states as well as consumption coagulopathy occur. In 2 cases schizozytes and in particular helmet-shaped forms could be demonstrated. On histology an obliterating necrotizing vascular change is seen which is limited to the kidneys as was demonstrated in one case by angiography. Therapeutic attempts included antibiotics, steroids, heparin, streptokinase, antihypertensive drugs, and haemodialysis. The 3 female patients died, the man survived after bilateral nephrectomy.

Renal vascular changes in severe hypertension were studied. Twenty-five cases selected from 4,629 autopsies were classified into 2 groups according to the cause of death: group 1 (9 cases died of renal failure) and group 2 (16 cases of extra-renal death). Group 1 had been clinically diagnosed as malignant hypertension and had the hallmarks of malignant nephrosclerosis characterized by arteriolar fibrinoid necrosis and edematous intimal thickening. Group 2 had been clinically diagnosed as benign hypertension and basically exhibited the changes of benign nephrosclerosis. However, about half of the cases of group 2 had arteriolar fibrinoid necrosis, though the lesion was usually less extensive than in group 1. Immunofluorescence revealed similar deposits of immunoglobulins and fibrinogen in the site of fibrinoid necrosis observed in both groups. As for the changes of interlobular arteries, a quantitative analysis disclosed a distinctive difference between groups 1 and 2 with respect to the narrowing ratio of arterial lumina, though edematous intimal thickening was recognized on relatively rare occasions in the distal interlobular arteries in a few cases of group 2. From the results, the problem of transition from the benign to malignant nephrosclerosis was discussed.

The role of renal biopsy in 46 patients with end stage renal failure was assessed. Renal tissue was obtained by open renal biopsy in 24 patients, by needle biopsy in 5, and at bilateral nephrectomy in 17. In 4 patients the renal biopsy specimens showed advanced changes that could only be diagnosed as "end stage kidney". In 42 patients (91 per cent), a precise renal diagnosis was made. In 20 patients (43 per cent) the prebiopsy clinical impression differed from the histologic diagnosis. In the 29 patients undergoing renal biopsy, minor postoperative morbidity occurred in 5. We conclude that a renal biopsy in patients with end stage renal failure will result in a change in clinical diagnosis in a significant number of patients and can be performed with low morbidity.

Fourteen autopsied cases of malignant nephrosclerosis were classified into 6 of pure form in which syndrome of malignant hypertension developed from the beginning of the disease, and 8 of exacerbated form with appearance of the syndrome in the course of essential hypertension. Pathohistological study of these cases elucidated the differences in histologic manifestations between pure and exacerbated forms of malignant nephrosclerosis as to which little had been known as yet. In the pure form arterioles and small arteries characteristically demonstrated acute or recent lesions such as fibrinoid necrosis and hemorrhage into intima, and intimal cellular hyperplasia of somewhat longer duration, whereas in the exacerbated form coexistence of vascular lesions of various intensities and durations, acute (fibrinoid necrosis and hemorrhage), intermediate (intimal cellular hyperplasia) to chronic (sclerosis and lamellar elastosis), and superposition of more recent vascular lesions on more advanced or older ones were noted. Superposition of vascular alterations was interpreted to be not necessarily specific for exacerbated form but histologic manifestation of recurrence which is liable to be the case more frequently in exacerbated form than in pure form in the longer course of essential hypertension or of malignant hypertension. Some other related problems were also considered and discussed.

This report describes a 45-year-old man who suffered from hemolytic-uremic syndrome. In his autopsy findings, kidney arteriolar walls showed marked hyaline degeneration and interlobular arteries were occluded by severe intimal proliferation. No vascular changes were found in other organs. There were no arteriosclerotic changes in either main branches from the aorta or the aorta. These vascular changes are correspond well with the early features of malignant nephrosclerosis without any clinical findings of malignant hypertension. This type is called primary malignant nephrosclerosis by Bohle et al. We would like to point out the significance of this case in the re-consideration of the pathogenesis of malignant nephrosclerosis.

150 patients dying from renal cell carcinoma are studied in order to reveal the background disease, incidence and character of the nephrosclerosis and the possible morphogenetic link between nephrosclerosis and carcinoma. Renal cell carcinoma is found to develop in 82.7% of cases in the kidneys with signs of nephrosclerosis. The diffuse nephrosclerosis developing in connection with the hypertension disease, atherosclerosis, diabetes mellitus, chronic pyelonephritis, nephrolithiasis is the most important. Proliferation of the canaliculi epithelium with the appearance of undifferentiated cells are regularly found in the nephrosclerotic areas. The disturbance of the epithelium differentiation is followed by the development of dysplasia the phenotypical variants of which are similar to those of renal cell carcinoma. Adenomas are found in 11.3% of cases of renal cell carcinoma which may originate from the adenomas developing against the background of nephrosclerosis.

