Beta-2-microglobulin-associated amyloidosis in chronic hemodialysis patients with carpal tunnel syndrome.

The clinical manifestations of beta-2-microglobulin (beta 2M)-associated amyloidosis in chronic hemodialysis patients with carpal tunnel syndrome from a medical center hospital are presented. The predominant morbidity of beta 2M-amyloid was musculoskeletal, with deposits identified in surgical or biopsy specimens from trigger fingers, carpal tunnels, fractures, and radiolucent bone lesions. Lucent bone lesions were the characteristic radiologic finding of beta 2M-amyloidosis and were most commonly found in carpal bones, humeral heads, and femoral heads. Carpal tunnel syndrome occurred in greater than 20% of our chronic hemodialysis patients. The longer the period of time on chronic hemodialysis the greater the morbidity from beta 2M-amyloid. Although significant amounts of beta 2M-amyloid were detected in the perivascular regions of viscera, clinical compromise of internal organs from this type of amyloid was not documented. In acute studies, beta 2M clearance during hemodialysis was markedly increased using the Fresenius polysulfone dialyzers compared to cuprophane dialyzers. In summary, beta 2M-amyloid is common and causes significant morbidity in chronic hemodialysis patients. Long-term dialysis with highly permeable membranes effects greater beta 2M clearance which may result in less tissue deposition of beta 2M-amyloid, and therefore, fewer clinical complications.

Hyperparathyroidism following parathyroid autotransplantation.

A patient with primary hyperparathyroidism underwent cervical exploration and hemithyroidectomy. Only one normal parthyroid gland was found and was removed. Hypercalcemia persisted and subsequent arteriography localized a large mediastinal adenoma which was excised. Parathyroid autotransplantation of a small part of this tissue was performed and the patient was well for over a year. He again became markedly hypercalcemic and graft-dependent elevation of parathromone levels was demonstrated. Autograft resection resulted in normocalcemia. Nineteen months later hypercalcemia and elevated parathormone levels prompted re-exploration of the graft site and another enlarged implant was removed. This restored normocalcemia and normal parathromone levels. Parathyroid adenomatous tissue has the potential for autonomous hyperfunction, and caution must be exercised in its use in autotransplantation.

Results of experimental endoscopic esophageal varix ligation.

Endoscopic Variceal ligation (EVL) is performed using a flexible gastroscope and a recently developed elastic band ligating device. Varices from 3-5 mm in diameter were created in a canine model. Thirty seven variceal sites underwent EVL with successful ligation on first attempt in 34 (92%). Gross and microscopic examination of treated sites at 1-60 days showed ischemic necrosis of mucosa and submucosa (24 hours), acute inflammation, demarcation of viable and necrotic tissue, and appearance of granulation tissue (3-7 days), full thickness replacement of mucosa and submucosa with maturing scar tissue and near complete re-epithelialization (14-21 days), and complete healing (50-60 days). Inflammation and scar tissue deposition consistently obliterated submucosal venous channels but left muscularis propria intact. No perforations or other adverse clinical or histological effects were observed. EVL treatment of canine esophageal varices appears to result in safe and effective obliteration of vascular channels in the submucosa by a process of inflammation and scar formation.

Renal vasculature and ischemic injury.

Functionally similar ischemic acute renal failure (ARF), as estimated by glomerular filtration rates (GFR), was induced by renal artery clamping (RAC) or intrarenal norepinephrine (NE) in rats and renovascular reactivity was examined at 1 week. With RAC-ARF induction there was total renal ischemia followed by abrupt return of renal blood flow (RBF). With NE-ARF induction there was subtotal ischemia (10-15% of basal RBF) with RBF recovery over several hours. Renovascular resistance (RVR) did not change to renal perfusion pressure (RPP) reduction in the autoregulatory range in RAC-ARF but paradoxically increased in NE-ARF. There was an exaggerated response to renal nerve stimulation in NE-ARF but no response in RAC-ARF. There was a vasoconstrictor response to intrarenal norepinephrine in the former but a negligible response in the latter. There was no vasodilation to acetylcholine in either group, but there was a normal response to prostacyclin in NE-ARF. Smooth muscle necrosis was found in 46% of resistance arterial vessels in RAC- but in only 8% of NE-ARF (p less than .001). When mean arterial pressure was reduced to 90 mm Hg for 4 h at 1 week, recurrent azotemia and fresh ischemic injury were noted in NE- but not RAC-ARF. It is concluded that different models of ischemic ARF induction result in different patterns of abnormal postischemic vascular reactivity. Differences in vascular smooth muscle and endothelial injury are due to differences in initial ischemia or rates of postischemic reperfusion.

