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The multidrug transporter MDR-1 P-glycoprotein (Pgp) has been recently pointed out as an important mechanism underlying chemical interaction between drugs and many commonly ingested substances, including grapefruit juice (GFJ). Modulation of intestinal Pgp dependent transport by GFJ may lead to changes in bioavailability of drugs that are substrates of Pgp itself, by affecting their presystemic clearance. Since other cellular sites expressing Pgp and devoted to drug disposition, like kidney proximal tubules, could be involved in these pharmacokinetic interactions, we investigated the effect of GFJ on the expression and activity of Pgp in the human immortalized tubular cell line HK-2. Two flavonoid compounds related to GFJ, kaempferol and naringenin, were also tested for their effects on HK-2 Pgp. HK-2 cells cultured for 4 days in the presence of GFJ, showed a dose-dependent decrease in Pgp immunoblottable amount as well as a decrease in MDR-1 mRNA level, as shown by western blot analysis and RT-PCR, respectively. Both kaempferol and naringenin were also able to significantly decrease Pgp immunoblottable amount. To test whether the downregulation of HK-2 Pgp due to GFJ exposition could influence the cell sensitivity to drugs that are transported by Pgp itself, HK-2 cells precultured with GFJ were exposed to scalar concentrations of Cyclosporin A or Vinblastine and cell viability examined 36 hours later. The cytotoxicity of both drugs was increased. The calcein-AM test in untreated cells showed that GFJ, kaempferol or naringenin inhibited Pgp activity. Downregulation of Pgp as well inhibition of its function by GFJ or its related components in tubular cells could have a role in changing disposition kinetics of some important therapeutic agents.

Matrix metalloproteinases (MMPs) are enzymes with metal ion-dependent activity that degrade extracellular matrix (ECM) glycoproteins. MMPs play a vital role in various biological processes, such as embryogenesis, tissue remodeling, angiogenesis, and wound healing, and in certain disease processes, for example, metastasis of cancer cells. Following their activation, MMPs are believed to modulate both cell-cell and cell-matrix interactions, which in turn regulate cellular differentiation, migration, proliferation, and cell survival. Being involved in pericellular proteolysis, they maintain a gradient of ECM proteins by balancing ECM synthesis and degradation. Such a balance is critical for various mammalian developmental processes during embryonic life and also for the homeostasis of various organs and reparative processes in later life. During the past two decades the role of MMPs in the morphogenesis of various organs, including that of the metanephros, has been investigated extensively. Mammalian nephrogenesis comprises a series of intricate events characterized by a sustained remodeling and turnover of ECM, suggesting a potential role of MMPs in renal development. Conceivably, reciprocal inductive epithelial-mesenchymal interactions that take place at the very commencement of nephrogenesis are modulated by a number of ECM proteins. Their expression, especially at the epithelial-mesenchymal interface, are critical for metanephric development, and such a strategic expression is likely to be modified by a number of different macromolecules that exhibit spatiotemporal and stage-specific expression. Among them the most suitable candidate that could exert such a control would be MMPs. This review addresses the current status of our understanding of the functions and the role of MMPs in renal development.

Background: Low molecular weight (LMW) proteins have been proposed for renal function assessment. This study aimed to ascertain the usefulness of tumor-associated trypsin inhibitor (TATI), a LMW protein (6.200 d), as a glomerular filtration rate (GFR) marker. The results were compared with those of beta2-microglobulin and of creatinine (Cr)., Methods: Renal handling of TATI labelled with 125I was first studied in rats. Then, in 198 patients, serum TATI levels and GFR (99mTc-DTPA clearance, bladder cumulative method) were determined. To evaluate urine excretion, the fractional TATI clearance was determined in 63 patients., Results: In rats, total body scan showed a large amount of radioactivity in the kidneys, but not in other organs. The duration of radioactivity demonstrated a peak-time of 11 min. In human beings, the relationship between TATI and GFR was similar to that of beta2-microglobulin and Cr. The increase in TATI with declining renal function was statistically significant, vs. patients with GFR > 100 mL/min, already in the group with GFR 80-100 mL/min (p < 0.05, Bonferroni-Dunn test). The beta2-microglobulin increase was significant in the group with GFR 60-80 mL/min and of Cr in the group with GFR 40-60 mL/min. In patients with renal failure (GFR < 20 mL/min) TATI increased, vs. patients with GFR > 100 mL/min, 13x, beta2-microglobulin 8x and Cr 5x. Urinary excretion of TATI, expressed as fractional clearance, was very low increasing when GFR fell < 40 mL/min., Conclusions: The kidney plays an important role in the handling of TATI. When GFR fell, the increase in blood levels of TATI was sooner and higher than that of beta2-microglobulin and CR. Consequently, TATI can be added to the group of renal function markers.

