Autoimmune hepatitis treated with cyclosporin revealed by acute hepatocellular failure

The kidney bears the brunt of the demands of a tropical climate for water and electrolyte homeostasis. We hypothesised that a tropical climate may cause adaptive changes in the entire organism leading to altered renal function in our subjects. Hence renal function data for residents of a temperate climate may not be applicable to tropical residents. We therefore sought to elucidate renal function in subjects residing in a tropical climate. We used lithium clearance, CLi, a non-invasive tool for assessing proximal tubular function in humans, and endogenous creatinine clearance, CCr, to estimate proximal tubular function and glomerular function, respectively, in our subjects. We did this in order to establish whether or not nephron function in our subjects differs from that for residents of a temperate climate. Nineteen male and 12 female Ghanaian subjects aged between 15 and 48 years were studied. The estimated GCr was 117.3 +/- 6.6 ml/min for male subjects and 97 +/- 6.4 ml/min for female subjects. CLi was 20.3 +/- 1.6 ml/min for male and 19.1 +/- 0.4 ml/min for female subjects, respectively. The estimated absolute reabsorption rate of fluid of proximal tubules was 97.0 +/- 6.0 ml/min for males and 78.1 +/- 6.0 ml/min for females. The percentage proximal fluid reabsorption for male and female subjects was 81.2 +/- 1.4 and 79.5 +/- 1.6, respectively. The differences between male and female values (mean +/- SEM) were not statistically significant. The data suggest that the proximal tubule in residents of a tropical climate may reabsorb more fluid compared to that in residents of a temperate climate. Our values for proximal tubular reabsorption are higher than those reported for residents of a temperature climate. Our estimate of glomerular filtration, however, is similar to published data for Caucasians. The difference in proximal tubular function may reflect possible renal adaptation to a hot, humid climate. We conclude that renal function of tropical residents differs from that of residents of a temperate climate. This difference may be due to renal adaptation to the hot, tropical climate.     

Nephrotoxicity of cyclosporine in humans: effect of cyclosporine on glomerular filtration and proximal tubular reabsorption

The chronic nephrotoxic effects of cyclosporine (CsA) include proximal tubular atrophy and vacuolization. This study investigated the effect of CsA on renal hemodynamics and segmental electrolyte transport in CsA-treated patients. The clearance of inulin (CIn) and PAH para-amino-hippuric acid (CPAH) was determined; proximal tubular function was studied using a lithium clearance method and calculating tubular phosphate reabsorption per milliliter of glomerular filtrate (TP/CIn). Twenty patients without renal disease were investigated: ten treated with CsA because of nonrenal grafting (group 1) and ten healthy volunteers (group 2). The results obtained were compared with those from 20 renal allograft recipients, of whom ten were treated with CsA and methylprednisolone (group 3) and ten with azathioprine and methylprednisolone (group 4). CIn and CPAH were significantly impaired in patients treated with CsA. No significant impairment of lithium clearance as induced by CsA was observed. The fractional excretion of lithium was slightly increased in patients treated with CsA compared to their respective controls. TP/CIn was lower in graft recipients compared to controls; no impairment of phosphate reabsorption as induced by CsA was found. The fractional tubular excretion of lithium was slightly increased compared to controls, rising evidence that proximal tubular reabsorption of lithium was decreased. Tubular reabsorption of phosphate was not impaired. The decrease in glomerular filtration and renal perfusion during chronic treatment with CsA was accompanied by a reduced proximal reabsorptive capacity, as was shown by lithium clearance. Our data do not support the hypothesis that functional parameters of the proximal tubular system can be used as indicators of CsA-induced nephrotoxicity.     