Renal iron handling in the nephrotic syndrome.

Renal iron handling was characterized in three experimental models of the nephrotic syndrome: puromycin aminonucleoside, adriamycin and nephrotoxic serum. In adriamycin-induced nephrotic syndrome, which has previously been shown to result from alterations in pore size of the filtration barrier, the transferrin leak was most severe with a fractional clearance of 25%, a value identical to albumin. In contrast, in puromycin nephrotic syndrome and nephrotoxic serum nephritis the fractional clearance of transferrin was never greater than 2% and consistently less than the fractional clearance of albumin. The fact that iron/transferrin ratios in urine and serum were frequently different, sometimes higher other times lower, documents that iron and transferrin can be dissociated in tubule fluid and handled differently in regards to tubule uptake. Kidney iron concentration is also increased in both immunological and non-immunological forms of nephrotic syndrome. In the proximal tubule iron is present largely on the luminal aspect of the cell. In contrast, the major deposition of iron occurs in the lysosomes of the distal tubule cells. Kidney iron concentration does not correlate with tubule fluid iron content but can be prevented from increasing by systemic iron and/or transferrin depletion. This suggests that iron enters the distal tubule cells with transferrin via its receptors from the basolateral side of the distal tubule cells. In association with the increase tubule fluid and kidney iron, there is a marked reduction in kidney selenium and copper content. It is concluded that urinary iron and transferrin losses can vary greatly in different types of experimental renal diseases, and that iron and transferrin can be dissociated in the tubule fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic peptide and dopamine in established acute renal failure in the rat.

Recent studies have shown that atrial natriuretic peptide (ANP) alone or combined with dopamine (D) markedly improved renal function when given immediately after an ischemic insult. However, the potential beneficial effect of ANP or ANP-D in the established phase of acute renal failure (ARF) and the duration of this effect have not been examined. In the present study atriopeptin III (APIII) and D, sufficient to maintain mean arterial pressure between 100 and 110 mm Hg, or normal saline were given i.v. for four hours to awake Munich-Wistar rats (N = 6 each group) two days after ARF induction with intrarenal norepinephrine (NE). Renal function and morphology were then examined two days after treatment (Day 4). Serum creatinine (SCr) was similarly increased in both groups at the time of APIII-D or saline infusion (Day 2). By Day 4 SCr had decreased to the pre-ARF induction level in APIII-D-treated rats (P less than 0.005), but continued to rise in saline-treated animals (P less than 0.025). Day 4 renal blood flow and glomerular filtration rate (GFR) were higher in APIII-D-compared to the saline-treated group (9.13 +/- 1.14 vs. 4.41 +/- 2.25 ml/min and 0.787 +/- 0.066 vs. 0.370 +/- 0.185 ml/min, respectively, both P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Differences in vascular reactivity in models of ischemic acute renal failure.

To determine the mechanism of observed differences in vasoreactivity in norepinephrine-induced (NE) and renal artery clamp (RAC) models of ischemic acute renal failure (ARF), induction renal blood flow (RBF) was measured and vascular reactivity examined one week thereafter in NE- and RAC-ARF rat kidneys that had identical levels of renal dysfunction. Morphology also was compared at 48 hours and one week. In NE-ARF, RBF was 14% during 90 minutes of induction and by 60 minutes post-NE infusion was only 18% of baseline. In contrast, in RAC-ARF RBF was effectively 0 for 75 minutes but returned to 95% of baseline by 60 minutes after clamp release. At one week there was a paradoxical increase in renovascular resistance (RVR) to renal perfusion pressure (RPP) reduction in the autoregulatory range and an augmented vasoconstriction to renal nerve stimulation (RNS) in NE-ARF, but no change in RVR and minimal reduction in RBF to these same respective stimuli in RAC-ARF (both different at P less than 0.001). NE-ARF were more sensitive to intrarenal norepinephrine than RAC-ARF kidneys (P less than 0.001). Neither NE- nor RAC-ARF kidneys responded to endothelium-dependent acetylcholine (ACh). Vasodilation to endothelium-independent prostacyclin (PGI2) in NE- was similar to sham-ARF, but there was an attenuated response in RAC-ARF kidneys (P less than 0.001). Morphology at 48 hours showed smooth muscle necrosis in half of the resistance vessels in RAC- but in less than 10% of those in NE-ARF. Except for a slightly greater frequency of tubular casts at 48 hours in RAC-ARF, tubular injury was indistinguishable. It is concluded that NE-ARF has evidence of a predominant functional endothelial vascular injury while RAC-ARF has both morphologic and functional evidence of a predominant smooth muscle injury. Differences in vascular injury between the two models, at least in part, may be the consequence of differences in severity of initial ischemia and/or the rates of recovery of RBF; however, an additional or separate toxic effect of infused NE cannot be excluded.