P-glycoprotein (Pgp), the MDR-encoded membrane transporter, is physiologically expressed in normal tissues with excretory functions, including kidney proximal tubules. In a preliminary report we have shown that HK-2, an immortalized cell line from normal human proximal tubule, expresses a functional Pgp and may be considered a valuable model for in vitro investigations on the Pgp role(s) in human renal pathophysiology. The present investigation was designed to further characterize the properties of HK-2 Pgp by exploring its responsiveness to a variety of exogenous or endogenous modulators. HK-2 cells were cultured in Dulbecco's modified Eagle's medium/Ham's F-12 supplemented with 5% FCS in the absence or in the presence of modulators. Pgp mRNA expression was studied by RT-PCR and the amount of Pgp was determined by Western blotting. Pgp activity was assessed by intracellular rhodamine-123 (R-123) accumulation. RT-PCR showed that HK-2 cells express MDR-1, but not MDR-3. Both MDR-1 Pgp and MDR-1 mRNA were significantly increased in cells cultured in the presence of cyclosporin A (CsA), 1,25(OH)(2)D(3), platelet activating factor, dexamethasone (Dex), or aldosterone. Verapamil (Vp), cimetidine, and trimethoprim did not affect HK-2 Pgp expression. Conversely, 2-acetylaminofluorene strongly downregulated Pgp expression. Vp, CsA, 1,25(OH)(2)D(3) and Dex significantly increased R-123 intracellular retention, indicating the inhibition of Pgp-mediated transport. Drug-pretreated, Pgp-overexpressing cells showed increased Pgp activity and were less susceptible to toxic concentrations of CsA. MDR-1 Pgp in HK-2 appears to be responsive to many compounds, including classical Pgp inhibitors and putative physiological substrates, but some of its pharmacological properties are different from those described in other experimental, in particular nonhuman, cell models.

The aim of this study was to evaluate the renal effects of cardiac angiography performed with three low-osmolar contrast media (CM): iopromide (IPR), ioversol (IVR) and ioxaglate (IOX). IPR and IVR are non-ionic CM, IOX is an ionic CM. Different parameters of renal function were determined before and 6, 24, 48, 72 hrs after angiography in 45 patients: 15 patients were examined with IPR, 15 with IVR and 15 with IOX. Glomerular effects--Plasma creatinine increased slightly at the 24th hour after IVR and IOX and at 48 hours after IOP. A significant increase in plasma beta2-microglobulin was observed, at the same time, only after IOX. A significant decrease in creatinine clearance was found at 6 hours after IOX. No significant variations in glomerular filtration rate (GFR) and in effective renal plasma flow were found at 48 hours after cardiac angiography; while filtration fraction was significantly reduced after IOP and IOX. Tubular effects--A marked decrease in sodium clearance and a relevant increase of urinary activities of different tubular enzymes were found after cardiac angiography with all CM, but were more evident after the ionic CM IOX, than after the two non-ionic agents. These tubular effects reached the maximum between 6 and 24 hours and returned to baseline within 72 hrs after cardiac angiography. In conclusion, slight glomerular effects were observed mainly after IOX. A reversible tubular malfunction was found with the three low-osmolar CM and was more evident after ionic CM IOX. thus suggesting that other mechanisms, besides osmolarity, play a role in tubular toxicity due to CM. In no patient did the glomerular and tubular effects of CM have a clinical relevance.