The influence of angiotensin-converting enzyme inhibition on renal tubular function in progressive chronic nephropathy

The influence of angiotensin-converting enzyme (ACE) inhibition on renal tubular function in progressive chronic nephropathy was investigated in 69 patients by the lithium clearance (C(Li)) method. Studies were done repeatedly for up to 2 years during a controlled trial on the effect of enalapril on progression of renal failure. The pattern of proteinuria was followed over the first 9 months. At baseline, the glomerular filtration rate (GFR) was 5 to 68 mL/min. Absolute proximal tubular reabsorption rate of fluid (APR), estimated as the difference between GFR and C(Li), was 1 to 54 mL/min. Calculated fractional proximal reabsorption (FPR) was moderately subnormal. During the study, GFR decreased and sodium clearance was unchanged; fractional excretion of sodium therefore increased. In the group of patients randomized to treatment with enalapril (n = 34), GFR at 1 month was 83% (P < 0.001) and C(Li) was 88% (P < 0.01) of the baseline values, APR and FPR had not changed significantly, and potassium clearance was significantly decreased. Through the rest of the study period, APR remained nearly unchanged and FPR even increased in the enalapril group. In the group of patients randomized to treatment with conventional antihypertensive drugs (n = 35), C(Li) was unchanged until severe reduction in GFR, APR and FPR decreased gradually, and potassium clearance was almost unchanged. These differences in tubular function between the two treatment regimens were significant (P < 0.05). An unchanged or increased APR in either treatment regimen was associated with a long-term slower progression of renal failure. Over 9 months, the 24-hour fractional clearance of albumin decreased in the ACE inhibitor group (P < 0.01), whereas the clearances of immunoglobulin G and retinol-binding protein were unchanged in this group. In the conventional group, the fractional clearances of these three plasma proteins all increased. It is concluded that in progressive chronic nephropathy ACE-inhibitor treatment was associated with different adaptive tubular changes in the handling of sodium, water, and protein compared with conventional antihypertensive therapy. During ACE inhibition, the reabsorptive capacity of the proximal tubule appeared to be better preserved, which might be of importance for the beneficial effect of this treatment in chronic renal disease.     

Renal elimination of lithium in rats with lithium intoxication

The relation between urine flow (V), lithium clearance (CLi) and sodium clearance (CNa) was studied in rats given food containing lithium in amounts leading to inhibition of distal reabsorption of water and sodium. Maximum inhibition of the reabsorption of water was reached at serum lithium concentrations of about 1 mM. At higher serum lithium levels the rats developed intoxication due to a lowering of CLi and a consequent rise of the serum lithium concentration. The intoxication was characterized by a proportional decrease of V and CLi. The decrease of V and CLi was not related to changes of CNa. The results indicate that lithium is reabsorbed in the proximal tubules in parallel with sodium and that the lowering of CLi is due to increased fractional proximal reabsorption of lithium and sodium compensatory to inhibition of the distal reabsorption of sodium.     

Renal effects of a urodilatin infusion in patients with liver cirrhosis, with and without ascites

This study reports the effects of a short-term (60 min) low-dose (20 ng x kg(-1) x min(-1)) infusion of synthetic urodilatin (URO) in patients with liver cirrhosis. URO is a natriuretic peptide. A total of 15 cirrhotic patients with ascites and nine without ascites participated in a randomized, double-blind, placebo-controlled study in a crossover design. Renal hemodynamics were estimated by a clearance technique using radioactive tracers, and tubular handling of sodium was evaluated by the lithium clearance method. The renal effects of URO were characterized by a significant increase in urine sodium excretion rate (UNa) and urine flow rate (V) in the cirrhotic patients without ascites (UNa: 173%; V: 94%) and with ascites (UNa: 219%, P < 0.01; V: 42%, P < 0.01) when compared with placebo infusions. Fractional excretion of sodium increased significantly, indicating a tubular effect of URO on sodium handling. Filtration fraction, lithium clearance (a marker of end-proximal fluid delivery), and fractional excretion of lithium increased, fractional proximal tubular sodium reabsorption decreased, and absolute proximal tubular sodium reabsorption remained unchanged, suggesting increased delivery of isotonic fluid from the proximal tubule during URO infusion. In addition, a significant decrease in fractional distal tubular sodium reabsorption contributed to the natriuresis. In conclusion, URO improved sodium and urine output in cirrhotic patients with and without ascites by enhancing fluid delivery from the proximal tubules in addition to inhibiting fractional sodium reabsorption in the distal nephron.     