Inherited diseases of the glomerular basement membrane.

The inherited diseases of the glomerular basement membrane include Alport's syndrome (AS), nail-patella syndrome, and thin basement membrane nephropathy. Classical AS is inherited in an X-linked manner and accounts for approximately 85% of the cases. Its manifestations include hematuria, sensorineural hearing loss, ocular defects, and a progression to renal failure. A defect(s) in the alpha 5 (IV) chain of type IV collagen is believed to be the etiology of classic AS, and alterations in its encoding gene localized to the X-chromosome have been elucidated. Although isolated cases of anti-glomerular basement membrane glomerulonephritis have been reported following renal transplantation in patients with AS, it is considered an effective form of renal replacement therapy. Less is known regarding the genetic basis of the autosomal-dominant form of AS, which apparently accounts for the remaining 15% of the cases. Nail-patella syndrome is characterized by nail dysplasia, patellar hypoplasia or aplasia, and nephropathy. It is inherited in an autosomal-dominant fashion with the gene locus assigned to the long arm of chromosome 9. Possible linkage between the COL5A1 gene and the gene for nail-patella syndrome has been suggested. Approximately 30% of the patients progress to end-stage renal failure. Renal transplantation has been successful in treating patients who progress to end-stage renal failure. Thin basement membrane nephropathy is an autosomal dominant trait that accounts for approximately 30% of the cases presenting as persistent, asymptomatic hematuria. The cause of thin basement membrane nephropathy is unknown at present. No decline in renal function is associated with thin basement membrane nephropathy.

Role of iron in the tubulo-interstitial injury in nephrotoxic serum nephritis.

We studied the possibility that tubule fluid iron could be involved in the pathogenesis of the tubulo-interstitial injury associated with primary glomerular disease. Tubule fluid iron is determined by the magnitude of the glomerular leak for transferrin and the iron saturation of transferrin. To minimize tubule fluid iron in an experimental model of glomerulonephritis, iron deficiency was induced in rats prior to the induction of nephrotoxic serum nephritis. Iron deficiency did not effect the development of glomerular disease as determined by proteinuria, but had a marked effect on preventing the development of tubulo-interstitial disease and renal functional deterioration. There was also a strong correlation between the amount of functional deterioration and extent of tubulo-interstitial disease and urinary iron excretion in both the control and iron deficient animals. It is proposed that injury results from iron being dissociated from transferrin at the more acid pH of the tubule fluid. Iron, a transition element, is able to catalyze the Haber-Weiss reaction with the formation of free hydroxyl radicals which causes renal tubule cell injury. This tubulo-interstitial injury is the major determinate of progressive renal functional deterioration in this experimental model of glomerulonephritis.

Squamous cell carcinoma of the skin and lip in renal homograft recipients.

Forty-four squamous cell carcinomas (SCC) of the skin and lip were observed in 9 of 464 renal homograft recipients. Clinically and histologically the SCC's fell into two groups. Two patients with widespread warts, suggestive of epidermodysplasia verruciformis, showed multiple SCC's predominantly on the upper extremities which were associated with minimal solar elastosis of the adjacent dermis. The other seven patients did not have widespread warts; their SCC's occurred predominantly on the head and neck and were associated with prominent solar elastosis of the adjacent dermis. The degree of solar elastosis was particularly striking in view of the young age of this group (mean age: 37 years). Inflammatory cellular response to the transplant SCC's was significantly diminished in comparison with a group of control SCC's from non-immunosuppressed patients. In both transplant groups sunlight appears to be an important etiologic factor; in the first group viruses may also be important.

