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P W Sanders

Publications and source records attributed to P W Sanders.

14 recordsLinked to original sources
PubMed1992

Pathobiology of cast nephropathy from human Bence Jones proteins.

Renal failure is a common accompaniment of multiple myeloma and is usually due to cast nephropathy, or "myeloma kidney." To understand this lesion, four human Bence Jones proteins (BJP) were purified from the urine of volunteers who had either no evidence of renal dysfunction (BJP1) or renal failure from cast nephropathy (BJP2, BJP3, BJP4). When infused directly into the rat nephron in vivo, BJP2, BJP3, and BJP4 produced intraluminal obstruction by precipitating in the distal nephron; protein casts were never identified before the tip of the loop of Henle. Obstruction was related to the concentration of BJP in the perfusate. Addition of furosemide to the perfusate augmented obstruction in a concentration-dependent fashion. Pretreatment of rats with colchicine completely prevented obstruction and cast formation of perfused nephrons; beta-lumicolchicine did not prevent obstruction. Tamm-Horsfall glycoprotein purified from beta-lumicolchicine-treated and untreated rats coaggregated with BJP3 in vitro. Tamm-Horsfall glycoprotein from colchicine-treated rats did not contain sialic acid and did not aggregate with BJP3 in vitro. Thus, cast-forming human BJP coaggregated with Tamm-Horsfall glycoprotein and obstructed the rat distal nephron. Intranephronal obstruction was aggravated by decreasing extracellular fluid volume or adding furosemide. Finally, by decreasing secretion and altering the carbohydrate moiety of Tamm-Horsfall glycoprotein, colchicine prevented intraluminal cast formation and obstruction of the rat nephron.

Animals↗
PubMed1991

L-arginine abrogates salt-sensitive hypertension in Dahl/Rapp rats.

This study examined the contribution of nitric oxide (NO) to the susceptibility or resistance to the hypertensive effects of high sodium chloride (8.0% NaCl) intake in young Dahl/Rapp salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) rats. Using NG-monomethyl-L-arginine (L-NMMA) as a probe for NO production in vivo, we found that increasing dietary sodium chloride increased NO activity in salt-resistant rats, but not in salt-sensitive rats. Exogenous L-arginine, the substrate for NO synthesis, decreased blood pressure to normotensive levels in salt-sensitive rats made hypertensive for 2 wk from 8.0% NaCl chow. D-arginine had no effect on blood pressure of these rats and L-arginine did not change blood pressure of salt-resistant rats. Intraperitoneal injections of L-arginine and its precursor, L-citrulline, and oral L-arginine, but not D-arginine, prevented the increase in blood pressure in salt-sensitive rats on the high salt chow over 2 wk of observation. In contrast, L-arginine did not alter the development of hypertension in spontaneously hypertensive rats. Mean urinary cGMP levels were higher in salt-sensitive rats on oral L-arginine than salt-sensitive rats on D-arginine. Infusion of L-NMMA acutely decreased, whereas intravenous L-arginine rapidly increased, urinary cGMP in both groups. L-arginine and L-citrulline increased production of NO and prevented salt-sensitive hypertension in Dahl/Rapp rats.

Animals↗
PubMed1991

Spectrum of glomerular and tubulointerstitial renal lesions associated with monotypical immunoglobulin light chain deposition.

The purpose of this study was to characterize the spectrum of renal lesions associated with plasma cell dyscrasias from a population of patients who had renal disease identified by kidney biopsy. Thirty-six patients (2.6% of 1361 kidney specimens examined over 6 years) had evidence of monotypical light chain with or without concomitant heavy chain deposition. A variety of lesions was found, including (a) AL-amyloid and glomerular nonamyloid light chain deposition manifesting as nodular, membranoproliferative, mesangioproliferative, and "minimal-change" glomerulopathies; (b) fibrillary glomerulopathy; (c) tubulointerstitial lesions (cast nephropathy, acute tubular necrosis, and tubulointerstitial nephritis); and (d) vascular (arterioles and small and medium-sized arteries) lesions. AL-amyloid was the most common renal lesion (39%), nonamyloid deposition occurred second most commonly (33%), and cast nephropathy ("myeloma kidney") was third most frequent (14%). Clinical and laboratory manifestations of a plasma cell dyscrasia were frequently subtle. Immunoelectrophoresis of both serum and urine did not demonstrate a monotypical light chain or immunoglobulin in almost 35% of this population. Thus, the correct diagnosis was not considered in the majority of these patients before biopsy. Progressive deterioration of renal function was common with all of the lesions, except for proximal tubule injury, which tended to improve over the period of study. Renal biopsy with careful examination for monotypical light chain with or without associated heavy chain deposition using immunofluorescence or immunoelectron microscopy was crucial in identifying and characterizing the varied lesions associated with lymphoplasmacytic disorders.

Amyloid↗
PubMed1990

Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins.