Lithium secretion in kidneys of amphibians and reptiles under hydrated conditions

Renal lithium transport was studied at different hydration levels in five species of anuran amphibians (Bufo bufo, B. danatensis, B. viridis, Rana ridibunda, and R. temporaria), two species of urodeles (Triturus vulgaris and T. cristatus) and four species of reptiles (lizards Eremias multiocellata, Lacerta vivipara, Trapelus sanguinolentus, and Teratoscincus scincus). Under dehydration conditions, Li+ was reabsorbed in the kidneys of amphibians ans reptiles, but to a lesser degree than in mammalian kidneys: the ratio of lithium clearance (CLi) to glomerular filtration rate (GFR)--fractional lithium excretion--in dehydrated animals was in the range 0.5-0.8. The transition to the hydrated state resulted in a cessation of net renal lithium reabsorption. Under condition of high hydration, all the animals studied, except for urodeles, showed net renal secretion of Li+, i.e., CLi exceeded GFR. The ratio CLi/GFR was 1.2-1.3 in hydrated anurans and 1.7-2.3 in hydrated lizards. In urodeles, this ratio was approximately unity. It is suggested that renal lithium secretion in hydrated amphibians and reptiles reflects fluid secretion in the proximal tubule, which is additional to the glomerular filtration mechanism of fluid delivery to nephron under water loading.     

Significance of the karyopyknotic index in the course control of hormone-treated prostatic carcinoma

Renal function was evaluated in 40 patients with fulminant hepatic failure, They were divided into two groups on the basis of glomerular filtration rates greater than 40 ml/min or less than 25 ml/min. A number of patients in group 1 had markedly abnormal renal retention of sodium together with a reduced free water clearance and low potassium excretion which could be explained by increased proximal tubular reabsorption of sodium. The patients in group 2 had evidence that renal tubular integrity was maintained when the glomerular filtration rate was greater than or equal ml/min (functional renal failure), but evidence of tubular damage was present when this was less than 3 ml/min (acute tubular necrosis).     

Effects of hyperventilation and hypocapnic/normocapnic hypoxemia on renal function and lithium clearance in humans

BACKGROUND: Using the renal clearance of lithium as an index of proximal tubular outflow, this study tested the hypothesis that acute hypocapnic hypoxemia decreases proximal tubular reabsorption to the same extent as hypocapnic normoxemia (hyperventilation) and that this response is blunted during normocapnic hypoxemia. METHODS: Eight persons were studied on five occasions: (1) during inhalation of 10% oxygen (hypocapnic hypoxemia), (2) during hyperventilation of room air leading to carbon dioxide values similar to those with hypocapnic hypoxemia, (3) during inhalation of 10% oxygen with the addition of carbon dioxide to produce normocapnia, (4) during normal breathing of room air through the same tight-fitting face mask as used on the other study days, and (5) during breathing of room air without the face mask. RESULTS: Hypocapnic and normocapnic hypoxemia and hyperventilation increased cardiac output, respiratory minute volume, and effective renal plasma flow. Glomerular filtration rate remained unchanged on all study days. Calculated proximal tubular reabsorption decreased during hypocapnic hypoxemia and hyperventilation but remained unchanged with normocapnic hypoxemia. Sodium clearance increased slightly during hypocapnic and normocapnic hypoxemia, hyperventilation, and normocapnic normoxemia with but not without the face mask. CONCLUSIONS: The results indicate that (1) respiratory alkalosis with or without hypoxemia decreases proximal tubular reabsorption and that this effect, but not renal vasodilation or natriuresis, can be abolished by adding carbon dioxide to the hypoxic gas; (2) the increases in the effective renal plasma flow were caused by increased ventilation rather than by changes in arterial oxygen and carbon dioxide levels; and (3) the natriuresis may be secondary to increased renal perfusion, but application of a face mask also may increase sodium excretion.     

