Search

Renal cell activity of p38 mitogen-activated protein kinase (p38) is increased in the diabetic milieu. p38 mediates signals relevant for the development of diabetic nephropathy (DN). However, renal p38 in Type 1 diabetes in vivo, particularly in conditions reflecting the differences in metabolic control, and its activity in advanced stages of DN, has received less attention. We examined the p38 pathway in renal cortex of rats with streptozotocin diabetes (4 weeks) with poor (DS), moderate (DM), and intensive (DII) metabolic control, achieved by varying doses of insulin therapy. Renal p38 was also studied in 12-month diabetic rats with established nephropathy (DM12) and compared with age-matched controls. p38 activity (in vitro kinase assay and expression of phosphorylated (active) p38 (P-p38)) was increased in DM and DS rats, as compared with non-diabetic controls, and attenuated by intensive insulin treatment. In all groups, P-p38 was predominantly localized in macula densa cells. Diabetic rats also demonstrated P-p38 immunoreactivity in the distal tubule and glomeruli. Enhanced p38 activity in DS and DM rats was not associated with increases in expression of active mitogen-activated protein kinase 3/6, an activator of p38, but paralleled with increased expression of scaffolding protein transforming growth factor-beta-activated protein kinase 1-binding protein 1. Expression of mitogen-activated protein phosphatase-1 (MKP-1), one of the phosphatases involved in inactivation of mitogen-activated protein kinase signaling, was increased in all diabetic groups, irrespective of metabolic control. Renal p38 activation was also detectable in D12 rats with established albuminuria and glomerulosclerosis. In summary, renal cortical p38 activity was increased in diabetic rats at early and advanced stages of nephropathy, as compared with non-diabetic animals, and attenuated by improved metabolic control. p38 activation in diabetes is likely to occur via multiple pathways and cannot be explained by downregulation of MKP-1.

The NZM2410 and NZM TAN (TAN) are two of 27 inbred strains derived from an intercross between the NZW and NZB strains. NZM2410 mice develop a highly penetrant lupus nephritis mediated by three susceptibility loci, Sle1, Sle2 and Sle3. These three loci have been combined on a C57BL/6 background in a triple congenic strain that reconstitutes the NZM2410 autoimmune phenotype. Remarkably, inspite of the presence of Sle1, Sle2 and Sle3, TAN mice display a mild autoimmune phenotype reminiscent of NZW. Contrary to the lupus-prone strains, the majority of TAN CD4(+) T cells are in a naïve-inactivated stage. TAN mice show B-cell developmental abnormalities similar to lupus-prone mice, such an accumulation of transitional T1 cells and peritoneal B-1a cells. TAN mice show, however, a unique expansion of the splenic marginal zone, in which B cells express high levels of CD5 and CD9, fail to migrate to the follicles in response to LPS, and show sub-optimal binding of T-independent type 2 antigens. Therefore, TAN mice present a functional silencing of marginal zone B cells, which have been previously implicated with autoimmune process. The TAN strain thus provides a novel model for the analysis of the genetic determinants of B-cell autoreactivity.

