Characteristics of acute glomerulonephritis associated with human parvovirus B19 infection.

BACKGROUND: Acute glomerulonephritis (AGN) is a rare complication of human parvovirus B19 (HPB19) infection. The clinical and pathological features of AGN associated with HPB19 (HPBAGN) have not yet been fully elucidated. METHODS: We analyzed 10 HPBAGN cases, focusing on their clinical and serological features. We also performed histopathological examinations of renal biopsy specimens obtained from three of the 10 patients on day 15, 19 and 23, respectively, after the onset of symptoms. The phenotype of the glomerular infiltrating leukocytes in HPBAGN was determined by immunohistochemical staining and compared with that of glomerular infiltrating leukocytes in poststreptococcal AGN (PSAGN) and lupus nephritis. RESULTS: The clinical course and laboratory data of the HPBAGN patients revealed female preponderance (male = 0, female = 10), erythema in 9 of the 10 patients, leukopenia in 3, positive antinuclear antibody titer in 4, hypocomplementemia with low levels of C3, C4, and CH50 in 9, and liver dysfunction in 7. Endocapillary hypercellularity of leukocytes was demonstrated in all three patients who underwent renal biopsy. In comparison with PSAGN and lupus nephritis with crescents there were less neutrophil in HPBAGN compared to marked macrophage infiltrates that were equally intense in both the control and the HPBAGN group. CONCLUSIONS: Our findings indicate that HPBAGN is characterized by female preponderance, erythema, leukopenia, positive antinuclear antibody titer, and hypocomplementemia, and that minor neutrophil infiltration may be related to mild clinical manifestations despite the marked fixation of glomerular leukocytes in HPBAGN.

Tonsillectomy and steroid pulse therapy significantly impact on clinical remission in patients with IgA nephropathy.

We conducted a retrospective investigation of renal outcome in 329 patients with immunoglobulin A (IgA) nephropathy with an observation period longer than 36 months (82.3 +/- 38.2 months) in our renal unit between 1977 and 1995. Clinical remission, renal progression, and the impact of covariates were estimated by Kaplan-Meier analysis and a Cox regression model. In 157 of 329 patients (48%), disappearance of urinary abnormalities (clinical remission) was obtained. None of these 157 patients showed progressive deterioration, defined as a 50% increase in serum creatinine (Scr) level from baseline, during the observation period. Conversely, in patients without clinical remission, the Kaplan-Meier estimate of probability of progressive deterioration was 21% +/- 5% at 10 years. In the multivariate Cox regression model with 13 independent covariates, initial Scr level, histological score, tonsillectomy, and high-dose methylprednisolone therapy had a significant impact on clinical remission, whereas proteinuria, age, sex, levels of hematuria, blood pressure, conventional steroid therapy, angiotensin-converting enzyme inhibitor therapy, and cyclophosphamide therapy had no significant effect. These findings indicate that interventions aimed at achieving clinical remission have provided encouraging results applicable to managing patients with IgA nephropathy.

Familial lobular glomerulopathy: first case report in Asia.

A 23-year-old male Japanese student presented a unique lobular glomerulopathy characterized by mesangial and subendothelial expansion with numerous periodic acid-Schiff-positive deposits. Electron microscopy showed massive fine granular deposits with a homogeneous distribution. Fibrillar or microtubular structures were not demonstrated. Fibronectin was positive on immunostaining, as was immunoglobulin G and fibrinogen. Familial study revealed that the patient's grandfather, two aunts, and one cousin on his father's side had developed end-stage renal failure. Clinicopathologic features of this patient are identical with those of familial lobular glomerulopathy, which has been previously described by several investigators. Seven of the previously reported families were white and resided in the United States or in European countries. This is the first report of an Asian case, and indicates that this disease universally occurs independently of racial specificity.

Involvement of neutrophil elastase in crescentic glomerulonephritis.

