Recertification: a challenge to those trained in the "good old days".
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Certification↗
Biomedical subjects
W M Bennett
Publications and source records attributed to W M Bennett.
Djenkol bean poisoning (djenkolism): an unusual cause of acute renal failure.
This report describes a patient with acute renal failure that resulted from the ingestion of djenkol beans. Features of acute djenkolism include nausea, vomiting, bilateral loin pain, gross hematuria, and oliguria. The blood urea level was 16.2 mmol/L and the serum creatinine was 460 mumol/L. Phase contrast microscopy of the urinary sediment indicated that the hematuria was nonglomerular. Ultrasound of the kidneys showed slightly enlarged kidneys with no features of obstruction. Renal biopsy showed acute tubular necrosis similar to the single animal study reported in the literature. With conservative therapy, which included rehydration with normal saline and alkalinization of the urine with sodium bicarbonate, the acute renal failure resolved. Based on its chemistry, djenkol bean-associated acute renal failure may be analogous to acute uric acid nephropathy.
Acute Kidney Injury↗
Cyclosporine A induced arteriolopathy in a rat model of chronic cyclosporine nephropathy.
Chronic cyclosporine (CsA) nephrotoxicity is a major complication of heart, bone marrow, and renal transplantation, and is characterized in humans by striped interstitial fibrosis, tubular dilatation and atrophy, and hyalinization of hilar arterioles. This last feature is highly specific for cyclosporine injury and has been difficult to reproduce in normotensive animal models. Salt-depletion has been shown to sensitize rodents to the effects of CsA and accelerate the disease process. We conducted sequential studies in chronically salt depleted, pair fed rats treated with CsA (15 mg/kg, s.c.) or an equivalent dose of olive oil vehicle, and found a histologic lesion associated with CsA that consisted of striped cortical interstitial fibrosis, tubular dilatation and atrophy, and hyalinization of many afferent arterioles. The arteriolopathy was first detected at day 10 with progressive hyalinization of arterioles continuing until termination of the study at day 35. The arteriolopathy consisted initially of eosinophilic granular transformation of smooth muscle cells comprising afferent hilar glomerular arterioles, and progressed to foci of smooth muscle cell vacuolization and accumulation of discrete hyaline deposits in vessel walls. Electron microscopy demonstrated marked accumulation of typical renin granules throughout the smooth muscle cell cytoplasm, corresponding to the eosinophilic granular transformation revealed histologically. Immunocytochemistry confirmed the up-regulated production of renin in these vessels. This study documents a rodent model for CsA arteriolopathy and CsA-associated interstitial fibrosis that strikingly reproduces the most characteristic nephropathic effects of cyclosporine found in human patients treated with this agent.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Cellular proliferation and macrophage influx precede interstitial fibrosis in cyclosporine nephrotoxicity.
Chronic cyclosporine (CsA) nephrotoxicity is a major complication of solid organ transplantation, and is characterized histologically by striped tubulointerstitial fibrosis, tubular atrophy, and hyalinization of the afferent arteriole, a highly specific finding in cyclosporine injury. The salt-depleted rat model of chronic cyclosporine nephropathy mimics these lesions in humans. We conducted sequential studies of this model in groups of pair fed rats (N = 6) treated with CsA (15 mg/kg, s.q.) or an equivalent dose of olive oil. Proliferation of tubular and interstitial cells was documented early in the medulla by day 5 (3.2 +/- 2.1 vs. 0.81 +/- 0.4 cells/HPF in CsA vs. control, P < 0.02), and was maximal in areas of interstitial fibrosis by day 35 (7.9 +/- 3.7 vs. 0.52 +/- 0.2 cells/HPF in CsA vs. control, P < 0.005). The interstitial fibrosis was associated with a significant macrophage influx by day 35 (13.9 +/- 3.5 vs. 1.5 +/- 0.32 cells/HPF, CsA vs. control, P < 0.005), which correlated with increased cortical tubular staining for the macrophage adhesion protein, osteopontin. Elevated serum creatinine correlated with interstitial fibrosis at day 35 (0.85 +/- 0.11 vs. 0.40 +/- 0.03 mg/dl Cr, CsA vs. control, P < 0.005) by linear regression (r = 0.9, P < 0.05). Medullary proliferation and interstitial fibrosis correlated with decreased tubular concentrating ability, and higher urinary volume. Cortical interstitial fibrosis was maximal at day 35 and was associated with an increase in type I and type IV collagen deposition, while tubular injury was associated with increased vimentin expression. Tubular interstitial cells also expressed increased vimentin early in the medulla (day 10) and later in the cortex. Both groups remained normotensive despite significantly elevated juxtaglomerular (JG) apparatus renin expression in CsA treated animals, implicating the intrarenal-renal renin-angiotensin system in this disease. We conclude that cyclosporine nephrotoxicity is associated with early tubular and interstitial cell proliferation, and a significant macrophage influx that precedes the development of cortical interstitial fibrosis and afferent arteriolar hyalinosis. These early cellular changes correlate with functional abnormalities including decreased creatinine clearance (CCr) and decreased medullary concentrating ability, which stabilized despite progressive fibrosis. These cellular events may be important in the pathogenesis of chronic CsA nephrotoxicity.