Although renal sinus vein invasion is the most common site of extrarenal involvement in clear cell renal cell carcinoma (CC), CC also spreads by lymphatics. As cortical lymphatics drain into the sinus, some involved sinus structures may be lymphatics, not veins. This possibility was investigated with podoplanin, a specific lymphatic endothelial marker, in 40 CC with sinus vein invasion. Ten blocks of uninvolved kidney, serving as controls, showed lymphatics within the adventitia of midcortical intralobular arteries. Lymphatics became more numerous and enlarged with progression towards the medulla. No lymphatics were among glomeruli or within the medulla unless associated with inflammation. The largest lymphatics occurred within the sinus, and were also noted within pelvic muscularis, and media of large veins. Intralymphatic tumor was observed and divided into two Groups. Group 1 (four cases) involved lymphatics within the invasive edge of tumors lacking a pseudocapsule. The lymphatics were small (0.045-0.19 mm), irregularly shaped, often incomplete, and contained single cells or small clusters of tumor cells. Group 2 (four cases) involved sinus lymphatics separate from tumor. One case each also involved adventitial lymphatics of an intralobular artery, the muscularis of the renal pelvis, and media of a muscular vein. The intralymphatic tumor in Group 2 often appeared discohesive, not endothelial cell invested, and larger than in Group 1 (0.4-0.5 mm). Conversely, tumor within muscular veins was cohesive, contained a capillary plexis, and was endothelial cell invested. In conclusion, intralymphatic tumor can be demonstrated in CC. Lymphatic involvement is less frequent than venous involvement and involves smaller structures. The potential for lymphatic spread may not be equal among involved lymphatics. Small peritumoral lymphatics may be destined for destruction by tumor growth. However, involved lymphatics within sinus and associated with renal pelvis, are likely sources for lymphatic spread and lymph node metastases.

Objective: To present a case of untreated long-term idiopathic neurohypophysial diabetes insipidus (DI) with structural and functional renal abnormalities that regressed after treatment., Methods: We describe the clinical course, biochemical data, and imaging findings in a man with idiopathic neurohypophysial DI in whom structural and functional abnormalities involving the urinary tract diminished after treatment. The patient underwent intravenous pyelography, retrograde pyelography, computed tomographic (CT) scanning of the kidneys and abdomen, iodohippurate renal scanning, and voiding cystourethrography. Ultrasonography of the kidneys at presentation and at 8-year followup and serial determinations of serum creatinine for a period of 9 years were also done., Results: A 43-year-old man had polyuria for 30 years attributable to untreated idiopathic neurohypophysial DI. He presented with bilateral flank pain and a high serum creatinine level (156 mmol/L). Ultrasonography, intravenous pyelography, retrograde pyelography, and CT scan of the kidneys demonstrated severe bilateral hydronephrosis, notably dilated and tortuous ureters, a distended bladder, and atrophy of the left renal cortex. Retrograde pyelography and voiding cystourethrography confirmed the absence of mechanical obstruction or urinary reflux. A renal scan study showed bilaterally impaired function. Treatment with intranasally administered desmopressin and clean intermittent straight bladder catheterization resulted in resolution of flank pain, improvement of renal function, normalization of serum creatinine levels, and decreased hydronephrosis during 9 years of follow-up., Conclusion: This case provides information about renal abnormalities in the natural history of a long-term polyuric state, idiopathic neurohypophysial DI, before and after treatment. Reversibility of renal structural and functional abnormalities after treatment is documented. Recognition of renal abnormalities associated with untreated neurohypophysial DI is important for prevention and treatment of such complications.

Individual animals in the closed colony population of ddY mice were analyzed to clarify the major cause of age-dependent elevation of serum IgA and the appearance of human IgA nephropathy (IgAN)-like symptoms. Based on the serum IgA levels, the mice were classified into two subgroups. One was a high serum IgA group with some manifestations of IgAN through aging (ddY(High)), and the other was a normal serum IgA group without IgAN (ddY(Norm)). The ratio of urinary IgA to serum IgA was significantly reduced in ddY(High) mice, suggesting an impaired IgA clearance via secretion through the epithelial barrier. The actual clearance rate of the intravenously injected dimeric IgA in ddY(High) mice was found to be slower than that in ddY(Norm) mice. Furthermore, we found that the polymeric Ig receptors (pIgRs) that mediate transcytosis of IgA were poorly expressed in the glomeruli as well as in the intestine of ddY(High) mice, whereas the pIgRs were more abundantly expressed in ddY(Norm) mice. In addition, the comparative study using polymerase chain reaction showed that decreased pIgR expression occurred at the transcriptional level in the ddY(High) population. Taken together, these results suggest that a systemic defect in pIgR expression may result in impaired IgA secretion and accumulation of IgA in the serum of ddY(High) mice. The age-dependent changes of pIgR expression in the dimeric IgA secretion sites of ddY(High) mice suggest a possible cause for the elevation of serum IgA level and the pathogenesis of IgAN-like disease.

