Jan A. Christensen

Acute renal failure in man: new aspects concerning pathogenesis. A morphometric study.

The morphometric investigation of the proximal and distal tubules, the cortical interstitium, the intertubular capillaries, the renal corpuscles and the juxtaglomerular apparatuses (JGAs) in 56 cases in the oligoanuric, polyuric, and normuric phases of human acute renal failure (ARF), 6 cases of myeloma kidney with clinically confirmed ARF and 21 control kidneys revealed the following: (1) The main pathological change in human ARF is swelling of the epithelial cells of the proximal and distal tubules. Necrosis of these cells was observed in some cases but usually only as single cell necroses. (2) The interstitium of the cortex and of the outer stripe of the outer medulla is significantly widened in most cases of ARF. (3) In proximal tubules proximal to occluding casts (which were observed only in the plasmacytoma cases), the lumina are not widened but are narrower than normal, and the cross-sectional area of the epithelium is not greater but smaller than normal. (4) The JGAs were significantly larger in kidneys in the oligoanuric phase of ARF (with 1 exception) than in normal kidneys. In the normuric and polyuric phases they were slightly (not significantly) smaller than normal. In myeloma kidneys with occluding casts and/or diffuse interstitial fibrosis, the JGAs were significantly smaller than normal. From these findings it is concluded that: (1) The fall in glomerular filtration rate (GFR) in the postshock phase of ARF is not caused by nonselective back-diffusion of the primary urine through necrotic tubules or by compression of the lumina of the proximal and distal tubules by interstitial edema. A fall in GFR associated with occluding casts in the distal tubules is found only in the myeloma kidney and does not lead to widening of the proximal tubules but to tubular atrophy and narrowing of the lumen. (2) The casts seen in the lumina of the ascending limb of Henles loop in some cases of ARF, which consist of hemoglobin, Tamm-Horsfall protein or desquamated blebs, do not occlude the lumen, since they are not associated with atrophy or luminal dilatation of the proximal tubules. (3) The JGAs with their secretory product renin-angiotensin II, together with adenosine, which is released in kidneys with ischemic or toxic damage, play a critical role in the pathogenesis of ARF. (4) In myeloma kidneys with ARF, in which the JGAs are markedly atrophic, the potentiated effect of adenosine that has been observed with a chronic absence of urine flow probably leads to a progressive, irreversible drop in GFR associated with tubular atrophy.

The juxtaglomerular apparatus in the normal rat kidney.

Fifty Juxtaglomerular apparatuses (JGA) from 6 normal rats of two different strains (BD9 and Sprague-Dawley) were studied with serial section technique after vascular perfusion with 1% Glutaraldehyde and embedding in Plexiglass. The macula densa basal area and the contact area between macula densa and the Goormaghtigh cell field were significantly greater in the BD9 rats than in the Sprague-Dawley rats, The contact area between the efferent arteriole and the Goormaghtigh cell field was greater in the Sprague-Dawley than in the BD9 rats. The contact area between the afferent arteriole and the Goormaghtigh cell field was equal in both strains of rat. Significant correlation was found in both strains between the size of the macula densa basal area and its contact area with the Goormaghtigh cells. Similarly there was a significant correlation of the area of contact between the Goormaghtigh cells and the macula densa on the one side and with the afferent arteriole on the other. No correlation was found with the efferent arteriole. Direct contact between macula densa and the arterioles was not present in all Juxtaglomerular apparatuses. It occurred in the BD9 rats in 92% on the afferent and in 52% on the efferent side. In the Sprague-Dawley rats direct contact between macula densa and the arterioles occurred in 59% with the afferent and 72% with the efferent arteriole. Epithelioid cells were found in the preglomerular segment of the afferent arterioles. They replaced the smooth muscle cells in the whole thickness of the media. The results point to the Goormaghtigh cells as the morphological link between the tubular and vascular parts of the Juxtaglomerular apparatus.

Hyperperfusion Injury of the Human Kidney in Different Glomerular Diseases

Investigations of biopsy material from human kidneys with different forms of glomerulonephritis (n = 1,240) and with diabetic glomerulosclerosis (n = 406) performed in order to find changes caused by hyperperfusion of the kidney tissue gave the following results: (1) Hyperperfusion injury occurs in the different forms of glomerulonephritis with varying frequency. It was rarely found in immunologically negative mesangioproliferative glomerulonephritis. The highest incidence was found in patients with membranoproliferative glomerulonephritis type I. (2) Hyperperfusion injury was also found in kidneys with diabetic glomerulosclerosis. The frequency of this finding increased with the degree of the diabetic changes. (3) The hyperperfusion injury was seen as a complication of glomerulonephritis or diabetic glomerulosclerosis only when the patient clinically had developed malignant hypertension and when the serum creatinine level was elevated, a sign of compensated retention. (4) In patients with glomerulonephritis, the hyperperfusion changes occurred more frequently in males than in females. Diabetic glomerulosclerosis was complicated by hyperperfusion injury with the same frequency in both sexes. (5) Patients with hyperperfusion changes of the kidneys always excrete large amounts of protein in the urine. (6) Hyperperfusion changes occur first in the juxtamedullary glomeruli. The intermediate glomeruli are affected later and the subcapsular glomeruli last.

