Biomedical subjects
Publications and source records attributed to J J Grantham.
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Recent advances in technology have not substantially changed the relatively low survival rate associated with acute renal failure (ARF). Several clinical prognostic variables and multivariate models have been reported to predict survival in individual patients, but these are either cumbersome to use or restrictive in their application. A straightforward clinical index has been developed to predict survival in ARF based on data obtained for all patients receiving dialysis for ARF at the University of Kansas Medical Center from November 1979 through October 1985. During this period, 126 patients received dialysis for ARF, with an overall survival of 25% (32/126). There were no significant differences between survivors and nonsurvivors in age, gender, or indication for dialysis. Eleven variables were statistically related to survival, and were reduced to five when clinically similar variables were combined or eliminated. A clinical survival index was based on these five easily determined variables that were significantly related to survival: systolic blood pressure less than or equal to 110 mm Hg, assisted ventilation, congestive heart failure, proven or suspected sepsis, and gastrointestinal (GI) dysfunction (bleeding, ileus, obstruction, or recent abdominal surgery). Survival was directly related to the number of factors present: zero, 62% (8/13); one, 44% (8/18); two, 30% (10/33); three, 19% (5/26); four, 0% (0/20); and five, 6% (1/16). This straightforward index, derived from easily obtained clinical data, is useful for judging survival prognosis in patients with ARF severe enough to warrant treatment with dialysis.
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Autosomal dominant polycystic kidney disease is characterized by the formation of large fluid-filled epithelial cysts. To obtain renal cyst wall epithelium for in vitro study, we employed an explant culture technique using medium-hydrated collagen gel as the culture substrate. Pieces of excised cyst wall were submerged within collagen gel. Cells of the cyst lining migrated to form a polarized epithelium at the surface of the surrounding collagen gel. Regions of the outgrowth were isolated by microdissection and used as a source of cells for subculture. Cyst-derived epithelium retained the ultrastructural features of the renal cyst of origin. The cells were cuboidal and bore short apical microvilli. Cells often were joined by apical tight junctions. Intercellular channels were narrow and bordered by short microvillus projections at the basolateral membrane. Epithelial cells rested on a densely staining basal lamina. The explants commonly developed small solitary cysts within their wall that were filled with fluid. These mural cysts were lined by a simple epithelium morphologically similar to the cells that lined the explant. Explantation of human renal cyst wall to culture within collagen gel provides a reproducible method to isolate autosomal dominant polycystic kidney disease epithelium for subculture. This method offers an alternative to the use of proteolytic enzymes to establish morphologically stable cultures of cyst lining cells for use in experimental renal cystic disease.
The C57BL/6J-cpk genetic murine model of autosomal recessive polycystic kidney disease was examined to gain insight into the pathogenesis of renal cystic disease. Fetal through 3-week-old offspring of heterozygote matings were used to study growth parameters and morphology of this genetic form of cystic disease. The kidneys were examined by light and electron microscopy and nephron segments were microdissected. Two phases of cystic disease development were morphologically identified. The first phase in fetal and newborn affected pups was characterized by proximal tubule enlargement and a general increase in the tubular mitotic index. The proximal tubules showed cytologic abnormalities along with an increased necrotic cell index. The later phase, in one through 3-week-old cystic pups, was characterized by progressive enlargement of the kidneys due mainly to cystic change of the collecting ducts and by development of azotemia. Secondary to the azotemia was a stunted body growth. Significant tubular epithelial hyperplasia was not found by mitotic index during the second phase, but an increase in collecting duct cellularity was present. Histone H4 gene expression, which is tightly coupled to DNA synthesis and thus an index of cell proliferation, showed only a minimal increase in cystic kidneys at 1, 2, and 3 weeks of age. Therefore, the degree of cell proliferation necessary to allow the observed tubular enlargement appears to be minimal.