Objective: To discuss our experience with a case of Riedel's thyroiditis manifesting in conjunction with several other fibrosclerotic lesions., Methods: We describe a case of multifocal fibrosclerosis and its response to glucocorticoid therapy., Results: A 46-year-old man with dyspnea, dysphagia, and hoarseness was found to have Riedel's thyroiditis, sclerosing cholangitis, retroperitoneal fibrosis, and renal cortical fibrosis. Treatment with high-dose glucocorticoids in the early stages of the disease and maintenance therapy with low-dose glucocorticoids in later stages of the disease had a beneficial effect. Serial follow-up assessments with determination of the erythrocyte sedimentation rate and computed tomographic imaging of the abdomen and thorax are recommended for monitoring of disease activity., Conclusion: Glucocorticoids are currently the treatment of choice for progressive multifocal fibrosclerosis. Accumulation of further clinical data is needed to determine more precise treatment strategies.

Background: The thrombomodulin-dependent protein C anticoagulant pathway plays a major physiologic role in the down-regulation of the coagulation process. In cell culture, inflammatory cytokines or endotoxin can down-regulate endothelial thrombomodulin (TM) suggesting that suppressed TM expression may contribute to thrombotic complications noted in Gram-negative sepsis., Experimental Design: In the present study, we have examined TM expression in the kidneys of septic rats utilizing indirect immunofluorescence and have quantified TM antigen and TM activity in extracts of the same kidneys by enzyme-linked immunosorbent assays and protein C activation assays, respectively. Conscious Sprague-Dawley rats were injected intravenously with LD95 doses of live E. coli (N = 30), or endotoxin (N = 30). Control animals (N = 30) were injected with equivalent volumes of saline. The rats were killed 30, 90, 180, 360, and 720 minutes after the initiation of sepsis., Results: Glomerular capillary thrombosis developed by 180 minutes in approximately half of the animals after the initiation of sepsis. We failed to demonstrate suppressed TM expression in the kidneys of septic animals using immunofluorescence. Neither enzyme-linked immunosorbent assays, nor protein C activation assays showed decreased levels in TM antigen expression or activity at different time points during the sepsis., Conclusions: These results indicate that suppressed TM expression does not contribute to the development of the glomerular capillary thrombosis in this septic rat model.

Background: Cytokines are intercellular polypeptide messengers that mediate immune and inflammatory responses. The temporal profile of interleukin-1 beta (IL-1 beta), IL-6, tumor necrosis factor alpha (TNF-alpha), and monocyte chemotactic protein 1 (MCP-1) expression was examined in anti-tubular basement membrane (TBM) antibody-associated tubulointerstitial nephritis (TIN)., Experimental Design: TIN was induced by immunization of Brown Norway rats with bovine cortical TBM, whereas control rats received ovalbumin. Whole kidney RNA was assessed with the RNase protection assay 3, 7, 8, 9, 10, 12, and 14 days after immunization. Cytokine mRNA expression was correlated with TNF-alpha bioactivity, renal intercellular adhesion molecule-1 expression, and CD18-positive leukocyte infiltration by immunohistochemistry., Results: Increased IL-1 beta, TNF-alpha, and MCP-1 mRNA relative to glyceraldehyde-3-phosphate dehydrogenase appeared on day 7 when TIN involved 10 to 40% of the cortex, and peaked rapidly on day 8 when there was 60 to 80% cortical involvement (at which time 75 to 80% of the infiltrating cells were neutrophils). The increase in TNF-alpha mRNA correlated with increased bioactivity. The influx of mononuclear cells on day 8 was preceded by the expression of MCP-1 mRNA. The infiltrating leukocytes expressed the leukocyte beta 2-integrin (CD18) and were found in areas with increased intercellular adhesion molecule-1 expression. The mRNAs for IL-1 beta, TNF-alpha, and MCP-1 were undetectable by day 10 (at which time 95% of the infiltrating cells were mononuclear). An increase in IL-1 receptor antagonist mRNA paralleled those of IL-1 beta. The expression of IL-6 mRNA was similar to that for IL-1, except that it disappeared by day 9., Conclusions: There is a temporal association in the expression of IL-1 beta, TNF alpha, MCP-1, and IL-6 with the upregulation of intercellular adhesion molecule-1 and leukocyte infiltration within the tubulointerstitium in anti-TBM antibody-associated TIN. The narrow window of time through which these cytokines are expressed and the coincidence of their peak expression on day 8 suggest complex cytokine interactions in the pathogenesis of anti-TBM antibody TIN.