Serial glomerular and tubular dynamics in thyroidectomized rats with remnant kidneys.

Serial measurements were performed in Munich-Wistar rats with five-sixths nephrectomy that had undergone prior selective thyroidectomy (Tx group) or thyroidectomy with thyroxine replacement (TxT4 group) to determine the effects of Tx on glomerular and tubular dynamics in relation to Tx attenuation of renal failure progression. At 1 week, inulin clearance rates (Cin) in TxT4 and Tx rats were 0.367 +/- 0.171 and 0.120 +/- 0.036 mL/min, respectively, different at P less than 0.01. Corresponding single-nephron filtration rate (SNGFR), glomerular plasma flow (QA), glomerular transcapillary hydraulic pressure (delta P), and proximal tubular reabsorption (Jv) were all reduced in Tx compared with TxT4 rats (P less than 0.01). Protein excretion (UPROT) was 151 +/- 40 in TxT4 rats, and 9 +/- 5 mg/d in Tx animals. Glomerular mesangial matrix expansion and focal tubulointerstitial changes were more frequent in TxT4 than Tx rats. By 4 weeks, Cin, SNGFR, QA, glomerular ultrafiltration coefficient (Kf) and Jv were similar in Tx and TxT4. Only glomerular capillary pressure (PGC) remained lower in Tx rats (35 +/- 3 v 50 +/- 3 mm Hg in TxT4, P less than 0.001). UPROT was 161 +/- 24 in TxT4 and 17 +/- 12 mg/d in Tx rats. While 7% +/- 4% of glomeruli showed focal sclerosis in TxT4 rats, there was none in the Tx group. Maximal glomerular planar area increased between 1 and 4 weeks in the TxT4 group, but not in the Tx group. However, this measurement was not significantly different between TxT4 and Tx glomeruli at 1 or 4 weeks. Minimal focal tubulointerstitial changes were found in TxT4, but there were not progressive from those observed at 1 week. The reduced PGC at 1 week was the result of a disproportionately greater increase in afferent (RA) than efferent arteriolar resistance (RE) in Tx rats (P less than 0.025); however, at 4 weeks, both RA and RE had decreased to values identical to those in TxT4 animals and the lower PGC in Tx rats was the result of a reduced mean arterial pressure. In conclusion, a reduced PGC was the sole functional correlate of decreased proteinuria and glomerulosclerosis afforded by Tx in this partial nephrectomy model. Suppression of either nephrectomy-related hypertrophy or tubulointerstitial injury by Tx could not be excluded as at least partially protective factors.

Causes of death in autosomal dominant polycystic kidney disease.

To determine the causes of death in autosomal dominant polycystic kidney disease (ADPKD) patients and to examine whether the extrarenal manifestations of ADPKD influence the causes of death, the medical records of 129 patients who died between 1956 and 1993 were reviewed; 58% of the 129 patients had an autopsy performed. Seventy-seven percent died after reaching ESRD. The mean age at death increased from 51 yr for those who died before 1975 to 59 yr for those who died after 1975, reflecting the introduction of renal replacement therapies. The most common cause of death before 1975 was infection (30%), followed by uremia (28%) and cardiac disease (21%); after 1975, these were cardiac disease (36%) and infection (24%). Infection was equally prevalent before and after 1975, presenting as sepsis in 94% and directly relating to ADPKD in 47% of these patients. Underlying factors for cardiac death were cardiac hypertrophy, seen in 89% of all autopsied patients, and coronary artery disease, seen in 81%. A neurologic event was the cause of death in 12% of patients; these were ruptured intracranial aneurysm in 6%, hypertensive intracranial hemorrhage in 5%, and ischemic stroke in 1%. The mean age of those who died of ruptured intracranial aneurysm was 37 yr. No patient died of renal cancer. Liver cysts were the most common extrarenal manifestation, seen in 70% of the autopsied cases; cysts in other organs were very rare. Colonic diverticula were found in 21%. Thus, the renal and extrarenal manifestations of ADPKD are important contributors to morbidity and mortality.

Laser probe coagulation of bleeding canine ulcers.