Previous morphologic studies on kidneys from adult patients with autosomal dominant polycystic kidney disease (ADPKD) indicates that the cysts developed from nephrons and collecting ducts in association with hyperplasia of epithelial cells lining the cyst walls. In the present study, we systematically evaluated by scanning electron microscopy 387 cysts in polycystic kidneys obtained from 10 adult patients. Some cysts were lined by cells typical of collecting duct (7.2%), proximal tubule (1.8%) or glomerular visceral (2.1%) epithelium. The remaining cysts were lined by a single layer of phenotypically undefined (84.0%) or markedly hyperplastic (4.9%) epithelium. The median plane surface area of individual cells within cysts was 182 X 10(-8) cm2. Among all cysts the surface area of single epithelial cells ranged between 22 and 2530 X 10(-8) cm2, but within single cysts the range of individual cell surface areas was more narrow. Mean cell surface area did not increase in direct proportion to cyst diameter; thus, epithelial hyperplasia is a central element in the progressive enlargement of cysts. In some cysts hyperplasia was accentuated by projections into cyst lumens of polyps, small adenomas and cord-like arrangements of cells. Epithelial polyps were found in the cysts of one non-azotemic patient, excluding renal failure as a cause of this accentuated type of epithelial proliferation. Morphologic evidence that cysts compressed adjacent renal parenchyma was observed in all kidneys. In 11 cysts bisected and then both halves thoroughly examined by scanning electron microscopy, one or two tubule openings were seen in one of the hemisections in three cysts (27.3%).(ABSTRACT TRUNCATED AT 250 WORDS)
To determine the extent to which proximal tubule function is altered beta 2microglobulin (beta 2m), creatinine and Na were measured in serum, urine and cyst fluid of patients with autosomal dominant polycystic kidney disease and various degrees of renal insufficiency. Fractional excretion (FE beta 2m) was 0.11 +/- 0.03% in six normal subjects and 0.13 +/- 0.05% in nine patients with serum creatinine levels less than 1.6 mg/dl. In five patients with serum creatinine levels above 3.0 mg/dl, FE beta 2m was elevated (range 3.5 to 196%) and serum levels were higher than normal (30,600 +/- 6,910 micrograms/liter vs. 1,268 +/- 111). In seven patients beta 2m levels in 33 proximal cysts (cyst/serum Na greater than 0.8) equalled those in serum (cyst/serum beta 2m 0.98 +/- 0.20), whereas in 21 distal cysts (cyst/serum Na less than 0.4) beta 2m was less than in serum (cyst/serum beta 2m 0.17 +/- 0.07). Analysis of fluid in two patients with polycystic kidney nephrectomy several weeks posttransplant indicated that proximal cyst epithelium is permeable to beta 2m, but less so than to creatinine or urea. These studies show that proximal cysts cannot develop or maintain gradients for beta 2m, whereas distal cysts maintain low levels of the protein despite end-stage renal failure. The normal FE beta 2m values in nonazotemic autosomal dominant polycystic kidney disease patients and the low distal cyst levels of beta 2m in end-stage kidneys indicate that the cystic proximal nephrons do not contribute appreciably to the final urine.(ABSTRACT TRUNCATED AT 250 WORDS)
Hereditary and acquired renal cysts develop from tubule segments that enlarge progressively. We measured the deformability of basement membranes surrounding individual normal tubules and cysts to determine if cysts might develop by simple extension of abnormally-deformable basement membrane in response to normal or increased transtubule hydrostatic pressures. Deformability (cm/dyne) was measured in individual tubules and cysts in vitro by a micropipet aspiration technique that related negative pressures within the pipet to the distance the tubule or cyst wall was aspirated into the pipet. Viscoelastic creep was determined from the time-dependent effect of pipet aspiration on membrane deformation. Proximal and collecting tubules, glomerular capsules and cysts were microdissected from controls and animals with acquired (Diphenylthiazole [rats]. Nordihydroguaiaretic acid [rats]), hereditary (C57 BL/6J [cpk/cpk] mice) and spontaneous (CFWw mice) renal cystic diseases. The major resistance to deformation was localized to the basement membrane since collagenase destroyed the elasticity of tubule and cyst walls. Tubule basement membranes adjacent to cysts appeared abnormal by electron microscopy in the animals fed DPT, but measurements of deformability and viscoelastic creep showed no differences between normal and cystic tubules in any animal model. Deformability values of cysts (7.7 +/- 1.1, 10.9 +/- 1.1, 11.2 +/- 0.6, 9.4 +/- 0.8 X 10(-3) cm/dyne in DPT, NDGA, C57 BL/6J and CFWw, respectively) are consistent with the interpretation that high transtubule pressures ranging from 39 to 134 cm H2O would be required if cysts form by simple stretching of the basement membrane secondary to a transepithelial hydrostatic pressure-gradient. Since in vivo measurements of hydrostatic pressures across cyst walls are not high enough we conclude that cysts do not enlarge due to increased deformability of tubule basement membranes.