P-glycoprotein (PGP) is an efflux pump physiologically expressed in the apical membrane of the proximal tubular cells. PGP may play a role in the elimination of exogenous substances such as chemotherapeutic drugs, calcium channel blockers and immunosuppressors. The involvement of renal PGP in the transport of endogenous substrates is under investigation. HK-2 is an immortalized proximal tubule cell line from normal adult human kidney, reported to retain a phenotype indicative of a well-differentiated state. No data regarding expression and/or activity of PGP in this cell line are available. The aim of this study was to ascertain the usefulness of HK-2 cell line to investigate the properties and roles of PGP in proximal tubular cells. PGP expression in HK-2 cells was determined by immunoblotting analysis using the monoclonal antibody C219. The activity of PGP was assessed by measuring the transport of the fluorescent probe Rhodamine 123 (R-123) in intact cell monostrates. The interactions of putative PGP modulators, including verapamil and cyclosporin A were also evaluated. Western blot revealed a C219 immunoreactive band of about 150 kDa consistent with the presence of PGP. HK-2 cells preloaded with R-123 rapidly effluxed the dye, the efflux being inhibited by verapamil. Verapamil and, to a major extent cyclosporin A, significantly increased R-123 intracellular accumulation. PGP immunoblottable amount was increased when cells were cultured in the presence of either cyclosporin A or dexamethasone. The results suggest that the HK-2 cells, among the various differentiation features of proximal tubules, retain also the expression of a functional PGP in their membranes and that both PGP activity and expression may be modulated by drugs. Therefore, HK-2 line appears a suitable and promising tool for the study in vitro of renal transport processes dependent on PGP.

Glucose is the main source or energy for the mammalian cells and its entry is mediated via various transporters. About 7 facilitative (GULT-1 to -7) and 2 concentrative glucose transporters (SGLT-1 and -2) have been identified. The facilitative glucose transporters allow the glucose entry into the cell interior due to the concentration gradient and the latter via the Na+-dependent electrochemical gradient. They have similar structural motifs with 12-14 putative transmembrane domains with a predicted protein size varying from 50 to 76kDa. Some of the facilitative glucose transporters (GLUT-1, -2, -4 and -5) and both the sodium glucose co-transporters (SGLT-1 and -2) are expressed in the kidney. The transporters that are involved in the major transport of glucose in the kidney include GLUT-2 and SGLT-2. They are of high capacity and low affinity type and are expressed in the S1 segment of the proximal tubule. All the transporters expressed in the kidney are developmentally regulated. The mRNA expression of renal GLUTs is variable during the fetal and postnatal periods. On the other hand the mRNA of SGLTs increases steadily from the fetal period to maturity along with the increase in their functional activity, i.e., glucose uptake. Recent studies indicate that the SGLTs are believed to selectively regulate tubulogenesis since they are expressed in the metanephric tubules very early in the embryonic life in mammals.

Beta2-microglobulin (beta2M) is highly accumulated by the kidneys of normal rats. The aim of this study was to verify if uninephrectomy can modify the renal uptake of labeled beta2M. For this purpose the radioactivity of plasma and those of the remaining kidney, liver and urine have been measured in uninephrectomized rats (NX) and in controls (C) at different times after the injection as i.v. bolus of 131I-beta2M. The experiments were performed in 114 Sprague-Dawley male rats. Fifty seven animals underwent right nephrectomy, the other animals being the C. NX and their C were divided in 3 groups, studied 2, 4 and 6 weeks after nephrectomy, respectively. Part of the animals were sacrificed 12 min after the injection of labeled beta2M (peak-time, i.e. time of highest kidney accumulation of 131I-beta2M in the normal rat) and part 10 min later. The results demonstrate that: - uninephrectomy increases plasma retention of 131I-beta2M - kidney uptake (total and per gram) is always higher in NX - liver uptake (much lower than that of kidney) is not influenced by uninephrectomy - urine excretion of radioactivity is minimal in both NX and C. The behavior of beta2M is similar to that we previously observed with alpha1-microglobulin and lysozyme. The higher kidney content of some low mw proteins after uninephrectomy could play a role in the progressive reduction of renal function determined by the reduction of renal mass.

Introduction: Beta 2 microglobulin (beta2M) is filtered by the glomeruli and reabsorbed by the proximal tubular cells where it is metabolized. Its plasma concentration increases with decreasing renal function., Aim: To compare serum creatinine (Cr) and serum beta2M as markers of GFR., Patients and Methods: In 160 adult patients, with various kidney diseases and different GFR, serum Cr (autoanalyzer), serum beta2M (RIA) and GFR (bladder cumulative method using 99mTc-DTPA as glomerular tracer) were measured in the same day., Results: A linear relationship was observed between In GFR and both In serum Cr (lnCr=3.112-0.716 lnGFR; r=0.92) and ln serum beta2M (lnbeta2M= 4.274-0.814 lnGFR; r = 0.90). With decreasing GFR the increase in serum beta2M was higher than that of serum Cr (see regression coefficients that are significantly different). The normal upper limit of serum Cr corresponds to a GFR 48.1 mL/min while that of serum beta2M to a GFR 65.0. With decreasing GFR the increase of serum beta2M occurs before than that of serum Cr., Conclusions: With declining renal function, serum beta2M increases more and before than serum Cr. Serum beta2M is a good endogenous marker of GFR, better than serum Cr.