To elucidate the role of neutrophils in the tissue damage of crescentic glomerulonephritis (GN), we examined neutrophils infiltrated in renal tissues and the localization of neutrophil elastase (NE), as a neutrophil-derived tissue destructive mediator, using an immunohistochemical technique with antibodies specific for neutrophils and neutrophil elastase; the enzyme histochemical technique (chloroesterase staining) also was used to detect neutrophils. In normal controls, neutrophil infiltration was scarce, and NE was localized in neutrophil cytoplasm. Neutrophils were abundant in crescentic GN and infiltrated in the glomerulus and interstitium; the infiltrating neutrophils were often aggregated. NE was localized in the cytoplasm of neutrophils and also appeared extracellularly (in granular or diffuse patterns) in glomerular necrotizing lesions, crescents, ruptured portions of Bowman's capsules, and in periglomerular and perivascular sites of the interstitium. Moreover, urinary concentration of NE measured by enzyme-linked immunosorbent assay (ELISA) in crescentic GN patients was significantly higher than in normals (93.6 +/- 13.3 v 1.4 +/- 0.5 microg/g x Cr, respectively; P < .001). These data suggest that NE plays a significant role in renal tissue damage, especially in the formation of glomerular necrotizing and crescentic lesions and in periglomerular interstitial lesions of crescentic GN.

Analysis of mononuclear cells in urine using flow cytometry in glomerular diseases.

Analysis of urinary substances, such as low molecular weight proteins and enzymes localized in the proximal tubulus and cytokines, has been proposed as being useful in monitoring the disease activity of glomerulonephritis [1-4]. However, most of these markers are more closely associated with renal tubulointerstitial injury than glomerular injury. It has been demonstrated that mononuclear cells (macrophages and lymphocytes) are involved in the pathogenesis of various types of human glomerulonephritis, as well as in animal models [5-7]. If mononuclear cells are involved in glomerular injury, it can be assumed that such cells could be detected in urine; however, to our knowledge, the characterization of mononuclear cells in urine has not been investigated. We have recently demonstrated that increased numbers of mononuclear cells are observed in the urine of patients with active IgA nephropathy and that the extent of active crescents in biopsy specimens is significantly correlated with the number of urinary macrophages and natural killer cells [8]. The aim of the present study is to evaluate the clinical usefulness of analyzing mononuclear cells in urine as a non-invasive diagnostic tool for glomerular injury.

Clinicopathological characteristics of interstitial foam cells in membranous nephropathy.

BACKGROUND: Interstitial foam cells are occasionally observed in various renal diseases, and they have been reported to belong to the monocyte/macrophage (M phi) lineage and to be associated with heavy proteinuria and hyperlipidemia. We investigated the characteristics of interstitial foam cells and their association with proteinuria and hyperlipidemia in idiopathic membranous nephropathy (MN). METHODS: Patients with MN (N = 320) were divided into two groups: group I consisted of 51 patients with interstitial foam cells, and group II consisted of the other 269 without foam cells. We compared clinical parameters and the findings of an immunohistochemical study using monoclonal antibodies to various types of leukocytes and adhesion molecules. RESULTS: The age at renal biopsy, the degree of proteinuria, serum levels of lipids, and other clinical parameters except for sex ratio were not different between the two groups. The ratio of nephrotic patients was compatible between groups I (56.9%) and II (52.8%). All interstitial foam cells were positive for CD68 and 25F9, which are markers for M phi and mature M phi, respectively, but were negative for CD3 or cytokeratin. Interstitial infiltrating cells were positive for CD68 and CD3 but were negative for 25F9. Furthermore, most of interstitial foam cells were positive for both leukocyte function associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1), but not for ICAM-3 (the third ligand for LFA-1). By contrast, most of infiltrating nonfoamy M phi s were positive for ICAM-3 and LFA-1, however, ICAM-1 was observed on only some of them. CONCLUSION: These results suggest that interstitial foam cells in MN may not depend on proteinuria nor hyperlipidemia directly. The accumulation of foam cells, which have characteristics of mature M phi, may be related to ICAM-1 as a ligand of LFA-1, whereas infiltration of nonfoamy M phi s has a close relationship with ICAM-3. Thus, the formation of interstitial foam cells may be related to the phenotypical transformation of M phi s.

Urinary macrophages as activity markers of renal injury.