Animals↗
Clinical aspects of autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease is the most common genetic disorder encountered by nephrologists. Clinically relevant areas of which the physician must be knowledgeable are reviewed, emphasizing recent genetic advances with clinical implications for patients and their families. Recent information on hypertension, infection, pain and discomfort, hepatic cysts, and intracranial aneurysms is summarized.
Humans↗
Functional and structural characteristics of experimental FK 506 nephrotoxicity.
1. FK 506 (Tacrolimus, Prograf) is a novel immunosuppressant which is effective in solid organ transplantation and autoimmune diseases. The lack of a suitable animal model has hindered the study of the nephrotoxicity of the drug which has emerged as a common adverse effect in clinical trials. We report both acute and chronic nephrotoxicity with tacrolimus (FK) in which renal structure and function are worsened by sodium depletion. 2. Pair fed male Sprague-Dawley rats were given FK (3 or 6 mg/kg, p.o.) or vehicle for 7, 21 and 42 days on low salt or normal diet. The FK whole blood trough levels achieved (3-10 ng/mL) were similar to those observed in FK treated transplant patients. 3. In salt depleted animals treated for 7 days, FK (6 mg/kg) decreased renal blood flow and glomerular filtration rate (1.8 +/- 0.1 and 0.2 +/- 0.1 mL/min per 100 g vs 2.9 +/- 0.2 and 1.1 +/- 0.1 mL/min per 100 g in the vehicle group, P < 0.01). 4. After 21 days of treatment of FK on low salt diet but not normal salt, FK induced focal collapse and vacuolization in proximal tubules and discrete or confluent zones of tubulointerstitial oedema and mononuclear cell infiltration. 5. After 42 days in salt depleted rats, there was significant tubulointerstitial scarring that was associated with an increased plasma renin activity (PRA) (64 +/- 10 vs 30 +/- 4 ng AI/mL per h in the vehicle group, P < 0.05). Animals given normal salt diets did not develop significant histological lesions even up to 42 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Prevention of experimental cyclosporin-induced interstitial fibrosis by losartan and enalapril.
The pathogenesis of renal scarring in chronic cyclosporin nephropathy is unknown. In this study, we evaluated the effects of renin-angiotensin system blockade by enalapril and losartan in a salt-dependent model of cyclosporin-associated chronic tubulointerstitial fibrosis (TIF). Rats kept on normal or low-salt diet were given cyclosporin, cyclosporin+enalapril, cyclosporin+losartan, cyclosporin+enalapril#losartan, or vehicle for 14 and 28 days. Cyclosporin reduced glomerular filtration rate (GFR) in rats fed either diet, but only salt-depleted animals developed significant TIF. Cyclosporin also impaired renal concentrating ability and caused tubular enzymuria. Renin-angiotensin system blockade decreased blood pressure (BP) and promoted afferent arteriolar vasodilatation. Losartan reduced plasma renin activity and prevented cyclosporin-induced increment of cortical alpha 1(I) procollagen mRNA. Renin-angiotensin blockade did not improve GFR and tubular function; however, it strikingly prevented TIF development, even in presence of very low BP. Rats treated with cyclosporin, hydralazine, and furosemide achieved BP values similar to losartan or enalapril groups, but there was no protection against interstitial fibrosis development. These results suggest that cyclosporin-related chronic interstitial injury is mediated by angiotensin II and that the mechanisms promoting the interstitial scarring can be dissociated from glomerular and tubular dysfunction in cyclosporin nephropathy.
Animals↗
Pathogenesis of cyclosporine nephropathy: roles of angiotensin II and osteopontin.