Proteinaceous cast formation in the distal nephron of the kidney from low molecular weight proteinuria is a significant, but poorly characterized, cause of renal failure. To study this phenomenon, we: (a) microperfused the loop segment (LS) of rats in vivo with artificial tubule fluid (ATF) containing four different low molecular weight proteins, 0.01-50 mg/ml, to detect alterations in LS function, and (b) examined the interaction between several proteins and Tamm-Horsfall glycoprotein (THP) in vitro with turbidity and dynamic light-scattering measurements. Perfusion of the LS for less than 2 min with cast-forming proteins (Bence Jones protein [BJP3] and myoglobin) decreased chloride absorption and elevated early distal tubule fluid (ED) [Cl-], compared with results obtained with control perfusions that used ATF alone. BJP3 decreased chloride absorption in a concentration-dependent fashion. Perfusion with non-cast-forming proteins (albumin and BJP1) enhanced chloride absorption and decreased ED [Cl-]. In vitro, proteins that had isoelectric points (pI) greater than 5.1 aggregated with THP. Aggregation was enhanced with increasing [NaCl] or [CaCl2]. Albumin (pI 4.8) and beta-lactoglobulin (pI 5.1) did not coprecipitate. The molecular size of THP alone increased when [NaCl] greater than 80 mM. Thus, cast-forming proteins aggregated with THP in vitro and caused in vivo LS dysfunction, which elevated ED [Cl-], facilitating aggregation. In contrast, non-cast-forming proteins either did not interact with THP or lowered ED [Cl-], which did not provide an environment for aggregation. Altered LS function and interaction of some proteins with THP were related to different physicochemical properties of the proteins and independently contributed to the formation of proteinaceous casts in the kidney.

Animals↗
PubMed1988

Morphologic alterations of the proximal tubules in light chain-related renal disease.

Previous studies from our laboratory have shown that human immunoglobulin light chains (LC) can be toxic to the epithelium of the rat proximal tubule. To examine the toxicity of monoclonal LC's in man, 11 kidney specimens (EXP group) obtained from patients with monotypical LC-related renal disease (7 lambda, 4 kappa), documented by the presence of monoclonal LC's in the serum or urine and in the tissue, were examined by light, immunofluorescence, electron, and immunoelectron microscopy. This EXP group had monotypical LC deposition in the tubules and/or the glomeruli and did not have evidence of intraluminal LC precipitation and cast formation, which alters tubule morphology. A control group (CON; N = 12) of kidney specimens was obtained from patients who had proteinuria greater than 2.5 g/24 hr and mean age (49 +/- 4 vs. 59 +/- 3 years; P = NS), serum creatinine concentration (2.4 +/- 0.5 vs. 3.2 +/- 1.5 mg/dl; P = NS) and creatinine clearance (65 +/- 13 vs. 63 +/- 12 ml/min; P = NS) similar to the EXP group. All of the EXP specimens demonstrated varying degrees of proximal tubule damage, manifested by cell vacuolation, desquamation, loss of the luminal brush border, and, often, coagulation necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Differential nephrotoxicity of low molecular weight proteins including Bence Jones proteins in the perfused rat nephron in vivo.

To investigate the pathogenetic mechanisms of tubule nephrotoxicity of low molecular weight proteins (LMWP), proximal tubules (PT) of rats were perfused in vivo with artificial tubule fluid (ATF) containing one of five LMWPs: three human Bence Jones proteins (BJP), beta-lactoglobulin (BLG), and rabbit myoglobin (MYG). Volume (JV), chloride (JCl) and glucose (JG) fluxes in these perfused PTs were compared with those determined using ATF alone. In separate experiments, perfused nephrons were examined with electron and immunoelectron microscopy. After exposure to BJP1 or BLG, JV, JCl, and JG were less (P less than 0.05) than corresponding control fluxes. Cell damage of these perfused PTs, along with cellular debris in the distal tubules, was prominent. The PT lysosomes often appeared atypical and contained crystals. In contrast, perfusion with BJP2, BJP3, or MYG did not alter JV, JCl, or JG. These findings were corroborated by the normal ultrastructure of these PTs despite immunohistochemical evidence of endocytosis of the BJPs. Isoelectric point, molecular form, and isotype were not factors associated with PT damage. In addition, proteins with pI less than 7.4 precipitated in the distal nephron, forming acellular casts. Thus, certain nephrotoxic LMWPs damaged the PT, while others precipitated in the distal tubule, obstructing the nephron. These two pathogenetic mechanisms may independently be responsible for tubulointerstitial nephropathy of LMWPs in humans.

Animals↗
PubMed1987

Human Bence Jones protein toxicity in rat proximal tubule epithelium in vivo.