Renal cortical and glomerular mRNA for alpha 1 (I) and alpha 1 (IV) collagen were measured by filter hybridization during experimental anti-glomerular basement membrane disease in the rabbit. The abundance of alpha 1 (IV) mRNA was 5 times greater in total RNA isolated from glomeruli as compared with whole renal cortex from normal rabbits. In contrast, there was no difference in the relative amounts of alpha 1 (I) procollagen mRNA in these two fractions. Four days after the administration of anti-glomerular basement membrane antisera, a time histologically characterized by glomerular inflammatory cell infiltration without crescent formation, beta-actin mRNA were increased 17-fold in glomeruli and 4-fold in whole renal cortex. Renal cortical mRNA for alpha 1 (I) and alpha 1 (IV) were increased 7-fold (p = 0.07) and 9-fold (p less than 0.05), respectively compared with normal rabbit kidney cortex. In contrast, there was no significant difference in the abundance of these mRNA in glomeruli at day 4. By day 7, cortical alpha 1 (I) and alpha 1 (IVP mRNA had increased 17- and 10-fold, respectively, and these transcripts had increased 13- and 7-fold in glomeruli. Cortical alpha 1 (I) mRNA remained elevated for 35 days. These data show that large changes in collagen mRNA levels occur early in this model of crescentic nephritis in the rabbit, and that extraglomerular collagen mRNA accumulates very rapidly when glomerular inflammation occurs. Extraglomerular collagen synthesis associated with intraglomerular inflammation may help to explain the common association of interstitial fibrosis with glomerulonephritis, particularly in the periglomerular area.

The following findings were obtained in a comparative morphometric and clinical study of 130 adult men and women with immunologically confirmed IgA nephritis: (a) IgA nephritis develops in varying frequency as minimal proliferating intercapillary glomerulonephritis, low-grade mesangioproliferative glomerulonephritis, moderate to severe mesangioproliferative glomerulonephritis, or variously severe mesangioproliferative glomerulonephritis with signs of focal accentuation. (b) Tubular epithelial surface area and interstitial width in 62 of 130 cases of IgA nephritis was the same as in normal kidneys. IgA nephritis was complicated in 33 cases by interstitial cortical fibrosis, in 23 cases by acute renal failure, and in 12 cases by acute renal failure and interstitial fibrosis. (c) In IgA nephritis with acute renal failure, the tubular epithelium (only proximal tubular epithelium was measured) was significantly swollen. In IgA nephritis with interstitial fibrosis, the epithelial surface area of the proximal tubules was significantly smaller than the normal surface area. In IgA nephritis with acute renal failure (ARF) and interstitial fibrosis, tubular swelling was less severe than in ARF. Proximal tubular epithelial surface area, however, was significantly larger than the normal surface area. (d) In IgA nephritis, like in other inflammatory and noninflammatory glomerular diseases, a significant positive correlation existed between width of the cortical interstitium and height of serum creatinine level. Moreover, in IgA nephritis, significantly negative correlation existed between width of the cortical interstitium and C creatinine. (e) In IgA nephritis, significant negative correlations existed between C creatinine and age. (f) In IgA nephritis, a significant correlation existed between proximal tubular epithelial surface area and serum creatinine level and a significant negative correlation, between C creatinine and proximal tubular epithelial surface area, when ARF cases were excluded from the total group of IgA nephritis. (All correlations are closer when the cases with accompanying ARF are eliminated.) The discrepancy between the findings of Bennett et al. (Bennett WM, Walker RG, Kincaid-Smith P: Lab Invest 47:330, 1982) and ours is clarified when it is presumed that the group of patients investigated by Bennett et al. (N = 85) included just as many ARF cases as our material. Consequently, there is no reason to correct our interpretation of the influence of tubulointerstitial changes on glomerular function.