Chromogranin A (CGA) is a low MW (49,000) acidic hydrophilic protein. It is synthesized in the chromaffm granules of the neuroendocrine cells, and has been found circulating in the blood of healthy subjects. The aim of this study was to assess the relationship between serum levels of CGA and renal function. One hundred two renal patients (45 M and 57 F; age 14-76 years, mean 52) participated in the study. Glomerular filtration rate (GFR) was measured by the bladder cumulative method, using 99mTc-DTPA as a tracer. Blood CGA was determined by RIA. Plasma creatinine, beta2microglobulin (beta2m) and tumor associated trypsin inhibitor (TATI) were also determined. The reduction in renal function was associated with an increase in all of the above studied parameters. In patients with advanced renal failure (GFR <20 mL/min) CGA levels increased by 22-fold as compared to the patients with normal renal function (GFR> 100 mL/min). The other studied parameters were also increased but to a lesser degree, e.g., TATI 14-, beta2m 8- and creatinine 5-fold. The results of this study demonstrate that renal handling of the CGA is similar to other low MW proteins, and it accumulates in the blood in renal failure.

Aldo-keto reductases (AKRs) are a family of monomeric oxido-reductases with molecular weight ranging from 35-40 kDa and currently includes upwards of 60 members. They are expressed in a wide variety of tissues, where they catalyze the NADPH-dependent reduction of various aliphatic and aromatic aldehydes and ketones. The functions of most of the family members are not well defined. But two members, aldehyde reductase (AKRIA) and aldose reductase (AKRIB), have been extensively studied. The latter has received the most attention since being relevant to the complications of diabetes mellitus. It is up-regulated during hyperglycemia, and at the same time there is an increased activity of the sorbitol pathway and non-enzymatic glycation of proteins with ensuing damage in various tissues. It is developmentally regulated in the ocular lens, and is believed to modulate lens fiber morphogenesis during fetal life. Unlike the other AKR family members that are ubiquitously expressed, recently a renal-specific oxio-reductase has been described that is expressed exclusively in the proximal tubules. Although, it has no homology with other AKR members, it binds to NADPH with high affinity and is up-regulated in streptozotocin-induced diabetes in mice. It is also developmentally regulated and seems to selectively modulate renal tubulogenesis during embryonic life.

The aim of this study was to evaluate the relationship between renal function and the blood level of some tumor markers that are low molecular weight proteins, that is, tumor-associated trypsin inhibitor (TATI), squamous cells carcinoma antigen (SCC), cytokeratin 19 fragments (CYFRA 21-1), tissue polypeptide antigen (TPA), and M3-specific epitope of tissue polypeptide antigen (TPS). In 41 adult patients without evidence of neoplastic disease, glomerular filtration rate (GFR) and the blood levels of creatinine and of the tumor markers were determined. The decrease in GFR was accompanied by an increase in serum levels of TATI, SCC, CYFRA 21-1, and TPA. The serum level of tumor markers increased particularly when GFR fell below 40 ml/min. On the basis of these results, the renal function must be taken into account for the clinical evaluation of the studied tumor markers.

The aim of this study was to evaluate the early effects of high and low-osmolar contrast media on glomerular function in rats by using a new method based on the measurement of the urinary excretion of 99mTc-DTPA. Thirty-six Sprague-Dawley male rats were examined: nine rats were injected with diatrizoate (ionic high-osmolar contrast medium), nine rats with iohexol (nonionic low-osmolar contrast medium), and nine rats with saline as controls. The urinary excretion of 99mTc-DTPA in the first minutes after i.v. injection was assumed as an index of glomerular filtration rate. A lower urinary excretion of 99mTc-DTPA was found in rats treated with contrast media in comparison with control rats. This effect was more evident after diatrizoate but was statistically significant also after iohexol. In conclusion, a reduction in the glomerular filtration rate probably occurs in the first few minutes after contrast media administration. The measurement of urinary excretion of 99mTc-DTPA could be a simple method to detect acute glomerular effects due to contrast media or to other drugs.