Low-salt-diet, cyclosporine (CsA; 15 mg/kg per day)-treated rats develop striped interstitial fibrosis, arteriolar hyalinosis, and azotemia similar to the chronic nephropathy observed in humans. To examine the role of angiotensin II in this model, rats on a low-salt diet were given CsA, CsA and the angiotensin II receptor Type I antagonist Losartan (10 mg/kg per day), CsA and hydralazine/furosemide, or vehicle. At Day 35, CsA-treated rats had tubular injury, arteriolopathy of the afferent arteriole, increased expression of the monocyte-macrophage adhesive protein osteopontin, interstitial macrophage infiltration, increased interstitial transforming growth factor-beta expression, and interstitial fibrosis. This study provides new insight in both pathogenic and therapeutic aspects of CsA nephropathy. The pathogenesis of CsA nephropathy involves the expression of osteopontin by tubular epithelial cells, the level of which closely correlates with the degree of macrophage infiltration and interstitial fibrosis in all groups (r = 0.79 and 0.74, respectively; P < 0.001). Therapeutic conclusions can be drawn from the observation that both losartan and hydralazine/furosemide reduced osteopontin expression, macrophage infiltration, transforming growth factor-beta expression, and interstitial fibrosis, but did not prevent the decrease in GFR. Treatment with losartan, but not with hydralazine and furosemide, markedly reduced arteriolopathy. It was concluded that angiotensin II contributes to the vasculopathy (hyalinosis) induced by CsA. In contrast, the interstitial fibrosis mediated by CsA can be partially prevented by both an angiotensin II Type I receptor antagonist or by hydralazine and furosemide. This suggests that the interstitial fibrosis can be dissociated from the vascular effects of CsA. The beneficial effects of lowering blood pressure or vasodilation per se may be difficult to distinguish from the specific effects of angiotensin II receptor blockade.
Angiotensin II↗
The nephrotoxicity of immunosuppressive drugs.
Nephrotoxicity from immunosuppressive drugs can complicate otherwise successful therapy. This paper reviews the clinical and pathophysiologic aspects of nephrotoxicity. The chronic progressive nephropathy is emphasized based on a recently developed animal model. Experimental and clinical data regarding FK506, new cyclosporine analogs, and Rapamycin are also discussed.
Animals↗
Cardiovascular consequences of immunosuppressive drug treatment: a comparative study of cyclosporine A and cyclosporine G.
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Acetylcholine↗
FK506 nephrotoxicity: morphologic and physiologic characterization of a rat model.
BACKGROUND: FK506 is a useful agent in the prevention of allograft rejection but has recently been shown to be nephrotoxic. EXPERIMENTAL DESIGN: Sprague-Dawley rats (n = 40) were divided into four groups: control (C); low-salt (LS); FK506, 3 mg/kg daily by gavage (FK); and FK506-low-salt (FK-LS). After 6 weeks, the animals underwent physiologic studies and were sacrificed with perfusion fixation of the kidneys. Semiquantitative analysis of morphologic injury was performed as well as grading of juxtaglomerular apparatus (JGA) granularity (1-micron plastic sections). Computer-assisted morphometry was used to measure medullary thick ascending limb (mTAL) size within the inner stripe. RESULTS: Serum creatinine and plasma renin activity were significantly elevated only in the FK-LS group, but both FK groups had significantly increased fractional excretion of Mg. Tubular atrophy and fibrosis involving medullary rays and inner stripe (areas of low oxygen availability) was minimally present in FK, but prominent in FK-LS (P < 0.001). Injury correlated with decreased function (P < 0.001). Variance of mTAL size, an expression of co-existent tubular atrophy and hypertrophy was significantly greater in FK-LS and correlated with decreased renal function and urine osmolality (P < 0.001). JGA granularity was increased by FK506 (P < 0.006) with the highest values in FK-LS (P < 0.001), and strongly correlated with injury (P < 0.001). JGA granularity did not correlate with circulating renin activity levels, suggesting local activation of a renin-angiotensin system. CONCLUSIONS: FK506 compromises renal parenchymal zones which are known to have limited oxygen availability (medullary ray and inner stripe), a pattern that has been observed with other nephrotoxins. The injury is potentiated by salt depletion and may be mediated by the renin-angiotensin system. Furthermore, these findings illustrate the close correlation between the medullary injury that was observed and the impaired function that was documented.
Animals↗
Efficacy and safety of cyclosporine in renal-transplant recipients.
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Cyclosporine↗
Marijuana has no medicinal value.
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Cannabis↗
Enhancement of FK506 nephrotoxicity by sodium depletion in an experimental rat model.