The proliferation of renal interstitial cells was studied by the use of tritiated thymidine incorporation following unilateral ureteral obstruction in the rabbit. There was a nonuniform response with significant increase in nuclear labeling in the obstructed kidney in all zones at 24, 48, and 72 hours following obstruction with the exception of the inner medulla where the counts at 24 and 48 hours were not significantly different from sham-operated controls. The major labeling occurred in interstitial fibroblasts. Within the zones of high labeling (cortex and outer medulla) these cells were separated by widening of the intersittial space. In the zone of low labeling (inner medulla) the interstitial cells maintained their normal spatial relationships.

Potassium deprivation has recently been reported to potentiate the degree of functional impairment in a gentamicin-induced model of acute renal failure. The present study investigated the effects of two different states of potassium homeostasis on the development of cellular injury in the early stage of gentamicin nephrotoxicity in dogs. Gentamicin (15 mg. per kg. intramuscularly twice daily) was administered for 4 and 7 days to potassium-depleted or potassium-supplemented animals. The results show that potassium supplementation markedly lessens the severity of pathologic alterations induced by gentamicin. In both groups of animals, the S1 and S2 segments of the proximal tubule were the most consistently damaged regions of of the nephron. Potassium-supplemented dogs had a significantly higher number of normal proximal tubule cells than did the animals deprived of potassium and viewed 7 days after gentamicin treatment (77.3 versus 36.9 per cent; p less than 0.025). The degree of total injury to the proximal tubule was significantly higher in potassium-depleted animals than in those supplemented with potassium (59.9 versus 21.9 per cent; p less than 0.05). Only those dogs depleted of potassium prior to the administration of gentamicin had a markedly elevated plasma creatinine level of proximal tubular injury and functional impairment (r = 0.81; p less than 0.005). Potassium supplementation appears to lessen the extent of structural alterations seen in this model of gentamicin-induced acute renal failure in dogs.

It has recently been proposed that renal cortical interstitial fibrosis is causally related to progressive decreases in glomerular filtration rate in a variety of renal diseases including glomerulonephritis. One hundred and eighty-eight renal biopsies in 81 patients with mesangial IgA nephropathy were analyzed for the percentage of relative interstitial volume by a point-counting technique. These data were correlated with serum creatinine, endogenous creatinine, endogenous creatinine clearance, and from age-matched donors were used as controls for the interstitial volume measurement. There was a negative nonlinear correlation between percentage of interstitial volume measurement. There was a negative nonlinear correlation between percentage of interstitial volume and creatinine clearance (r = 0.601, p less than 0.001). These correlations were not explained by age. However, serial biopsies in 39 patients clearly demonstrated that the percentage of interstitial volume could be dissociated from creatinine clearance. The prognosis in individual patients for progression to chronic renal failure could not be predicted from the relative interstitial volume at initial biopsy. Patients with mesangial IgA nephropathy demonstrated higher interstitial volumes than age-matched cadaver donors (p less than 0.001). Although interstitial volume and creatinine clearance are inversely related, the ability to dissociate these two variables in serial biopsies draws into question the hypothesis that interstitial fibrosis is causally related to changes in creatinine clearance. Studies to validate this hypothesis should involve patients followed with serial biopsies and renal function studies. In mesangial IgA nephropathy, interstitial changes are most likely secondary to the activity of the glomerular process.