The polycystic kidney diseases (PKDs) are a group of disorders characterized by the growth of epithelial cysts from the nephrons and collecting ducts of kidney tubules. The diseases can be inherited or can be provoked by environmental factors. To investigate the molecular basis of the abnormal cell growth associated with PKD, c-myc protooncogene expression was studied in a mouse model for autosomal recessive PKD. Homozygous recessive C57BL/6J (cpk/cpk) mice develop massively enlarged cystic kidneys and die from renal failure shortly after 3 weeks of age. Quantitative dot blot and RNA blot hybridization experiments in which whole kidney poly(A)+ RNA was hybridized with a c-myc RNA probe showed a 2- to 6-fold increase in c-myc mRNA at 2 weeks, and a 25- to 30-fold increase in c-myc mRNA at 3 weeks of age in polycystic mice, as compared to normal littermates. c-myc expression was also examined under two conditions in which kidney cell growth was experimentally induced in normal adult mice: compensatory renal hypertrophy and tubule regeneration following folic acid-induced renal cell injury. While compensatory hypertrophy resulted in only a small (less than 3-fold) increase in c-myc, folic acid treatment gave rise after 24 hr to a 12-fold increase in c-myc mRNA. The induction of c-myc by folic acid is consistent with increased cellular proliferation in regenerating tubules. In contrast, polycystic kidneys show only a minimal increase in cellular proliferation over that seen in normal kidneys, while c-myc levels were found to be markedly elevated. Thus, the level of c-myc expression in cystic kidneys appears to be out of proportion to the rate of cell division, suggesting that elevated and potentially abnormal c-myc expression may be involved in the pathogenesis of PKD.
Macromolecules in rabbit serum inhibit the cellular uptake and transepithelial secretion of [14C]urate and p-[3H]aminohippurate ([3H]PA) in rabbit S2 proximal tubule segments. To understand better the potential role these inhibitors may have in the regulation of renal organic anion excretion, we examined the specificity and relative inhibitory effects on tubule urate and PAH transport of albumin and gamma-globulin, the major inhibitory proteins in rabbit serum. Native rabbit serum markedly inhibited the cellular accumulation of urate and PAH by isolated nonperfused segments [50% inhibition (K0.5) = 0.4 and 0.65 g/dl, respectively]. Urate and PAH transport was also inhibited by bovine serum, human serum, Cohn-fractionated rabbit albumin, and rabbit gamma-globulin, but not by Cohn-fractionated bovine serum albumin. alpha-Lactalbumin and beta-lactoglobulin, derived from milk, also inhibited urate and PAH transport, but to a lesser extent than albumin and gamma-globulin. The transport inhibitory effects of proteins were independent of their binding to urate and PAH. Unidirectional influx and the steady-state intracellular accumulation of urate and PAH in suspensions of proximal tubules were decreased by rabbit serum proteins, suggesting that these inhibitors act on the external face of the cells to diminish the uptake of the organic anions. These studies indicate that the principal plasma proteins (albumin and gamma-globulin) significantly inhibit urate and PAH transporters in the basolateral membranes of S2 proximal tubules. We suggest that circulating plasma proteins that can penetrate the basement membrane of proximal tubules may directly modulate the renal excretion of urate and PAH.