To investigate the direct toxicity of human Bence Jones protein (BJP), individual nephrons of male Sprague-Dawley rats were perfused in vivo at 20 nl/min with an artificial tubule fluid (ATF) that contained no protein, a human kappa BJP (5 g/dl), or bovine serum albumin (5 g/dl), and proximal convoluted tubule function and morphology were examined. Perfusion with BJP perfusate for less than or equal to 5 minutes produced no changes (P = NS) in absorption of water, Jv, (1.09 +/- 0.20 vs. 1.50 +/- 0.25 nl/min/mm), chloride, JCl, (95 +/- 47 vs. 123 +/- 41 pEq/min/mm), and glucose, JG, (39 +/- 3 vs. 40 +/- 5 pmol/min/mm) compared to perfusions with only ATF. However, perfusion for at least 20 minutes with the same BJP perfusate produced decreased (P less than 0.025) in Jv (0.58 +/- 0.12 vs. 1.15 +/- 0.14 nl/min/mm) and JG (27 +/- 3 vs. 38 +/- 3 pmol/min/mm) compared to perfusions with ATF alone; the decrease in JCl (64 +/- 47 vs. 119 +/- 27 pEq/min/mm) did not reach statistical significance. Perfusion for 20 minutes with ATF containing albumin resulted in no changes in Jv (1.22 +/- 0.21 vs. 1.15 +/- 0.14 nl/min/mm), JCl (207 +/- 29 vs. 119 +/- 27 pEq/min/mm), and JG (31 +/- 1 vs. 38 +/- 3 pmol/min/mm), when compared to the ATF perfusions. Immunocytochemistry, immunofluorescence and immunoelectron microscopy of the BJP-perfused tubules demonstrated the kappa light-chain protein in endosomes and activated lysosomes. In addition, cellular desquamation and fragmentation, prominent cytoplasmic vacuolation, and focal loss of the microvillus border were found in the BJP-perfused tubules, but not in the albumin-perfused tubules. In conclusion, these functional and morphologic data show that a human kappa light-chain is toxic to the proximal convoluted tubule of the rat. This toxicity occurred in a time-dependent fashion when the lysosomal system was markedly activated. Direct damage of the tubule epithelium by BJP's may be involved in the development of the tubulointerstitial nephropathy associated with multiple myeloma.

Animals↗
PubMed1985

Effect of urinary pH and diatrizoate on Bence Jones protein nephrotoxicity in the rat.

Both low urinary pH and radiocontrast agents may intensify myeloma nephrotoxicity. To study the effects of these factors, we determined inulin clearances (CIn) before and after infusions of human Bence Jones protein (BJP) in male Sprague-Dawley rats in a dose previously shown to be nephrotoxic. Rats that drank 0.15 M NaHCO3 for 48 hr before study had no change in CIn (+3 +/- 20%) after BJP unlike those that drank 0.15 M NH4Cl (-33 +/- 14%, P less than 0.05); urinary pH differed (7.6 +/- 0.1 vs. 6.2 +/- 0.1, P less than 0.05), but urinary flow rates did not. The acidifying regimen was used in all subsequent groups. Infusion of diatrizoate (DTZ) after BJP produced a further decrease in CIn (-85 +/- 8%, P less than 0.05). In contrast, infusion of albumin, which raised plasma protein concentration to that seen in BJP-infused rats, did not change CIn (+39 +/- 17%). Infusion of beta-lactoglobulin also led to a greater decrease in CIn after DTZ (-35 +/- 9 vs. -67 +/- 8%, P less than 0.05), but myoglobin did not (-58 +/- 7 vs. -54 +/- 12%). Urinary pH and flow rate did not differ between any DTZ-infused group and its appropriate control. These data suggest that aciduria independent of urinary flow rate increases the nephrotoxicity of BJP. In this setting, DTZ further intensifies the nephrotoxicity of BJP as well as some but not all filterable proteins.

Acute Kidney Injury↗
PubMed1978

The antiarrhythmic action of amitriptyline on arrhythmias associated with myocardial infarction in dogs.

The antiarrhythmic activity of amitriptyline, a tricyclic antidepressant, was evaluated in anesthetized dogs 24 h after coronary occlusion, during the period of spontaneous ventricular arrhythmias. In all experiments amitriptyline was administered i.v. in incremental doses of 0.3 mg/kg at 1 min intervals until a conversion to normal sinus rhythm was evident. Amitriptyline administration resulted in conversion of the ventricular arrhythmia to a normal sinus rhythm in 100% of the animals tested at a mean dose of 1.3 +/- 0.1 mg/kg. Smaller doses also resulted in a dose-related decrease in non-sinus nodal pacemaker activity. Lidocaine, when administered to the same group of animals, produced a reduction of ectopic pacemaker activity, but did not eliminate it at a cumulative dose of 2 mg/kg. Antiarrhythmic doses of amitriptyline did not produce significant changes in arterial blood pressure, cardiac output or electrocardiographic parameters associated with atrioventricular or intraventricular conduction. The results of this study suggest that at very low doses amitriptyline may be an effective antiarrhythmic agent in ventricular arrhythmias associated with myocardial ischemia.

Amitriptyline↗
PubMed1977

Primary amyloidosis of urinary bladder and ureter: cause of mural calcification.

Primary amyloidosis is seen in the absence of predisposing disease. It may affect most organs in the body, including the collecting system of the urinary tract. Submucosal calcifications have been described in the renal pelvis and may be pathognomonic for primary amyloidosis of the renal pelvis. We have been able to demonstrate similar submucosal calcifications in the ureter and bladder. The differential diagnosis of submucosal calcification of the distal ureter and bladder must include bilharziasis and tuberculosis. With the recognition of submucosal calcifications, diagnosis of the underlying disease may be readily made. An illustrative case is presented.

Amyloidosis↗