Peripolar cells in the avian kidney

Four white leghorn chickens were injected with furosemide (20 mg per kg body weight) three times at 12 h intervals and the kidneys fixed by perfusion after 36 h. Five chickens were injected with DOCA (desoxycortone trimethylacetate, 75 mg per kg body weight) three times at 12 day intervals and the kidneys fixed by perfusion after 36 days. Serial sections from the kidneys of these two groups of birds were made and the number of peripolar cells recorded. These recordings were compared with the number of peripolar cells in four normal, untreated chickens. A significant increase in the number of peripolar cells was recorded in the furosemide treated group. No significant change was seen in the DOCA treated group. However, in the DOCA-group heavily granulated podocytes were found. No distinct morphological difference was found between the granules in the podocytes and the granules in the peripolar cells. A possible lysosomal nature of the peripolar cell granules is discussed.

Renin-positive granulated Goormaghtigh cells

SummaryIt is difficult to distinguish between Goormaghtigh cells (G-cells) and media cells of the glomerular arterioles at the border of the Goormaghtigh cell field. Consequently, it has been unclear whether renin-positive G-cells are normally present and also whether renin-producing cells are recruited from the pool of renin-negative G-cells upon stimulation of the renin-angiotensin system (RAS). In the present study, immunohistochemical and electron-microscopic experiments have been carried out on serially sectioned kidney biopsies from four patients with pseudo-Bartter syndrome. The results strongly suggest that with longlasting stimulation of the RAS all renin-negative (“secretory resting”) G-cells are ultimately converted into renin-producing granular cells.

The juxtaglomerular apparatus in the avian kidney

SummaryThe domestic fowl has two types of glomerulus (mammalian and reptilian type). 30 of each were studied morphometrically in semi thin and PAS-stained sections. The juxtaglomerular apparatus was larger in the mammalian type, but complete in both, containing macula densa, Goormaghtigh (lacis) cells and hilar arterioles. Granular epithelioid cells were occasionally found in the afferent arterioles and within the glomerulus in the mammalian type only.All glomeruli studied had a prominent mesangial cell mass (MCM), which was larger in mammalian type glomeruli. Hilar arterioles often penetrated the mesangial cell mass and regularly ramified within it. There was always extensive direct contact between the Goormaghtigh cell mass and the macula densa on the one side and the MCM on the other. In mammalian type glomeruli, the afferent arterioles were invariably found centrally within the MCM, but in the reptilian type no distinct pattern was found. The close relationship between the MCM and the hilar arterioles, especially in mammalian type glomeruli, suggests that the MCM regulates the glomerular filtration rate.

The granular epithelioid cells in the kidney of the lemon sole (Pleuronectes microcephalus Donovani)

SummarySerial sections from kidneys of 5 aglomerular lemon soles (Pleuronectes microcephalus) demonstrated the presence of anastomosing arteriolar networks in the caudal half of the organs. There was no preferred location of the networks, which were found both near the surface and in the deeper parts of the kidney. The size of the networks varied; the largest measured more than 900 μm in the longest axis and covered an area larger than 500000 μm2, whereas the smallest measured about 60 μm in diameter with an area of 2040 μm2. The larger networks were invariably located close to large intrarenal veins. Anastomoses were found between the arteriolar networks and the peritubular capillaries and also associated with veins.The walls of the arterioles were composed of granulated epithelioid cells, exhibiting numerous intracytoplasmic granules. These granules occasionally had a rod-like appearance with a paracrystalline substructure. Using antibodies directed against murine and human renin, the epithelioid cells in the walls of the arteriolar networks and the cytoplasmic granules revealed a positive immunoreaction.The results suggest that the renin-angiotensin system in the aglomerular lemon sole may be important for both the regulation of the systemic blood pressure and the blood supply to the peritubular capillaries of the kidney.

Role of Hyperperfusion in Different Glomerular Diseases

In various forms of glomerulonephritis, diabetic glomerulosclerosis and decompensated benign nephrosclerosis hyperperfusion injury of the glomeruli may be found in addition to the basic disease in patients with malignant hypertension. The changes consist of adhesions, subendothelial capillary hyalinosis and fat droplets in the hyalin material and in endothelial cells. They occur far more often in males than in females. The highest frequency of hyperperfusion injury was found in patients with membranoproliferative glomerulonephritis type I. The lowest frequency was found with membranous glomerulonephritis. The juxtamedullary part of the kidney, which is not autoregulated, is earlier and more severely affected than the subcapsular part. Hyperperfusion changes occur in the middle and eventually in the subcapsular part of the cortex only when the glomeruli in the juxtamedullar cortex are sclerotic.

Effect of volume depletion on the afferent arterioles in the avian kidney

Nine white leghorn chickens were injected i.m. with furosemide (10 to 60 mg/kg body weight) twice daily for 18 days. The birds were then anesthetized with a combination of equithesin and diazepam and the kidneys perfused via the heart. Kidney tissue was sectioned serially and the granular epithelioid cells were counted in the juxtaglomerular apparatuses of the furosemide treated birds and in 3 normal chickens. Hyperplasia and hypergranulation of the epithelioid cells was found to occur in the juxtaglomerular apparatuses of both mammalian and reptilian type nephrons (with and without Henles loop) in the furosemide treated group. This finding was interpreted as an effect of hypovolaemia on the juxtaglomerular apparatuses. Furosemide caused an immediate stop in weight gain, an increase in the erythrocyte volume fraction and a sudden drop in blood pressure. The blood pressure later rose to subnormal levels. The heart rate was not altered. Plasma sodium and chloride fell significantly one day after furosemide administration and remained low throughout the experiment. Potassium fell during the second part of the experimental period. Captopril was injected after 18 days of furosemide treatment and lowered the blood pressure significantly. This was interpreted as indirect evidence for the presence of renin in the granular epithelioid cells and indicates the importance of the renin angiotensin system in maintaining the blood pressure in hypovolaemic conditions.