The presence of macrophages (Mφ) in the urine of patients with glomerulonephritis (GN) reflects the pathological events in the kidney, and we have discovered the following correlations between the Mφ phenotype and the pattern of renal injury. (1) Urinary macrophage (Mφ) counts increase in patients with proliferative GN, especially in the presence of active glomerular lesions (glomerular tuft necrosis, crescent, and endocapillary proliferation). In patients with hematuria, a combination of urinary Mφ and T-lymphocyte counts can be used to differentiate proliferative GN from non-proliferative renal disease (hereditary nephropathy and idiopathic renal hematuria). (2) The urinary Mφ of patients with active proliferative GN express FcgammaRIII (CD16) regardless of the type of GN. (3) There are two types of urinary CD68(+) cells, CD68(+)25F9(-) cells (infiltrating Mφ) and CD68(+)25F9(+) cells (mature Mφ). The CD68(+)25F9(-) cell counts in the urine correlate well with the activity of proliferative GN, and the CD68(+)25F9(+) cell counts in the urine correlate with the magnitude of non-selective proteinuria and with the subsequent decline of renal function. The CD68(+)25F9(+) cell count increases in the urine of patients with focal segmental glomerular sclerosis, but their numbers are negligible in minimal change nephrotic syndrome. These findings indicate that the analysis of the urinary Mφ phenotype is a useful strategy for evaluating renal injury as a 'risk-free renal biopsy'.

Pathogenic role of glomerulo-tubular junction stenosis in glomerulocystic disease.

Glomerulocystic disease is an uncommon cystic renal condition characterized by cystic dilatation forming a glomerular cyst. The pathogenesis of this familial disease is unknown. We performed a serial section study using a biopsy specimen of a 16-year old female patient with glomerular cystic disease who had a family history of end stage renal failure. A total of 14 different glomeruli were analyzed, four of which exhibited a cystic appearance. Five glomerulotubular junctions were observed by serial sections, two of which had a stenotic appearance where glomerular cystic changes and periglomerular fibrosis were observed concomitantly. There were no such cystic glomerular changes in the other three glomeruli with non-stenotic glomerulo-tubular junctions. These findings suggest that the glomerular cystic lesion develops as a consequence of glomerulo-tubular junctional stenosis probably caused by periglomerular fibrosis.

Analysis of CD14+ cells and CD56+ cells in urine using flow cytometry: a useful tool for monitoring disease activity of IgA nephropathy.

The interrelationship between glomerular inflammatory activity and urinary leukocytes was investigated in IgA nephropathy (IgAN). The numbers of T cells, macrophages, and natural killer (NK) cells in urine were evaluated using flow cytometry. The glomerular changes were studied by routine histopathological methods and by immunohistochemical methods using monoclonal antibodies. Biopsies were classified into three categories: non-crescentic IgAN (n = 44), inactive-crescentic IgAN (n = 17), and active-crescentic IgAN (n = 18). Macrophages (Leu M3/CD14) and NK cells (Leu 19/CD56) were predominantly present within active crescents, whereas T cells (Leu 4/CD3) were less frequently observed. A significant increase of mononuclear cells in urine was observed in patients with active-crescentic IgAN as compared with other groups. Moreover, the extent of active crescents in biopsies was significantly correlated with the number of CD14+ cells and CD56+ cells in urine (CD14: r = 0.6858, p < 0.01; CD56: r = 0.6373, p < 0.01). These findings suggest that analysis of CD14+ cells and CD56+ cells in urine using flow cytometry can be a useful tool for monitoring disease activity of IgAN.

Effect of camostat mesilate on heavy proteinuria in various nephropathies.