The tissue repair subsequent to aminoglycoside-induced tubular necrosis has been evaluated for five different derivatives given at low doses. Gentamicin, dibekacin, netilmicin, and tobramycin were administered intraperitoneally three times a day at 10 mg/kg per day; amikacin was given intraperitoneally twice a day at 37.5 mg/kg per day. The drugs were administered for 4 or 10 days. Tissue regeneration in kidney cortex was assessed by: the rate of DNA synthesis (i.e., the specific radioactivity of DNA measured 1 hour after intraperitoneal injection of 200 microCi of [3H] thymidine per animal); the occurrence of less differentiated cells estimated by the morphometry of peroxisomes. In mature cells, identified by the presence of drug-induced myelin-like figures, peroxisomes occupied 3.0% of the cytoplasmic area, whereas in less differentiate cells devoid of myelin-like figures, the same organelles made 1.4% of the cytoplasmic area (mean values obtained from 20 treated animals). Gentamicin and amikacin were both shown to induce a dose-related enhancement of DNA synthesis in kidney cortex, except that the latter antibiotic was about 10 times less potent as compared to the former. When the five drugs were compared on the basis of their effect on DNA synthesis after 10 days of treatment, they gave the following ranking: gentamicin (5.6 times the mean control value) greater than or equal to dibekacin greater than netilmicin greater than tobramycin greater than amikacin (1.6 times the mean control value). The differences were less striking after 4 days of treatment. For each antibiotic, sections of proximal tubular cells obtained from four animals treated for 10 days (total surface, 2.10(4) microns2) were scanned for the presence of regenerative tissue (areas poor in peroxisomes). In gentamicin-treated rats, the areas poor in peroxisomes represented more than 18% of the scanned cytoplasmic surface in proximal tubular cells, as compared to about 4.5% in controls. The ranking of the five antibiotics according to the estimated area of undifferentiated tissue in proximal tubules was parallel to that found for DNA synthesis i.e., in gentamicin-treated rats undifferentiated tissue was much more prominent, as compared to amikacin-treated animals (about 6% of the scanned area). Since the relative extent of kidney cortex regeneration induced by each antibiotic at low dose is likely to reflect the degree of tubular necrosis, we conclude that the ranking outlined above indicates a difference in potential nephrotoxicity.

The sequential changes in renal morphology that occurred for 5 subsequent days after a subcutaneous injection of uranyl nitrate (10 mg. per kg.) were examined in saline- and water-drinking rats using light microscopy, transmission electron microscopy, and scanning electron microscopy. The cortical proximal tubule exhibited diffuse focal brush border loss and increased vacuolization by 1 hour after administration of the nephrotoxin. By 5 days, the P2 and P3 segments were completely necrotic. Cells of P1 segments accumulated large vacuoles throughout their cytoplasm, and distal nephron segments exhibited considerable cellular swelling and vacuolization. Scanning electron microscopy revealed abnormalities in glomerular epithelial cells similar to those seen in humans with chronic renal disease and in experimental animal models characterized by proteinuria. There was essentially no difference in the morphologic response of saline- and water-drinking rats. Although uranyl nitrate administered at this dosage resulted in the relatively slow development of tubular necrosis, changes in renal morphology could be seen within an hour and progressed insidiously throughout the study with little evidence of regeneration.

The effects of radiation on the developing canine kidney were investigated. Beagles were exposed to 330 R 60Co gamma-radiation on the 2nd postnatal day of life. The kidneys were examined at 2 days (6 hours after irradiation), 4, 8, 14, 22, 70, and 200 days of age with qualitative and quantitative light microscopy and scanning electron microscopy. The primary result of the radiation injury was a failure to form the normal number of nephrons. The kidneys of irradiated dogs had 42 per cent fewer nephrons (260,000) than the control dogs (445,000). In addition, extensive damage to forming nephrons produced dysplastic renal corpuscles and other corpuscles which were arrested in their development. Three mechanisms of radiation injury were identified. First, there was extensive mitosis-linked cell death in the nephrogenic zone. Second, mitotic delay resulted in only one-fifth of the normal mitotic activity in the nephrogenic zone through 2 days postirradiation. Third, there was an immediate and permanent cessation of nephron formation. The extensive injury in the outer renal cortex was compounded by the development of intercapillary glomerulosclerosis in some middle and inner cortical corpuscles by 200 days of age.