The aim of this study was to evaluate the usefulness of the measurement of urinary excretion of the brush-border enzyme gamma glutamyl-transferase (GGT), in comparison with that of alanine aminopeptidase (AAP), as a marker for tubular toxicity due to contrast media (CM). Urinary activities of AAP and GGT were measured prior to the administration of CM and 1, 3 and 5 days after in forty-nine adult renal patients undergoing a radiological examination with intravascular administration of CM. The behavior of GGT was similar to that of AAP. In fact, urinary activities of both AAP and GGT increased greatly after CM. This effect was maximal on the 1st day and statistically significant for both enzymes. Furthermore, on the 1st day a relevant increase of enzyme activity (at least +50% over the basal value) was observed in the same number of patients (67%) for AAP and GGT. The concordance between GGT and AAP variations was high and statistically significant. Finally, different variables (osmolarity, dose of CM, and baseline renal function of the patients) had a similar effect on urinary excretion of AAP and GGT. The repeatability of duplicated determinations of GGT resulted better than that of AAP. In conclusion, the good concordance of the results of GGT with those of AAP justifies the use of GGT as a marker for tubular effects due to CM. Furthermore, the measurement of GGT has a better repeatability than that of AAP.

TATI (tumor associated trypsin inhibitor) is a low molecular weight protein employed as a tumor marker. To evaluate the role of the kidney in the clearance of TATI, we studied the rat kidney uptake of 125I-TATI. Total body scan demonstrated a high radioactivity in the kidneys of the rats and none in other organs. The relationship between serum TATI and glomerular filtration rate (GFR) was studied in man. For comparison serum beta 2-microglobulin (beta 2M) arid plasma creatinine were also determined. The decrease in GFR was accompanied by an increase in the other parameters. Serum TATI increased in patients with renal failure (GFR < 20 mL/min) 12.4 times with respect to subjects with normal renal function (p < 0.001, non-parametric Mann-Whitney test), beta 2M increased 7.6 times (p < 0.001) and creatinine 4.7 times (p < 0.001). The increase in TATI is statistically significant already in patients with GFR 60-40 mL/min (p < 0.005). These results suggest that TATI is handled by the kidney. It is a sensitive marker of reduction in renal function.

The aim of this study was to evaluate the possibility of predicting creatinine clearance (CCr) from plasma creatinine (PCr) and body com-position analysis by means of electrical impedance, thereby avoiding urine collection. Fat-free mass (FFM) and body cell mass (BCM) were measured in 50 renal patients (M29, F21; aged 17-74 years; mean 52.6) with different degrees of renal function (PCr 0.8-9.0 mg/dL, mean 2.13) by using a tetrapolar impedance plethysmograph. The relationship between 24 h-urinary creatinine excretion (UCr) and FFM and BCM was evaluated in 20 of the above reported patients (MI I, F9; PCr 0.8-9.0 mg/dL, mean 2.27). The mean ratio of 24 h UCr/FFM was 25.6 mg/kg in males and 22.5 in females and that of 24 h UCr/BCM was 51.9 mg/kg in males and 48.1 in females. CCr was estimated in the remaining 30 patients (M18, F12; PCr 0.9-8.8 mg/dL, mean 2.04) from individual FFM and BCM values and PCr. In the same patients CCr was predicted also according to the Cockcroft and Gault formula and, for comparison, was measured with the conventional method by collecting 24 h urine, CCr predicted from the values of FFM and BCM gave a good estimate of 24 h CCr, more precise than that of Cockcroft and Gault CCR. Also, the repeatability of the predicted CCr was clearly better than that of 24 h CCr. In conclusion, creatinine clearance can be predicted, avoiding urine collection, from plasma creatinine and body composition analysis by means of electrical impedance.