Camostat mesilate, a developed derivative of gabexate mesilate for oral use, was administered in a daily dose of 600 mg for 4 weeks to 17 patients with heavy proteinuria due to various nephropathies. Five patients had glomerulonephritis (3 patients with IgA nephropathy, one each with membranoproliferative GN and membranous nephropathy) and 3 had systemic vasculitis. These patients had been treated with glucocorticoid, cyclophosphamide, anticoagulants, and dipyridamole. Five patients had diabetic nephropathy and had been treated with conventional therapy including angiotensin converting enzyme inhibitors. Two cases with benign nephrosclerosis, one with Alport syndrome, and the rest with end-stage renal failure of undetermined cause were also included in this study. Urinary protein decreased promptly within 2 weeks (from 5.2 +/- 0.7 to 3.5 +/- 0.5, mean +/- SE, p less than 0.005), and serum total protein and albumin levels increased significantly. Serum creatinine levels did not change. Decreases in urinary protein excretion of more than 50% were observed in five out of eight patients with glomerulonephritis or systemic vasculitis, two out of five with diabetic nephropathy, and one with chronic renal failure. However, urinary protein excretion values remained at the same level in two patients with benign nephrosclerosis and a patient with Alport syndrome. We suggest that camostat mesilate caused a change in glomerular capillary permeability for macromolecules through its inhibitory effects on the kallikrein-kinin system, complement system, coagulation system, and platelet function, which contributed to the treatment of the various nephropathies.

Role of neutrophil elastase in the development of renal necrotizing vasculitis.

To assess the pathogenetic mechanisms of renal vasculitis, we performed immunohistochemical studies using renal biopsy specimens which were obtained from a patient with microscopic polyangiitis during both the acute and the convalescent phase. Intense infiltration and aggregation of neutrophil elastase positive (NE+) cells were observed especially in the periglomerular and perivascular areas in the first biopsy in which vascular necrosis, rupture of Bowman's capsule, and necrotizing glomerulonephritis were present. In addition to intracellular NE expression, NE was also expressed extracellularly in both segmental glomerular tufts and the interstitium. Intensity of NE immunoreactivity in the glomeruli was closely correlated with the development of glomerular necrotizing lesions and crescents, but no such correlation was detected with the infiltration of macrophages, T cells or B cells. In the second biopsy (convalescent phase), patchy intracellular NE expression was present in the interstitium, but no aggregation of NE+ cells or extracellular NE expression was detected in either the glomeruli or the interstitium. These findings suggest that recruitment of polymorphonuclear leukocytes in perivascular and periglomerular areas as well as in glomerular tufts, and subsequent extracellular release of NE in situ may play an important role in the development of renal vasculitis characterized by vascular necrosis, rupture of Bowman's capsule, and tuft necrosis.

Membranoproliferative glomerulonephritis in the aged and its possible causal relationship with CD8+CD57+ lymphocytes.

Membranoproliferative glomerulonephritis (MPGN) is a chronic progressive glomerulonephritis that occurs primarily in patients under the age of 30, and is rare in the elderly. We report eight aged patients with MPGN associated with CD8+CD57+ lymphocytosis. All eight patients showed a significant increase in CD8+CD57+ lymphocytes with a significant decrease in the ratio of CD4+ cells to CD8+ cells. Infiltration of CD8+CD57+ lymphocytes was observed within capillary lumens to various degrees according to the severity of endocapillary proliferation in each case. Expression of endothelial-leukocyte adhesion molecule-1 was observed in a focal and segmental manner on glomerular endothelial cells and on the endothelium of arterioles and arteries in kidney tissue in four cases in which a pronounced endocapillary proliferation was simultaneously seen. These findings suggest that cell-mediated cytotoxic mechanisms against glomerular endothelial cells may be involved in the pathogenesis of MPGN in the aged.

Mesangiolysis associated with severe glomerular endocapillary proliferation of CD57 large granular lymphocytes.

A 54-year-old man developed renal failure, with renal biopsy findings of diffuse mesangiolysis with severe endocapillary proliferation. Immunohistochemical studies revealed that CD3-CD56-CD57+ large granular lymphocytes were present predominantly within glomerular tufts. Intercellular adhesion molecule-1 was more preferentially expressed in the glomerular endothelial cells with severe endocapillary proliferation as compared to those without endocapillary proliferation. These findings suggest that CD57+ large granular lymphocytes caused glomerular endothelial injury by a cell-mediated cytolytic mechanism, resulting in the development of mesangiolysis and microaneurysm formation.

Clinicopathological study of IgA nephropathy in patients with congenitally reduced nephron mass.