The late histologic and ultrastructural effects of complete unilateral ureteral obstruction in the rabbit kidney were studied from 7 to 32 days postobstruction. Papillary necrosis occurred in all animals by the 7th day. There was progressive widening of the cortical interstitial space with proliferation of fibroblasts. Increased interstitial collagen fibers first became apparent on the 7th day and showed a progressive increase with time. The fibroblasts underwent myofibroblast transformation beginning on the 7th day. All segments of the nephron showed ultrastructural evidence of sublethal cell injury with loss of cell specialization. The dedifferentiation of the tubular cells was associated with a repetitive formation of new lamellae of basement membrane on the luminal side of the original basement membranes beginning on the 16th day of obstruction. These morphologic changes are discussed in terms of the physiologic changes previously reported in this model and the known clinical abnormalities found in obstructive uropathy.

Hyperplasia and tumors of epithelium are found in "end stage" dialysis kidneys. Epithelial hyperplasia is most conspicuous within "atypical cysts" in which the lining cells are multilayered and occasionally papillary. These features were studied in the kidneys of 66 renal failure patients by means of multiple tissue blocks and serial histologic sections. Atypical cysts were observed in 20 of the 66 cases. Solid or cystic renal cell adenomas were found in nine cases. Six of the cases having adenomas were among the 20 cases having atypical cysts. Tumors occurred in kidneys having atypical cysts, as dintinguished from kidneys without such cysts, with a frequency greater than would be expected to be due to chance alone (P = 0.0106). Renal cell adenomas are found at a younger age in dialysis patients (mean = 41.2 years) than in a control group of autopsies and surgical cases that had not received chronic dialysis (mean = 61.8 years). These observations provide histologic evidence that renal cell neoplasms are prone to develop in relatively young renal failure patients when their uremia is treated by long term dialysis. The studies further indicate that the stimulus for neoplastic growth accompanies a cystic transformation of the kidneys. Kidneys in five cases in the series, although much smaller than normal, were grossly multicystic, corresponding to the recently recognized acquired renal cystic disease. Hyperplastic cells, like those observed in atypical cysts, were present focally along the cyst walls. This form of epithelial hyperplasia, common to both atypical cysts and the multicystic dialysis kidney, may give rise to the renal cell tumors that are reported to occur with increased frequency in acquired cystic disease.

Morphologic alterations and membrane metabolism were studied in the kidneys of rats fed a low potassium diet. Transmission and scanning electron microscopy following perfusion-fixation of kidneys revealed that the earliest morphologic change occurs in cells of the papillary tip in which multivesicular bodies, a specific type to lysosome, appear after 1 day. Increased depletion leads to extension of the lesion to all cells of the papilla. After 1 week, a narrow band of hyperplasia in the inner red medulla appears; this band is characterized by adenomatous proliferation of intercalated and light cells and partial obstruction of collecting tubules. These alterations and cortical growth in the normal pattern result in increased renal weight. New membrane formation for lysosomes and growing cells was studied by measuring the rate of [14C]choline incorporation into phospholipid in slices from five zones of the kidney. In the papilla the rate increased 39 per cent after 18 hours, the earliest change detected. After 36 hours the rate increased in inner red medulla by 28 per cent, inner cortex by 25 per cent and outer cortex by 40 per cent. [14C]choline was a specific precursor of the three renal phospholipids, phosphatidylcholine, lysophosphatidylcholine, and sphingomyelin. The relative distribution of the label did not change with growth induced by potassium depletion. The results indicate that potassium depletion induces early increases in the formation of cell membrane phospholipid which correlate with specific morphologic changes in different zones within the kidney.