In order to quantify the decline in renal function, repeated measurements of GFR are necessary. The conventional procedure is cumbersome and time expending so that alternative clearance techniques are needed. We propose a simple isotopic technique for measuring GFR by 99mTc-DTPA and external counting of the bladder by gamma camera (bladder cumulative method). This consists in the measurement by external counting of the amount of labelled filtration marker accumulated in the bladder after intravenous bolus injection. In 36 adult patients with all degrees of renal impairment (serum creatinine 0.9-9.3 mg/dL) GFR was measured twice, once by the conventional method (continuous i.v. infusion of the filtration marker and urine collection by spontaneous voiding) and once by the bladder cumulative method. 99mTc DTPA was used in performing both methods. A satisfactory agreement was found between GFR measured by bladder cumulative method (BCM) and by conventional method (CM). The BCM averaged 60.0 +/- 36.7 mL/min and the CM +/- SD averaged 62.8 +/- 36.6 mL/mm. The ratio BCM/CM +/- SD was 0.95 +/- 0.14 (y = 0.94x + 1.14; r = 0.94). Considering the 17 patients with renal insufficiency (GFR < 60 mL/min) an even better agreement between the two methods was found. In these patients the BCM averaged 28.4 +/- 17.2 mL/min; the CM averaged 29.1 +/- 16.6 mL/min; and the ratio BCM/CM was 0.96 +/- 0.08 (y = 1.03x - 1.47; r = 0.99). The day-to-day variability of BCM, studied in another 11 patients, was lower than that of creatinine clearance (variation coefficient for duplicate measurements: 7.18 +/- 6.65 SD for BCM, 15.68 +/- 8.80 SD for CM, p < 0.01). The bladder cumulative method is a simple procedure for the accurate measurement of GFR, in particular in patients with renal insufficiency. It represents a reliable tool for estimating the decline in renal function.

The aim of this study was to evaluate the agreement between the glomerular filtration rate (GFR) and an estimate of creatinine clearance (CCr), calculated from the values of body cell mass (BCM) and of plasma creatinine (PCr), thus avoiding urine collection. The value of BCM was obtained from the measurement of total body impedance in 80 renal patients. The relationship between 24-hour urinary creatinine excretion and BCM was evaluated in 30 of these patients. Body cell mass CCr (ml/min) was then calculated in each of the remaining 50 patients. For comparison, 24-hour CCr was measured in the same patients. The correlation coefficient of BCM CCr with GFR was 0.961, while that of 24-hour CCr with GFR was 0.869. Also, the agreement with GFR was better for BCM CCr than for 24-hour CCr. In conclusion, creatinine clearance predicted from body cell mass and plasma creatinine is a better indicator of renal function than measured 24-hour creatinine clearance.

Tumor-associated trypsin inhibitor (TATI) is a low molecular weight protein employed as tumor marker. To evaluate the role of the kidney in the clearance of TATI we studied the relationship of serum TATI with the glomerular filtration rate (GFR), and for comparisons the relationships of beta 2-microglobulin (beta(2m)) and creatinine with GFR. Urine excretion and renal extraction of TATI were also determined. The decrease in GFR was accompanied by an increase in blood levels of TATI, beta(2m) and creatinine. Serum TATI increased 12.4 times in patients with renal failure (GFR < 20 ml/min) with respect to subjects with normal renal function (P < 0.001, non-parametric Mann-Whitney test), while beta(2m) increased 7.3 times (P < 0.001) and creatinine 4.7 times (P < 0.001). In patients with GFR 60 to 40 ml/min, only the increase in TATI was statistically significant (p < 0.005). Renal excretion of TATI was low but it increased progressively in renal failure. Renal extraction ranged from 13% to 41%, for a mean 24.87. These results suggest that TATI is handled by the kidney and that it is a snesitrive marker of reduction in renal function.

The aim of this study is to evaluate the nephrotoxicity of two contrast media (CM), with different physicochemical characteristics: diatrizoate (ionic high-osmolar), iopromide (nonionic low-osmolar). Intravenous urography was performed in 34 patients: 17 were examined with diatrizoate and 17 with iopromide, randomly assigned. Different parameters of glomerular and tubular function were measured before and at 6, 24, and 48 h after urography. Both contrast media induced a reversible increase of urine enzymes, which was significantly higher after diatrizoate. In particular, diatrizoate determined a relevant increase of brush border enzymes gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP) and of cytosolic enzyme lactate dehydrogenase (LDH), while, after iopromide increases of urinary enzymes were less evident and were significant only for GGT and ALP. In addition, diatrizoate affected other tubular functions (clearances of phosphorus and uric acid) and slightly decreased glomerular function in a few patients. In no case did these glomerular and tubular effects have a clinical relevance. In conclusion, the nonionic low-osmolar contrast medium iopromide appeared less nephrotoxic than diatrizoate. The cost-benefit ratio needs further examination.