A nonlight-transmitting contact laser probe was used to treat acutely bleeding gastric ulcers in heparinized dogs. Thirty-five treated ulcers responded with complete hemostasis following 21-92 seconds (mean, 32 seconds) application per ulcer. Ten control ulcers left untreated bled for 5-30 minutes (mean, 11 minutes). Hemostasis was maintained at treated sites for the entire observation period (60 minutes). Perforations did not occur, and there was no evidence of full thickness injury. Histological assessment confirmed a limited (0.2-0.5 mm) zone of coagulation injury. The laser probe is effective for control of acute bleeding in this canine ulcer model.

The effect of prescription size on acquisition of maintenance medications.

OBJECTIVE: To determine whether large prescriptions (> or = 90 days' supplies) enhance the acquisition of maintenance medications by patients. DESIGN: Study 1: multisite, retrospective cohort study evaluating outpatient digoxin use. Study 2: single-site, retrospective cohort study to confirm Study 1. SETTING: Study 1: Ten Veterans Affairs Medical Centers in the Rocky Mountain region. Study 2: The only facility from Study 1 (site C) that dispensed large prescriptions of maintenance medications. PATIENTS: Randomly selected outpatients receiving two or more digoxin prescriptions (n = 176 in Study 1, n = 114 in Study 2). INTERVENTION: None. RESULTS: The main outcome measure was the proportion of prescribed doses of maintenance medications obtained. In Study 1, patients who received at least one large digoxin prescription obtained a mean of 137.2% of their prescribed digoxin doses over a mean of nine months, compared with 91.3% for patients who received only small prescriptions of < 90 days' supplies (p = 0.02). Patients receiving large prescriptions were more likely to obtain at least 100% of their prescribed amounts of digoxin (adjusted OR = 11.4, 95% CI = 1.3-96.8, p = 0.03). At site C, patients in Study 1 obtained a mean of 129.0% of all maintenance drugs given in large supplies, compared with 95.2% of drugs prescribed only in small supplies (p = 0.006). In Study 2, acquisition of digoxin increased progressively from 89.7% among individuals who received only small digoxin prescriptions to 113.0% for those who received only large supplies (p = 0.002), over a mean of 14 months. CONCLUSIONS: Large prescriptions facilitate the acquisition of maintenance medications but may lead to oversupplies, while small prescriptions impose a barrier to obtaining these drugs.

The microgenesis of some renal calculi.

We studied calcium oxalate stone formation in rats in which calculogenesis was induced by a diet deficient in pyridoxine (vitamin B6). We studied the sequence of stone formation using both a gross specimen transillumination technique, which is described, and histologic methods. A characteristic regional distribution of calculi is described and illustrated. Histologic studies reveal the interstitial site of calcium oxalate microlith formation. The progressive movement of these crystals through the tubular wall into the tubular lumen is described and illustrated. The formation of Randall's plaques is described and illustrated, as is a characteristic "geode" formation in the calyceal fornix. The significance of these findings is discussed and a new concept of stone formation proposed.

Evidence for a new mammalian organ. IV. Stone formation.

We studied calcium oxalate stone formation in rats after calculogenesis had been induced by a diet deficient in pyridoxine (vitamin B6). Urinary calculi had formed within 6 weeks in 86 per cent of 114 animals. The calcium handling properties of 17 tissues (including the renal sinus "gland") were compared in normal and pyridoxine deficient animals. A significant increase in calcium (85Sr) uptake was found in the renal sinus "gland" and the renal medulla after pyridoxine deprivation. The movement of calcium from the perihilar sinus tissues into the renal medulla was examined and the significance of our observations is discussed.

Glomerular dynamics in the hypothyroid rat and the role of the renin-angiotensin system.