A micropuncture study of the effect of parathyroid hormone on renal bicarbonate reabsorption

Renal micropuncture and clearance experiments were carried out in rats to study the effect of parathyroid hormone (PTH) on renal tubular HCO-/3 reabsorption. The rats were studied during an initial period of parathyroid deficiency (acute thyroidparathyroidectomy, TPTX) and during infusion of large amounts of bovine PTH. Under normal acid-base conditions, PTH administration to TPTX rats caused a significant rise in proximal tubular fluid HCO-/3 concentration (TFHCO-/3), a decrease in fluid reabsorption, and a fall in proximal HCO-/3 reabsorption from 94.0 to 88.2% (P less than 0.01). In control experiments with mannitol infusion, a comparable reduction in proximal fluid reabsorption occurred without any significant effect on intraluminal HCO-/3 concentration. During acute intravenous HCO-/3 loading, PTH inhibited proximal HCO-/3 reabsorption. However, no change in whole kidney HCO-/3 reabsorption was observed in these experiments or in the animals studied under normal acid-base conditions. The findings are consistent with the view that PTH inhibits proximal tubular HCO-/3 reabsorption with normal or high filtered loads of HCO-/3, but distal segments of the nephron are able to reabsorb the excess delivered from the proximal tubule. Measurements of urinary ammonium and titratable acid indicate that net acid excretion (NH+/4 + TA -- HCO-/3) increases significantly after PTH administration. These results do not provide support for the view that PTH excess causes metabolic acidosis by reducing renal acid excretion.     

Cyclosporine-induced hypertension and decline in renal function in healthy volunteers

OBJECTIVE: To investigate the effect of cyclosporine A (CsA; Sandimmun Neoral) on systemic and renal hemodynamics, tubular function, and sodium excretion in healthy volunteers. Furthermore, we studied whether CsA enhances the systemic and renal hemodynamic sensitivity to norepinephrine. METHODS: Eighteen healthy volunteers were administered 10 mg/kg CsA or placebo capsules in a double-blind fashion. The mean arterial blood pressure (MAP), renal vascular resistance (RVR), glomerular filtration rate (GFR), and renal clearances of lithium (CLi) and sodium (CNa) were measured for 8 h after ingestion of the capsules. Norepinephrine (2 microg/kg per h) was infused intravenously for 1.5 h into nine subjects. RESULTS: CsA increased the MAP by 17+/-2 mmHg. The GFR decreased by 18+/-2% (P < 0.001) and the RVR increased by 37+/-4% (P< 0.001) after ingestion of CsA. The CsA-induced increase in MAP preceded the CsA-induced fall in GFR. The rise in MAP was followed by an early 35+/-8/0 increase in CNa (P < 0.001). At the end of the 8 h study period, CNa decreased by 25+/-7% (P < 0.001). Using CLi, it was found that the initial natriuresis had been caused by a relative decrease both in proximal and in distal tubular reabsorption of sodium, whereas the late sodium retention was secondary to the CsA-induced fall in GFR. Infusion of norepinephrine increased the MAP, RVR, and filtration fraction, and decreased the renal plasma flow, without CsA having any additional effect. CONCLUSION: It was demonstrated that a single oral dose of CsA caused a rise in blood pressure and transient natriuresis, followed by a fall in GFR and antinatriuresis. Thus, the present study confirms and extends earlier observations that renal dysfunction and sodium retention are not the initiating events in CsA-induced hypertension. The study also affords evidence suggesting that such rises in blood pressure are not mediated by an increased sensitivity to norepinephrine.     

Trends in siting strategies

Renal function was measured by clearance technique before and after acute myocardial infarction (MI) induced by left coronary artery ligation in male Sprague-Dawley rats. The animals were anaesthetized with halothane-nitrous oxide, paralysed with pancuronium and artificially ventilated. All parameters were stable throughout the experiment in sham-operated time control animals (n = 8). After MI, rats developed left ventricular dysfunction with increased left ventricular end-diastolic pressure and decreased mean arterial pressure. MI produced antidiuresis and antinatriuresis without changes in glomerular filtration rate (GFR), lithium clearance or renal albumin excretion (n = 8). The antidiuretic and antinatriuretic responses to MI were similar in rats with chronic bilateral renal denervation (n = 5). Three additional rats with chronic bilateral renal denervation had cardiac arrest and were resuscitated with cardiac massage, i.v. lidocaine and intracardiac adrenaline administration. These animals showed a transient increase in urine flow rate, sodium and albumin excretion with maximum 30-60 min after resuscitation, while GFR and lithium clearance were normal. Since cardiac ischaemia and sympathetic stimulation are strong stimuli for the release of atrial natriuretic peptide (ANP), we examined if ANP (0.25, 0.50, and 1.00 microg kg(-1) min(-1), n = 8 per dose) affects urinary albumin excretion. ANP increased dose-dependently the urine/plasma concentration ratio of albumin relative to inulin, which suggests that ANP increases the glomerular permeability for albumin. We conclude that MI causes stimulation of renal tubular sodium and water reabsorption by a mechanism which is independent of intact renal innervation. MI does not produce any change in renal albumin excretion in rats, but transient albuminuria may be observed in rats following cardiac arrest and/or manoeuvres used in cardiac resuscitation. Since ANP produces albuminuria, we speculate that ANP may be an important mediator of albuminuria in states with elevated plasma concentrations of ANP.     