In experimental animal models, a reduction in the number of functioning nephrons is considered to play a role in the progression of glomerular injury. In human renal diseases, however, whether a superimposed reduction in the number of nephrons causes the exacerbation of preexistent glomerulopathy has not been elucidated. We herein report the results of a clinicopathological study of five patients with IgA nephropathy (IgAN) which occurred in a reduced nephron mass status (four cases of congenital solitary kidney and one case of bilateral hypoplastic kidneys). Four of the five patients had chronic renal failure (CRF) and exhibited a relatively rapid course to CRF as primary IgAN. Renal biopsy revealed that all four of the patients with CRF had glomerular hypertrophy and focal segmental glomerular sclerosis. In addition, two of them had a focal active lesion. In one patient with bilateral hypoplastic kidneys renal biopsies were performed twice in eight years. During this period her creatinine clearance deteriorated from 60.0 ml/min to 20.7 ml/min. Her first renal biopsy showed mild mesangial proliferation without sclerotic lesions, glomerular hypertrophy and mesangial IgA deposition, while all of them were prominent in the second renal biopsy. These observations suggest that IgAN superimposed on a nephron loss status may be frequently associated with a progressive course of disease, and careful follow-up and early treatment should be considered in such a condition.

Predictive value of small crescents in IgA nephropathy: analysis of four patients showing a deteriorated renal function during a long follow-up period.

Four patients with IgA nephropathy developed a chronic renal failure during a long follow-up period ranging from three to 8.5 years (mean 6.4 years). All patients showed a normal renal function, normal blood pressure and mild proteinuria at the time of the first renal biopsy. The first biopsies showed focal mesangial proliferation with small cellular crescents in a small percentage of the observed glomeruli. No case showed sclerotic changes in the interstitium and vessels. In contrast, at the second biopsies, all of them exhibited a deteriorated renal function, hypertension and massive proteinuria. The second biopsies revealed marked sclerotic changes in the glomeruli, interstitium, and vessels with significant focal segmental glomerular sclerosis and adhesions. Since no established factors predisposing the patients to chronic renal insufficiency had been observed at the time of the first biopsy, it was suggested that small crescents, even if focal, should be regarded as indicating an unfavorable prognosis.

Usefulness of dialysate fibrin degradation products and lactic dehydrogenase isoenzyme patterns in assessing the clinical course of peritonitis.

OBJECTIVE: To establish the usefulness of fibrin degradation products (FDP) and lactic dehydrogenase isoenzyme patterns (LDH isoenzyme) in assessing the clinical course of peritonitis. DESIGN: A retrospective study of patients with peritonitis who were divided into three groups according to their clinical course. SETTING: Single dialysis unit of a general hospital. INTERVENTIONS: Patients were treated by intraperitoneal and oral antibiotics. PATIENTS: Twenty-six patients with 34 episodes of peritonitis were studied. Group 1 consisted of 21 patients with 26 recoveries from peritonitis; Group 2 consisted of 5 patients with 5 relapsing episodes of peritonitis, and Group 3 consisted of 3 patients with 3 persistent episodes of peritonitis. MAIN OUTCOME MEASURES: Concentrations of WBCs, FDP, LDH isoenzyme and microbiological culture of the dialysate were determined. RESULTS: In most of Group 1, WBCs, FDP, and LDH isoenzyme returned to normal within 2 weeks. In 4 patients of Group 1, who had complications (diverticulitis, cholecystitis, cystitis, and tunnel infection), WBCs, FDP, and LDH isoenzyme returned to normal gradually within 3 weeks. In Group 2, WBCs returned to normal, but FDP remained relatively high and LDH isoenzyme did not normalize. In Group 3, WBCs, FDP and LDH isoenzyme did not normalize. CONCLUSIONS: Failure of normalization of FDP and LDH isoenzyme suggests an incomplete recovery from peritonitis. FDP and LDH isoenzyme are useful in assessing the course of peritonitis.

Useful antiglobulin crossmatch test for DST-sensitized patients.