The aim of this study is to evaluate the effects of contrast media on both tubular and glomerular function. Different parameters of tubular and glomerular function were determined before and at 1, 3, and 5 days after the intravascular administration of contrast media in 100 adult renal patients (plasma creatinine 0.6-10.8 mg/dL, mean: 1.3). Urinary activities of five tubular enzymes (alanine aminopeptidase, gamma-glutamyltransferase, alkaline phosphatase, lactate dehydrogenase, N-acetyl-beta-D-glucosaminidase) increased significantly on the first day after the administration of contrast media, indicating a tubular damage. Glomerular filtration rate and the conventional tests of glomerular function (plasma creatinine, creatinine clearance, and urinary proteins) presented only slight variations after the administration of contrast media. In conclusion, contrast media principally affected the renal tubule (as demonstrated by enzymuria), while their effects on glomerular function were very mild.

The effects of the treatment with benazepril (BEN) on blood pressure and renal function have been evaluated in nine adult patients affected by mild to moderate hypertension. BEN was administered orally, at a single daily dose of 10 mg for four weeks. BEN induced a clinically significant decrease in blood pressure, from a mean basal value of 155/98 mm Hg (+/- 15/7 SD) to 146/92 (+/- 12/9) after seven days of therapy and 139/88 (+/- 11/10) after 28 days in supine position and from 152/104 (+/- 17/6) to 144/97 (+/- 14/6) after seven days and 145/99 (+/- 16/9) after 28 days in a standing position. Plasma urea, creatinine, uric acid and their clearances as well as urine enzymes (GGT, ALP, LDH) remained stable throughout the duration of the therapy. GFR showed a modest increase, from 61.3 +/- 13.2 ml/min to 65.3 +/- 18.3 ERPF showed a slightly more evident increase, from 246.7 +/- 68.1 ml/min to 276.9 +/- 75.6. Plasma levels of glucose, cholesterol and triglycerides were not influenced by BEN. Plasma potassium increased from 4.0 +/- 0.3 to 4.4 +/- 0.5 mEq/liter. The results of this study indicate that BEN is a safe and effective antihypertensive agent that does not cause any adverse renal or metabolic effects.

The effects of diltiazem (DTZ) treatment on blood pressure, renal function and renal hemodynamics over a six week period of therapy were evaluated in 14 adult patients with mild to moderate hypertension. Their creatinine clearances were 64 to 153 ml/min. After a week of treatment with placebo, DTZ was administered orally at a daily dose of 120 mg b.i.d. Blood pressure decreased from a mean value of 152/99 mm Hg (+/-13/6 SD) up to 144/91 (+/-17/8, P < 0.005) in the supine position and from 149/107 (+/-14/9) to 141/96 (+/-16/9, P < 0.005) in standing position. Heart rate decreased from 74 (+/-9) to 69 (+/-8). Plasma urea, creatinine, uric acid and their clearances as well as GFR and ERPF remained stable throughout the trial. Plasma glucose increased from 81 (+/-15) mg/dl to 98 (+/-30, P < 0.05) and plasma potassium decreased from 4.0 mEq/liter to 3.7 (+/-0.3, P < 0.005). Plasma cholesterol and triglycerides were unmodified. DTZ is an effective antihypertensive agent which does not significantly affect renal function. The effects on plasma glucose and potassium require periodical check-ups of these parameters.

Alpha-1-microglobulin (alpha 1M) is highly accumulated by the kidneys of normal rats. Aim of this study has been to verify if uninephrectomy can modify this behaviour. For this purpose the radioactivity of the remaining kidney and those of plasma and urine have been measured in uninephrectomized rats after IV injection of radioiodinated alpha 1M. The experiments have been performed in 100 Sprague-Dawley male rats. Fifty animals underwent right nephrectomy, the others being the controls. Uninephrectomized rats and their controls have been divided in 3 groups, studied 4, 14 and 28 days after surgery, respectively. All the animals were injected with human alpha 1M labelled with iodine-131. They were sacrificed in part 18 minutes after the injection of labelled alpha 1M (time of highest kidney accumulation in the normal rat), and in part 28 minutes after the injection. Uninephrectomy increased plasma retention of labelled alpha 1M. Kidney uptake (total and per gram) was always higher in uninephrectomized animals. Similarly, urine radioactivity was higher in uninephrectomized rats. These results demonstrate that uninephrectomy remarkably increases the accumulation of alpha 1M in the remaining kidney.