Cardiorespiratory and renal responses to arterial chemoreceptor stimulation by hypoxia or almitrine in men

1. The cardiorespiratory and renal responses to 3 h of normobaric whole-body hypoxic hypoxia (FiO2 = 0.12) as well as to arterial chemoreceptor stimulation by the oral administration of 100 mg almitrine bismesylate during normoxia were measured in 12 normotensive young men undergoing water diuresis. A third series of responses obtained under comparable conditions in the same subjects served as time controls. 2. No significant changes could be detected over time in the parameters measured in control experiments. The subjects reacted to both whole-body hypoxic hypoxia and to pharmacological chemoreceptor stimulation with significant increases in heart rate, tidal volume, minute ventilation and filtration-fraction. Overall renal vascular resistance rose significantly in hypoxia; increases in renal vascular resistance in almitrine experiments were not significant. 3. Renal fractional lithium excretion decreased significantly in response to whole-body hypoxic hypoxia and increased slightly in response to almitrine. Fractional urine and sodium excretion showed negligible changes. 4. The data indicate that, in humans, both almitrine and whole-body hypoxic hypoxia affect not only alveolar ventilation but also renal haemodynamics. 5. The renal electrolyte excretion pattern suggests that under certain circumstances (e.g. dilated renal vascular bed) acute, but well-tolerated, whole-body hypoxic hypoxia can simultaneously stimulate renal proximal tubular sodium reabsorption and inhibit distal tubular sodium reabsorption. The renal tubular responses also indicate that almitrine may influence renal tubular lithium reabsorption by, thus far, unknown mechanisms.     

Acute cholestasis-induced renal failure: effects of antioxidants and ligands for the thromboxane A2 receptor

BACKGROUND: Acute biliary obstruction is associated with the development of renal impairment and oxidative stress. The F2-isoprostanes, formed during oxidant injury, are renal vasoconstrictors acting via thromboxane (TX)-like receptors. We determined whether the formation of F2-isoprostanes is increased in experimental cholestasis and whether thiol containing antioxidants or ligands for the TXA2 receptor could improve renal function. METHODS: The effects on renal function of acute bile duct ligation (BDL) in the rat were studied for two days. The consequences of administration of N-acetylcysteine (NAC), alpha-lipoic acid (LA), the TX receptor antagonist (TXRA) BAYu3405, or placebo were then examined. RESULTS: BDL caused a reduction in creatinine clearance from 1.10 +/- 0.05 to 0.55 +/- 0.05 ml/min and sodium excretion from 52 +/- 3 to 17 +/- 3 micromol/hr. Urinary F2-isoprostanes increased from 14 +/- 2 to 197 +/- 22 pg/ml following BDL. Renal functional changes were ameliorated by NAC (creatinine clearance 0.73 +/- 0.05 ml/min), LA (0.64 +/- 0.03 ml/min), and a TXRA (0.90 +/- 0.15 ml/min); P < 0.05. Similarly, sodium excretion was increased from 17 +/- 3 micromol/hr (placebo) to 34 +/- 3 micromol/hr (NAC), 29 +/- 3 micromol/hr (LA), and 38 +/- 5 micromol/hr (TXRA); P < 0.005. Hepatic glutathione concentrations increased from 6.5 +/- 0.3 micromol/g (normal liver) to 8.8 +/- 0.5 micromol/g (NAC) and 7.7 +/- 0.3 micromol/g (LA), P < 0.01. However, only LA markedly inhibited F2-isoprostane formation (197 +/- 22 to 36 +/- 11 pg/ml creatinine clearance; P < 0.05). Urinary TXB2 excretion was elevated after BDL (2.2 +/- 0.5 to 111.1 +/- 20.3 pg/min) but was unaffected by NAC and LA. CONCLUSION: NAC, LA, and TXRA can partially prevent renal dysfunction in experimental cholestasis. The effects of the antioxidants are independent of their ability to inhibit lipid peroxidation or TX synthesis.     