Clinical, CT, and pathologic findings were analyzed in six patients with spontaneous subcapsular or perinephric hematomas complicating end-stage kidney disease. Renal failure had been managed by hemodialysis in four patients, by renal transplantation in one, and by conservative methods in one. All patients had nonspecific abdominal pain. CT clearly showed in all cases that the pain resulted from hemorrhage and also revealed the extent and location of hematomas. In addition, in four patients, CT showed underlying acquired cystic kidney disease that was the probable cause of hemorrhage. In one of these patients, CT also showed a renal cell carcinoma in the opposite kidney. Other causes for renal hemorrhage encountered in the series included renal infarction due to small vessel disease, heparinization during hemodialysis, and thrombocytopenia. Abdominal CT is a useful technique for evaluating patients with end-stage renal disease who have abdominal pain or who exhibit clinical evidence of blood loss.
Percutaneous transluminal angioplasty (PTA) was performed in five instances of renal transplant artery stenosis (RTAS) in four patients. Hypertension was present in all cases and improved after angioplasty together with reduction in medicine requirements. Abnormal renal function in four instances also improved after PTA. This reflects the current literature in which 76 of 90 patients were successfully treated by PTA (follow-up to 24 months), with two cases of recurrent stenosis, no mortality, and only a single case of graft loss. Vascular surgical repair succeeded in 130 to 180 patients, but graft loss occurred in 20 cases and recurrent stenosis in 11. Mortality was reported in five cases. Our review of the literature and experience suggests that PTA may be preferred in the treatment of RTAS.
Renal proximal tubules secrete p-aminohippurate (PAH) and other endogenous anionic metabolites into the urine. The extent to which organic anion excretion is regulated is unknown, but recent studies indicate that peritubular serum proteins may have a role. We determined the relative effects of serum proteins and metabolic substrates (citrate, lactate, and alanine) on net PAH secretion in isolated perfused rabbit S2 proximal tubules. Net PAH secretion was calculated from the bath-to-lumen flux of [3H]PAH and the isotope specific activity. We corrected the flux for the important difference in PAH binding between rabbit serum proteins and bovine serum albumin (BSA); rabbit serum proteins (5.7 g/dl) and BSA (6 g/dl) bound 10 microM PAH 21 and 37%, respectively. BSA had no effect, but rabbit serum proteins reversibly inhibited PAH secretion in the presence of metabolic substrates in the bath (40.8%), the perfusate (42.6%), and both media (31.5%). In the absence of metabolic substrates, rabbit serum proteins decreased PAH secretion by only 16.8%. PAH secretion was inhibited by 1 g/dl rabbit serum proteins as effectively as 5.7 g/dl (30.3 and 31.5%, respectively), indicating that PAH transport is very sensitive to inhibition by rabbit serum proteins. In the absence of rabbit serum proteins, metabolic substrates in the bath had no effect on PAH secretion. We conclude that rabbit serum proteins inhibit basolateral membrane transport of PAH in proximal tubules. Inhibition by serum proteins is enhanced by bath or lumen citrate, alanine, and lactate, suggesting that peritubular plasma proteins and tubule cell metabolism may interact to modulate proximal tubule organic anion secretion and urinary excretion.