Munich-Wistar rats underwent thyroidectomy (TX) with reimplantation of the parathyroid glands. Systemic hemodynamic and micropuncture studies were performed at 1 and 3 wk post-TX, and the results were compared with levothyroxine replaced controls (TXT4). Cardiac output (CO) in TX rats fell progressively and was 40% of that in TXT4 at 3 wk. Renal blood flow declined in parallel with CO. Systemic blood pressure did not fall in TX rats because of a 50% increase in systemic vascular resistance by 3 wk post-TX. Glomerular dynamics were not significantly different between TX and TXT4 rats at 1 wk; however, by 3 wk single-nephron glomerular filtration rate (SNGFR) had fallen to 16.5 +/- 1.1 vs. 34.1 +/- 3.4 nl/min in TXT4 controls (P less than 0.001). In 3-wk TX rats, glomerular plasma flow (QA) was 50.9 +/- 3.7 vs. 108.0 +/- 8.7 nl/min in TXT4 rats (P less than 0.001), net hydraulic ultrafiltration pressure (delta P) was 33 +/- 2 vs. 37 +/- 1 mmHg in TXT4 rats (P less than 0.01), and the ultrafiltration coefficient (Kf) was 0.025 +/- 0.003 vs. 0.084 +/- 0.008 nl X s-1 X mmHg-1 in TXT4 controls (P less than 0.001). Although the changes in systemic and glomerular hemodynamics were progressive over 3 wk, proximal tubular reabsorption fell maximally within 1 wk. Similar patterns of alterations in glomerular dynamics are known physiological consequences of angiotensin II (ANG II).(ABSTRACT TRUNCATED AT 250 WORDS)

Verapamil protects against progression of experimental chronic renal failure.

Chronic administration of verapamil (Ver) decreases nephrocalcinosis and tubular ultrastructural abnormalities in the remnant model of chronic renal disease. In the present study, the effect of chronic Ver administration on renal function, renal histology and mortality after subtotal nephrectomy was examined. Fourteen days after staged subtotal nephrectomy rats were paired according to renal functional impairment, mean arterial pressure (MAP), and body weight. Rats were pair fed and received either Ver (0.1 micrograms/g sc bid, N = 10) or saline (0.1 ml sc bid, N = 10) for up to 23 weeks. Both members of each pair were sacrificed shortly before the uremic death of controls. At sacrifice, rats treated with Ver had a lower serum creatinine (2.29 vs. 2.99 mg/dl, P less than 0.05) and a higher creatinine clearance (318 vs. 164 microliters/min, P less than 0.05) than controls. In a second experiment, survival was superior in rats treated with Ver than in controls from week seven (P less than 0.0025 by week 14). Serum creatinine was higher at week 10 in control rats (1.68 vs. 1.10 mg/dl, P less than 0.05). MAP was no different between the two groups, irrespective of the time between Ver administration and the measurement of MAP. Histological damage and nephrocalcinosis were worse, and renal and myocardial calcium content was higher in controls. In conclusion, independent of any effect on systematic MAP, chronic administration of Ver protects against renal dysfunction, histological damage, nephrocalcinosis and myocardial calcification, and improves survival in the remnant model of chronic renal disease.

Phosphate restriction reduces proteinuria of the uninephrectomized, diabetic rat.

Proteinuria is the clinical hallmark of diabetic nephropathy and the harbinger of progressive renal disease. Therefore, the present study was designed to examine the effect of phosphate restriction on the proteinuria of streptozotocin-induced diabetes mellitus in the rat. Uninephrectomy was performed in experimental and control groups to worsen the degree of diabetic nephropathy. Proteinuria was prevented in Sprague-Dawley rats treated with the intestinal phosphate binder, dihydroxyaluminum aminoacetate (DHAAA) (24.75 +/- 20.35 mg/d at 3 months v control, 77.45 +/- 44.72 mg/d, P less than 0.001); an effect that was independent of protein and caloric intake, plasma albumin and lipids, severity of diabetes, mean arterial pressures, cardiac output, and renal calcium accumulation. The effect of DHAAA on protein excretion and glomerular hemodynamics was examined in similarly prepared Munich-Wistar rats; these rats did not tolerate long-term studies. Three weeks of DHAAA again caused a consistent fall in proteinuria (5.98 +/- 7.28 v 34.94 +/- 24.28 mg/d) and in transmembrane hydraulic pressure difference (41.1 +/- 1.2 v 46.4 +/- 2.8 mm Hg, P less than 0.005). In conclusion, phosphate restriction significantly decreases the proteinuria of Sprague-Dawley and Munich-Wistar uninephrectomized rats with streptozotocin-induced diabetes mellitus. Micropuncture of Munich-Wistar rats suggests that a reduction of intraglomerular pressure may be at least partially responsible for such an effect.