Unlabelled: EFFICACY, renal effects and nephrotoxicity of the cephalosporin cefonicid (CEF) were evaluated in 11 adult patients with urinary tract infection and varying renal function (creatinine cl 19-161 ml/min, mean 75). CEF was administered i.m. for 7 days at a daily dose adjusted to renal function of the patients., Efficacy: At the 4th day and at the end of the treatment urine cultures were negative in all cases; a recurrence of the infection was observed in 4 patients 10 days after completion of therapy. Renal effects and nephrotoxicity: CEF neither modified plasma creatinine, urea, uric acid and their renal clearances nor glomerular filtration rate. Only the urinary enzyme activity of alanine aminopeptidase increased slightly at the end of the therapy. It returned to basal values in the post-treatment period. Urinary enzyme activities of gamma-glutamyltransferase, alkaline phosphatase, N-acetyl-beta-D-glucosaminidase and lysozyme were unmodified during and after treatment with CEF. These results indicate that CEF is an effective antimicrobial agent which does not influence renal function, nor cause nephrotoxic effects.

Renal function was assessed in 20 (11 female and 9 male, age 21-76 years, mean 53) renal patients with a creatinine clearance 25-145 ml/min, mean 95, to evaluate the effects of iohexol, a non-ionic low-osmolar contrast medium. Intravenous urography was performed in 16 patients and computed body tomography in 4, using a dose of iohexol ranged between 0.6-3.3 (mean 1.17) g/kg b.w. Different parameters of renal function were determined in the week preceding and 1, 3 and 5 days after the administration of iohexol. The principal renal effect of iohexol was an increase of urinary alanine aminopeptidase, gamma-glutamyltransferase, lactate dehydrogenase, alkaline phosphatase and N-acetyl-beta-D-glucosaminidase. The maximum increase of enzymuria was observed on day 1 after the administration of iohexol. In most cases enzymes returned to base-line values within 3 days. No relevant variation of renal hemodynamics (glomerular filtration rate and effective renal plasma flow) was observed after iohexol. In conclusion, iohexol can increase of urinary enzymes, but the effect is rapidly reversible and is not accompanied by a clinically significant impairment of renal hemodynamics.

The efficacy, renal effects and nephrotoxicity of a short course of treatment with azthreonam were evaluated in 11 adult patients with urinary tract infection. Azthreonam was administered for 5 days at a daily dose adjusted to the residual renal function of the patients. In the pre-treatment period, during treatment and 10 days after completion of therapy, urine cultures, urinalysis and routine renal function tests (clearance of creatinine, urea and uric acid) were performed and urinary enzymes (alanine-aminopeptidase, gamma-glutamyl-transpeptidase, N-acetyl-beta-D-glucosaminidase, lysozyme) were determined. Renal haemodynamics (glomerular filtration rate and effective renal plasma flow) were measured in the pretreatment period and on the 5th day of therapy. The results confirm the efficacy of azthreonam for treatment of urinary tract infection. Results of renal function tests and measurements of urinary enzymes remained unchanged during and after treatment with azthreonam. These data support the conclusion that azthreonam is an effective antimicrobial agent which does not influence renal function or cause nephrotoxic effects.

Aprotinin (Ap), a low-molecular-weight polypeptide (6500 dalton), is a protease inhibitor which is electively and stably accumulated in the kidney. In 112 adult patients, with either uni- or bilateral renal disease with different degrees of renal impairment (from normal GFR to advanced renal failure), renal scans were performed by means of Ap labelled with 99mTc. Highly satisfactory renal scans were obtained in all patients. In 20 patients with renal failure (serum creatinine 1.8-8.5 mg/dl, mean 4.7) a comparison was made of the renal scans obtained with 99mTc-Ap and with 99mTc-DMSA. 99mTc-Ap was slightly better than 99mTc-DMSA, especially in patients with far advanced renal failure. Some aspects of the pharmacokinetics of 99mTc-Ap were studied in 72 cases. In 22 of these patients plasma clearance of 99mTc-Ap was determined by the single injection method using a two-compartment model. In patients with GFR greater than 90 ml/min plasma clearance of 99mTc-Ap was 67.6 +/- 8.4 SD ml/min. A good correlation was observed between plasma clearance of 99mTc-Ap and GFR (r = 0.74). After IV injection 99mTc-Ap was stably fixed by the kidney. Renal radioactivity remained stable between the second and eighth hour after the injection. Urinary excretion of radioactivity measured in 35 patients in the first and in the second 2-h interval after IV injection of 99mTc-Ap was negligible in all patients (2.7 +/- 1.5 SD percent of the dose in the first 2 h; 2.8 +/- 1.4 SD between the second and fourth hour). 99mTc-Ap is an excellent agent for renal imaging. It also seems promising for renal function studies.