A 10-month-old infant developed a steroid resistant nephrotic syndrome. The renal biopsy revealed diffuse mesangial sclerosis of the glomerula. The child died from interstitial pneumonia 3 months after onset of the renal symptoms. Post mortem, the glomerular changes were diffuse but prominent in certain segments of the glomeruli. The immunohistological examination showed granular deposits of IgM and C3 in the mesangium and in the subendothelial region of the basement membrane. These findings are compatible with the hypothesis that diffuseal sclerosis is caused by glomerular deposition of immune complexes.

The incidence of sclerotic glomeruli as a function of age in kidneys from 122 patients without clinical evidence of renal disease or hypertension was estimated by histologic quantitation. Based on statistical analysis of data from this sample, 95% of the normal population up to 40 years of age would be expected to have less than 10% sclerotic glomeruli. After the age of 40 years, the upper limit containing 95% of the normal population exceeds 10% sclerosis, and after the age of 50, there is a broad scatter of observed percentage of sclerotic glomeruli. These findings suggest that, in patients 40 years of age and younger, sclerosis of glomeruli at an incidence greater than 10% is disease-related, while in patients older than 40 years (and particularly those older than 50), there is a transition, and the distinction between abiotrophic involutional sclerosis and disease-related sclerosis becomes less clear.

The activity of lysyl oxidase which catalyzes the initial step of cross-linking of collagen and elastin polypeptides was measured in blood vessels of the hypertensive rat. The enzyme activity was increased in the aorta and mesenteric artery when hypertension was induced in 8-week-old rats with administration of deoxycorticosterone acetate (DOCA) and 1% saline. Reserpine diminished this increase in vascular lysyl oxidase activity concomitant with reduction in blood pressure. When beta-aminopropionitrile, a specific inhibitor of lysyl oxidase, was administered before the onset of DOCA-salt hypertension, the aortic collagen content was reduced markedly. Concomitant with reduction in the aortic collagen content, the development of hypertension and arteriosclerotic changes in the kidney was partially prevented. These results would indicate that hypertension increases the amount and the degree of cross-linking of vascular collagen and that the deposition of excess collagen in the vascular wall contributes to the development of hypertension and arteriosclerosis.

1. As proposed by Schürmann & MacMahon (1933), we suggest that two types of malignant nephrosclerosis exist. 2. In the type called primary malignant nephrosclerosis, renal vascular lesions precede hypertension. 3. In the second type, called secondary malignant nephrosclerosis, renal vascular lesions are considered to be the consequence of malignant hypertension.

The most frequent form of nephrosclerosis in human kidneys is the so-called benign variant. It may develop subsequent to even short-lasting hypertensive episodes. The interlobular arteries may be primarily affected, occasionally accompanied by glomerular and tubulointerstitial lesions. Consequently, progressive renal damage may occur potentially aggravating renal diseases of different origin. Malignant nephrosclerosis became a rare disease. Experimentally, it was impossible to induce its early intimal changes exclusively by high blood pressure values. Therefore, it was assumed that previous adaptive vascular changes, in addition to further advancing hypertension, may also be prerequisites for the development of malignant nephrosclerosis.

The renal microvasculature was examined stereoscopically after intraarterial injection of silicone rubber. Specimens studied were: 29 cases of normal kidney, 4 cases of sclerotic kidney, 10 cases of acute renal failure, and 10 cases of chronic renal failure from the final stage of chronic glomerulonephritis, malignant nephrosclerosis, diabetic nephropathy, and cortical necrosis. The following were common evidences for chronic renal failure: much reduction and wide deficiencies of filling in the cortex, increased filling of vasa recta, narrowing and spiralling of interlobular arteries and cortical afferent arterioles, appearance of giant glomeruli, rarefaction of the peritubular capillary plexus, and relative preservation of glomeruli in the juxtamedullary zone and vasa recta in the medulla may be the major pathway, after the interlobular arteries and afferent arterioles in the subcapsular cortex are destroyed, and these vascular architectural changes may be intimately related to the pathophysiology of chronic renal failure.

The investigation is based on 49 autopsies at which chronic glomerulonephritis (GN) was found. The glomerular findings were classified by the WHO classification of renal diseases. The ratio of kidney weight (g) to body height (cm) gave a constitutional kidney index which correlated with the degree of global and segmental (more than 50%) sclerosis of glomeruli in chronic GN (diffuse intracapillary type). The negative correlative coefficient from simple linear regression was rho = -0.606. Chronic GN was then further subdivided into four groups which mutually correlate: diffuse sclerosing GN (so-called end-stage kidney). Index: 0.27 g/cm; diffuse sclerosing GN (over 80% glomerular sclerosis). Index: 0.49 g/cm; diffuse proliferative and extensive sclerosing GN (more than 50% and less than 80% sclerosis) Index: 0.59 g/cm; diffuse proliferative and mild to moderate sclerosing GN (less than 50% sclerosing). Index: 0.93 g/cm. The indices of the diffuse extracapillary GN were high in comparison with diffuse intracapillary GN. The kidney index of diffuse extracapillary proliferative and extensive sclerosing GN with over 80% fibrous crescents was 0.78 g/cm. Index of diffuse extracapillary proliferative and mild to moderate sclerosing GN, mostly epithelial and fibro-epithelial, few fibrous crescents was 1.30 g/cm. The mean values of the indices for normal kidneys were (males) 0.78-0.81 g/cm and (females) 0.73-0.75 g/cm (age: 20-60 years). These results may be used for correlative investigations with morphometric parameters of renal osteopathy.