Renal function and oxygen consumption during bacteraemia and endotoxaemia in rats

BACKGROUND: The hypothesis that renal failure during septic shock may occur as a result of hypoxia-related cell dysfunction was investigated in two rat models of distributive shock. METHODS: Pentobarbitone-anaesthetized rats received either a bolus (1 ml) of living Escherichia coli bacteria (hospital-acquired strain, 1 x 10(9) CFU/ml; BA-group, n = 7), or a 1-h infusion of endotoxin (E. coli O127.B8: 8 mg/kg; ET-group, n = 7), or saline to serve as time matched controls (C-group, n = 7). RESULTS: Urine flow in the BA- and ET-group reached a nadir at 1 h, but thereafter increased and reached values higher than control at 3 h. At this time point, renal oxygen delivery had decreased, in the BA-group mainly due to a fall in arterial oxygen content and in the ET-group to a fall in renal plasma flow (clearance of 131I-hippurate). However, renal oxygen extraction had significantly increased, by 31% in the BA and by 59% in the ET group, while renal oxygen consumption remained the same. Net tubular sodium reabsorption had decreased by 55% in the BA and by 25% in the ET group, due to a fall in glomerular filtration rate (clearance of creatinine). Hence, an excess oxygen consumption was found which was caused neither by an increased renal glucose release nor by the presence of an increased number of leukocytes stuck in the glomeruli. Renal tubular cells showed normal morphology. An indication that proximal tubular function in the BA and ET group remained largely intact were normal ATP levels, absence of urinary glucose, and a normal fractional excretion of sodium. However, since urine flow had increased in shocked rats at 3 h, water appeared selectively lost. CONCLUSIONS: Our data indicate that in rat models of septic shock renal failure is not caused by cortical hypoxia or a shortage of cellular energy supply.     

Renal function in cystic fibrosis with special reference to the renal sodium handling

Renal function was studied in 16 patients with cystic fibrosis, aged 5 to 19 years. The mean glomerular filtration rate and filtration fraction were increased compared to those in controls. Basal urinary sodium excretion as well as renal responses to oral and intravenous sodium loads were low, indicating an increased renal sodium reabsorption. Diluting capacity, measured as free water clearance, was decreased because of a low distal sodium delivery which might indicate an increased proximal sodium reabsorption.     

Albuminuria and overall capillary permeability of albumin in acute altitude hypoxia

The mechanism of proteinuria at high altitude is unclear. Renal function and urinary excretion rate of albumin (Ualb) at rest and during submaximal exercise and transcapillary escape rate of 125I-labeled albumin (TERalb) were investigated in 12 normal volunteers at sea level and after rapid and passive ascent to 4,350 m. The calcium antagonist isradipine (5 mg/day; n = 6) or placebo (n = 6) was administered to abolish hypoxia-induced rises in blood pressure. Lithium clearance and urinary excretion of beta 2-microglobulin were used to evaluate renal tubular function. High altitude increased Ualb from 2.8 to > 5.0 micrograms/min in both groups (P < 0.05). In the placebo group, high altitude significantly increased filtration fraction (P < 0.05), but this response was abolished by isradipine. Lithium clearance and urinary excretion of beta 2-microglobulin remained unchanged by hypoxia in both groups. Exercise did not reveal any further renal dysfunction. In both groups, high altitude increased TERalb from 4.8 to > 6.7%/h (P < 0.05). In conclusion, acute altitude hypoxia increases Ualb despite unchanged tubular function and independent of effects of isradipine on filtration fraction. The elevated TERalb suggests an overall increase in capillary permeability, including the glomerular endothelium, as the critical factor in high-altitude induced albuminuria.     