FK506 can show efficacy in transplant rejection even after other immunosuppressive drugs have been ineffective. However, the lack of a suitable animal model has hindered the study of FK nephrotoxicity, which has been noted as a common adverse effect in human trials. In this paper, we report a model of chronic FK nephrotoxicity in which renal structure and function are worsened by sodium depletion. Pair-fed male Sprague-Dawley rats were given FK (6 mg/kg p.o.) or vehicle for 21 days on a low-salt or normal diet. There was no significant difference in body weight between FK and vehicle groups. The FK whole-blood trough levels (3-10 ng/ml) in rats are similar to those in FK treated transplant patients. In sodium-depleted rats, FK clearly decreased GFR (0.09 +/- 0.03 ml/min/100 g vs. 0.94 +/- 0.06 ml/min/100 g in the vehicle group, P < 0.01), urinary osmolarity (UOsm, P < 0.01) and plasma magnesium (P < 0.01) and increased plasma creatinine (Pcr, P < 0.01), fractional excretion of magnesium (P < 0.01), urine volume (P < 0.01), plasma renin activity (PRA, P < 0.05), and alanine aminopeptidase (AAP, P < 0.05) as compared with those in the vehicle group. Salt depletion significantly potentiated these functional changes as compared with those in the normal salt group (GFR, UOsm, Pcr, PRA, and AAP of the low salt group vs. those of the normal salt group, P < 0.05 by ANOVA). In the sodium-depleted rats, the main lesion in the rat kidneys was focal collapse and vacuolization in proximal tubules, but there was also significant interstitial fibrosis. In contrast, no injury was observed in the sodium-replete rat kidneys. In conclusion, an experimental model of FK nephrotoxicity in sodium-depleted rats has been developed that is characterized by reduced GFR and structural damage to the proximal tubule accompanied by interstitial fibrosis. Sodium depletion appears to potentiate these changes at blood levels similar to those achieved in patients receiving FK.
Animals↗
Legalisation of marihuana for medical use.
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Cannabis↗
A prospective, double-blind, randomized study of high-versus low-dose OKT3 induction immunosuppression in cadaveric renal transplantation.
We undertook a prospective, double-blind study of high-(5-mg) versus low-(2-mg) dose OKT3 for induction immunosuppression (12 days) in cadaveric renal allograft transplantation. Maintenance immunosuppression was identical in both groups and consisted of azathioprine and prednisone initially, with cyclosporine beginning on the 5th postoperative day. Twenty-six patients were randomized. The groups were similar in terms of age, kidney ischemia time, peak PRA, and latest PRA. There were more diabetics and women in the high-dose group. Patient survival at 12 months was 100% in both groups. Graft survival at 12 months was 92% and 100% in the high- and low-dose groups, respectively. Infections were mostly minor and equal in frequency in the two groups. All patients receiving high- or low-dose OKT3 had manifestations of the cytokine release syndrome; these were delayed in onset in the low-dose group. Eleven patients (85%) in each group produced anti-OKT3 antibodies. Lymphocyte depletion after 1 day was major (> 98%) and identical in both groups. CD3 antigens were removed more slowly in the low-dose group but eventually at equal rates in both groups. Cost was significantly lower in the low-dose group. We conclude that while both doses of OKT3 were effective and safe for induction immunosuppression, it may be prudent to use a lower dose of OKT3 for induction immunosuppression because of its potential to reduce cytokine-mediated effects and to avoid the complications of overimmunosuppression and because of the lower costs associated with it.
Adolescent↗
Chronic renal disease and papillary necrosis associated with the long-term use of nonsteroidal anti-inflammatory drugs as the sole or predominant analgesic.
The risk of renal papillary necrosis and renal dysfunction due to the chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) is unknown. In a prospective study of 259 heavy analgesic users seen in a general medical hospital over an 11-year-period beginning in January 1982, 69 new cases of analgesic nephropathy with renal papillary necrosis were confirmed by intravenous urogram (26.6%), ultrasonography (30.4%), and/or computed tomography (43%). Twenty-nine of these patients (42%) had consumed excessive quantities of NSAIDs alone; an additional nine patients (13%) had consumed NSAIDs predominantly in combinations with paracetamol, aspirin, phenacetin, caffeine, and/or traditional herbal medications. Of those patients who consumed NSAIDs alone, 17 had consumed only a single type of NSAID and the remaining 12 had consumed multiple types of NSAIDs. The amount of NSAIDs administered ranged from 1,000 to 26,600 capsules or tablets over a 2- to 25-year period. Renal impairment (serum creatinine, 126 to 778 mumol/L) was noted in 26 of these 38 patients (64.8%). The reasons given for consuming NSAIDs include gouty arthritis (18 patients), osteoarthritis (seven patients), rheumatoid arthritis (six patients), chronic headache (three patients), gouty arthritis plus chronic headache (three patients), and chronic backache (one patient). All patients were prescribed these drugs and were followed medically. The occurrence of analgesic nephropathy was predominantly in males (male to female ratio, 1.9:1). Most of the patients did not have the characteristic psychological profile attributed previously to analgesic abuse nephropathy. Associated addictive habits, such as the use of psychotropic drugs and sleeping tablets, purgative abuse, and alcoholism, were absent.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