A study of renal disease in familial dysautonomia identified excess glomerulosclerosis in 10 or 13 autopsied and biopsied patients. Sympathetic nerve terminals could not be found on renal vessels in biopsied tissue; they were invariably demonstrable in controls. Altered renovascular responsivity to systemic hypotension in familial dysautonomia may lead to ischemia and subsequent sclerosis of glomeruli. Review of 79 living outpatients showed that clinically overt renal disease was rare in familial dysautonomia. Nevertheless, frequent observations of elevations of serum creatinine concentrations (32% of patients) and blood urea concentrations (76% of patients) indicated a high prevalence of abnormality. An association was found between hypotension and renal dysfunction.

Syrian hamsters developed spontaneous renal lesions that resembled those of arteriolar nephrosclerosis in man, and differed from other spontaneously occurring or virus-induced renal diseases in other rodent species. Morphologic changes were mainly degenerative with little cellular exudation and were associated with histologic changes in the intrarenal vasculature. The renal lesions were progressive, often fatal and sometimes were complicated by glomerular amyloidosis with the nephrotic syndrome and uremia. Endstage kidneys often had fibrinoid necrosis of intrarenal arterioles and thus resembled lesions characteristic of the malignant phase of human essential hypertension. Fibrinoid necrosis of small arterioles was common in the uterus, ovaries or testes of affected animals; it was less frequent in mesenteric or coronary vessels. Cardiac thrombosis, often involving the left atrium or left atrioventricular valves, also was common. Changes occurred earlier and often were more severe in females than in males. This disease was a major cause of morbidity and mortality and hampered life-span studies.

Heavy proteinuria in patients with essential hypertension raises the question of underlying primary renal disease. While malignant hypertension may be associated with proteinuria in the nephrotic range, it is generally held that protein excretion in benign nephrosclerosis is almost invariably less than 0.5-1.0 g/24 h. We report 18 patients with biopsy-proven hypertensive nephropathy and heavy proteinuria, of which only 6 had malignant hypertension. In the remaining 12 patients with benign nephrosclerosis, protein excretion reached up to 6.5 g/24 h, and nephrotic range proteinuria was present in 3 patients. All patients with heavy proteinuria suffered from long-standing moderate or severe, poorly controlled hypertension and were azotemic. We suggest that hypertensive nephrosclerosis be included in the differential diagnosis of massive proteinuria accompanying azotemia in poorly controlled hypertensives.

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.

This case deals with a 15-month old male child affected with a nephrotic syndrome resulting in grave chronic renal failure, determined histologically as diffuse mesangial sclerosis. The most frequent causes of nephrotic syndrome in the first year of life are analyzed along wiht their diagnostic differential, with special attention to the Finish or microcystic congenital nephrotic syndrome and to diffuse mesangial sclerosis. In the discussion contradictions existing in the bibliography on diffuse mesangial sclerosis are shown in its clinical and developmental aspects as well as the prognostic and even in the pathological anatomy, which leads us to believe that this illness may be more complex than what it appears, and subdividing it into illnesses of different etiology, development and prognosis; or that some of the cases. described as such may not be the same as those described by R. Habib in 1973. In the present case the deposits of C3 and IgM are worth noting, as they were not described in the other 11 cases, also the study done with the electron microscope, which also was not done in the previous cases.

The pathogenesis of terminal renal failure is discussed. The following are distinguished: 1. Renal failure occurring against a background of decompensated benign nephrosclerosis, primary and secondary malignant nephrosclerosis, and stenosis of the renal artery. 2. Renal failure caused by loss of glomeruli. It is pointed out that in most glomerulopathies, including diabetic glomerulopathy and renal amyloidosis, terminal renal failure only develops when accompanying disease of the postglomerular vessels leading to interstitial fibrosis impairs the outflow of blood from the glomerulus to such an extent that no more urine is produced. 3. Renal failure in disease of the tubules themselves. It is emphasized that acute renal failure only becomes chronic when interstitial fibrosis develops from the interstitial edema occurring in the early stage of the disease. 4. Renal failure occurring in primary diseases of the renal cortical interstitium. The chronic sclerosing renal diseases arising from acute interstitial nephritis are dealt with, as also are reflux nephropathy, incomplete obstructive nephropathy, analgesic nephropathy, and chronic interstitial rejection reactions in transplanted kidneys.