Indications for photocoagulation with an argon laser. I. Anterior eye segment

1. Renal lithium clearance in healthy men was elevated while the subject was reclining, decreased upon standing and increased upon lying down during 45-60 min tests. 2. Parallel changes in renal clearance of creatinine, sodium and potassium, and urine flow rate occurred in response to the changes in posture. 3. The findings demonstrate for the first time that posture is a factor that can influence lithium excretion. Control of posture during lithium excretion tests is recommended.     

Renal effects of aspirin and low dose methotrexate in rheumatoid arthritis

OBJECTIVES: The aim of this investigation was to study the glomerular and tubular effects of low doses (15 mg) of methotrexate in patients with rheumatoid arthritis with and without combined treatment with aspirin (2 g single dose). METHODS: Renal function was measured by the plasma clearance of EDTA labelled with chromium-51 (51Cr-EDTA) and mercaptoacetyltriglycine labelled with technetium-99m (99mTc-MAG-3). RESULTS: Clearance of 51Cr-EDTA was reduced from 98 (6) to 87 (5) ml/min (mean (SEM)) for patients receiving methotrexate only and further reduced to 76 (5) ml/min for patients receiving methotrexate and aspirin. This effect was reversible as 51Cr-EDTA increased to 85 (6) ml/min during continued treatment with methotrexate alone. Clearance of 99mTc-MAG-3 also decreased from 366 (18) to 315 (17) ml/min in patients receiving methotrexate alone and further to 295 (17) ml/min during treatment with aspirin and methotrexate. Continued treatment with methotrexate alone resulted in a further decrease in the 99mTc-MAG-3 clearance to 253 (17) ml/min. CONCLUSIONS: The study shows that treatment with low doses of methotrexate particularly when combined with aspirin affects glomerular and tubular function. These effects may be of clinical importance and renal function should therefore be monitored with more sensitive methods than serum creatinine as this may not reflect these changes.     

Increased serum lithium concentration secondary to treatment with tiaprofenic acid and fosinopril

OBJECTIVE: To describe a patient in whom the administration of tiaprofenic acid and fosinopril was associated with decreased lithium clearance, resulting in increased serum lithium concentrations. CASE SUMMARY: A woman treated with lithium for bipolar affective disorder was concurrently treated with tiaprofenic acid 200 mg tid for shoulder pain. Previously initiated treatment with fosinopril was maintained during this time. The urinary lithium clearance was decreased during this combination therapy, necessitating a reduction in the lithium dosage. DISCUSSION: Lithium is approximately 80% reabsorbed in the proximal tubule, and the addition of tiaprofenic acid may have resulted in enhanced tubular lithium reabsorption. The possible influence of concurrent fosinopril therapy may also have contributed to altered lithium pharmacokinetics in this case. CONCLUSIONS: Serum lithium concentrations should be monitored if patients taking lithium are treated with tiaprofenic acid.     

Long-term nephrotoxicity of cisplatin, ifosfamide, and methotrexate in osteosarcoma

The acute renal effects of chemotherapy are known, but long-term nephrotoxicity has rarely been investigated. The aim of the present study was to assess long-term renal function in children and adolescents who received at-risk chemotherapy, including cisplatin, ifosfamide, and methotrexate, to treat an osteosarcoma. Renal function tests [creatinine clearance, microalbuminuria, and renal excretion of sodium, potassium, chloride, calcium, magnesium (Mg), phosphorus (P), and uric acid] were prospectively performed 5.4+/-2.2 (+/-SD) years after chemotherapy (total cumulative dose: methotrexate 41+/-31 g/m2, ifosfamide 39+/-14 g/m2, cisplatin 674+/-188 mg/m2) in 18 children and adolescents. The results were compared with 13 normal volunteers matched for age and sex. Creatinine clearance, which was greater than 80 ml/min per 1.73 m2 in all patients, correlated with the total dose of ifosfamide (r=0.55, P<0.05) and cisplatin (r=0.48, P<0.05). Microalbuminuria was noted in 4 patients. Hypomagnesemia was present in 4 and hypercalciuria in 3 patients; renal excretion of P, Mg, and uric acid was higher in patients than in controls. Glomerular function was not significantly altered and only mild tubular dysfunction was present. Since renal excretion of P and Mg were increased in patients compared with normal volunteers and hypercalciuria was occasionally seen, divalent ion disorders are the most-likely potential complications.