Sudden alteration in medium osmolality causes an osmometric change in proximal tubule cell size followed by restoration of cell volume toward normal in hypotonic but not in hypertonic medium. We determined the capability of isolated nonperfused proximal tubules to prevent a change in cell volume in anisotonic media. The external osmolality was gradually changed over a range from 110 to 480 mosM. At 1.5 mosM/min, cell volume remained constant between 167 +/- 9 and 361 +/- 7 mosM, a phenomenon termed isovolumetric regulation (IVR). Cells lost intracellular solutes in hypotonic and gained intracellular solutes in hypertonic media. Raffinose or choline chloride substitution showed that osmolality, rather than NaCl, signalled cell volume maintenance in hyperosmotic media. Cooling (7-10 degrees C) blocked IVR. IVR was maintained when osmolality was lowered at a rate of 27, but not at 42 mosM/min. IVR was not observed when the rate of osmolality increase exceeded 3 mosM/min. We conclude that proximal tubule cells sensitively regulate intracellular volume in an osmolality range of pathophysiologic interest by mechanisms dependent on the rate of net water movement across basolateral membranes and the absolute intracellular content of critical solutes.
Urate and p-aminohippurate (PAH) excretion was studied in New Zealand white rabbits to determine the extent to which the renal tubular handling of these organic anions by intact kidneys paralleled observations made in single isolated perfused tubules in vitro. At low plasma concentrations (less than 60 mumol/L) net reabsorption of urate was observed in the majority of animals; as plasma urate concentration was increased by infusing lithium urate, net urate secretion was demonstrated, the fractional excretion of urate (FE urate) reaching 270%, and net urate secretion (filtered urate minus urinary concentration of urate times volume flow rate) 1.8 mumol/min at mean plasma urate levels 200 and 310 mumol/L. A maximal urate secretion rate was not demonstrated. Probenecid (250 mumol/kg) reduced FE urate to 27%, thereby revealing concealed reabsorption despite high plasma urate levels. By contrast, net secretion of PAH at all plasma levels was achieved by infusing NaPAH. The highest secretory rate was 38.6 mumol/min at plasma PAH levels between 1000 and 1750 mumol/L. Probenecid reduced fractional excretion of PAH (FEPAH) from 796% to 265%, no evidence of PAH reabsorption being found after inhibition of secretion with probenecid. At comparable plasma levels (220 mumol/L), net PAH secretion exceeded net urate secretion (reflected by the decrement in urate and PAH excretion caused by probenecid) by a factor of 5.3:1. These experiments indicate that urate and PAH are filtered and secreted by the rabbit kidney; however, only urate is significantly reabsorbed over the range of plasma organic anion levels examined. The configuration of the relation between plasma levels and net secretion rates and the greater secretory rate for PAH for urate in the living rabbit are consonant with the characteristics of PAH and urate transport determined previously in studies of isolated perfused proximal tubules.
Urinary doubly refractile lipid bodies (oval fat bodies) are observed most frequently in patients with heavy proteinuria resulting from glomerular disease. We observed doubly refractile lipid bodies (DRLB) in the urine sediment of 60% of 35 patients with autosomal dominant polycystic kidney disease (ADPKD). All patients had clinical courses typical of ADPKD, and none exhibited the features of a second, unrelated renal disease. DRLB in the urine were correlated with a urine dipstick protein reading exceeding trace. Age, sex, BP, and serum creatinine concentration were not associated with the presence of DRLB in the urine. Examination of cyst fluid obtained from kidneys of six ADPKD patients revealed DRLB in 80% of cyst fluid samples that contained degraded blood (so-called chocolate cysts). The DRLB in cyst fluid were morphologically indistinguishable from those observed in urine, and DRLB from both sources were stained with oil red O. We conclude that urinary DRLB are a clinical feature of ADPKD.
The fibrinolytic enzyme streptokinase (streptase) was infused into the peritoneal catheter in 19 episodes of catheter failure in 16 patients. Intraabdominal bleeding prior to infusion was seen in seven of these episodes. Fibrin strands and clots were present in four additional successful cases. Streptokinase successfully relieved the obstruction in 13 episodes in 11 patients. The procedure failed in two cases of omental ingrowth and in another with catheter malposition. Streptokinase infusion also failed in two patients with Pseudomonas aeruginosa and one patient with Staphylococcus epidermidis peritonitis. Intraperitoneal streptokinase infusion is simple and free of side effects. Its use should be considered in peritoneal catheter failure, particularly in cases where bleeding or fibrin accumulation may play a role.