The AG-CDC tests were performed in parallel with C-CDC tests for studying sensitization of DST patients. Fourteen of 56 DST patients were positive by the AG-CDC tests after DST. Ten of 14 were also positive by both tests after DST. In 8 of 14 patients AG-CDC antibodies continued to be detectable even after C-CDC antibodies became undetectable as time passed and with plasmapheresis. Thus, AG-CDC tests are more sensitive compared to C-CDC tests and can extend the detection rate of DST-sensitized patients. Except for two DST patients (highly sensitized), 12 of 14 DST-sensitized patients were given transplants from specific blood donors at the time when their C-CDC tests became negative. One graft failed, another one had impaired function, and ten of them functioned. It should be noted that DST patients were transplanted successfully with or without plasmapheresis across a positive AG-CDC test if the titer was less than 1:4 at the time of transplant. All four DST recipients who developed antibodies detected only by AG-CDC tests after DST experienced severe accelerated rejections. In contrast, two of eight patients who were positive by both tests had "severe" accelerated rejections. The incidence of severe accelerated rejections was shown to be highly associated with the presence of AG-CDC antibodies. These facts suggest that AG-CDC antibodies may damage kidney grafts and result in severe accelerated rejections; and that AG-CDC tests are useful for predicting occurrence of severe accelerated rejections in DST recipients.

Comparative study of cystic variations of the kidneys in haemodialysis and continuous ambulatory peritoneal dialysis patients.

In recent years, many complications of renal cell carcinoma accompanying the increase in the number of peritoneal dialysis cases have been studied more often. Clinicopathologically, we studied comparatively cystic changes of the kidney, considered to be a background factor of cancerous development in 69 patients on peritoneal dialysis without past history of haemodialysis and in 192 patients on long-term haemodialysis. From the results, differences with respect to the duration of dialysis until the development of cysts and primary diseases commonly associated with cysts were not found between the two groups. Moreover, in the extirpated kidneys examined for cancerous development, cysts were found in both the peritoneal dialysis and the haemodialysis cases, and proliferative changes were found in the cystic epithelium. A relationship between cystic and cancerous development in the peritoneal dialysis cases was strongly suggested by these findings. Therefore, it was considered that careful follow-up studies for complications such as renal cell carcinoma would be necessary in both the peritoneal dialysis and the haemodialysis cases.

Anti-proteinuric and anti-coagulatory effects of camostat mesilate in azotemic diabetics.

The present study was conducted on 8 patients with advanced diabetic nephropathy who showed a significant reduction of proteinuria through ACE inhibition. Camostat mesilate, one of the most potent protease inhibitors developed for oral use, was administered to these patients at a daily dose of 600 mg starting after 4 weeks of ACE inhibitor administration. Laboratory data were obtained 1) just before the ACE inhibition, 2) after 4 weeks of the ACE inhibitor single treatment, and 3) after another 4 weeks of the additional treatment with camostat mesilate. The urinary protein excretion decreased from 1) 10.1 +/- 1.3 to 2) 7.3 +/- 1.1, and 3) 4.6 +/- 0.9 g/day [mean +/- SEM; significance of difference 1)-2), p less than 0.05; 2)-3), p less than 0.01], and the serum total protein values increased from 1) 5.0 +/- 0.3 to 2) 5.2 +/- 0.2, and 3) 5.4 +/- 0.3 g/dl [1)-3), p less than 0.05]. The plasma levels of fibrinogen, and of E fragment and D-dimer of FDP changed from 1) 476 +/- 43 to 2) 477 +/- 41, and 3) 374 +/- 33 mg/dl [2)-3), p less than 0.01], from 1) 125 +/- 19 to 2) 147 +/- 27, and 3) 104 +/- 30 ng/ml [2)-3), p less than 0.05], and from 1) 261 +/- 60 to 2) 272 +/- 86, and 3) 185 +/- 56 ng/ml [2)-3), p less than 0.05], respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

[Usefulness of serum cystatin-C as a marker of the renal function: a comparative evaluation with beta 2-microglobulin, alpha 1-microglobulin and creatinine].

We evaluated the usefulness of cystatin-C as a marker of renal function. Serum cystatin-C level was measured using latex agglutination tests in 885 patients with various forms of renal disease and 200 healthy subjects. In addition to cystatin-C, serum beta 2-microglobulin, alpha 1-microglobulin and serum creatinine (Scr) were measured concomitantly in the same sample. The serum cystatin-C level inversely correlated more closely with creatinine clearance (Ccr) (r = -0.90) than serum beta 2-microglobulin (r = -0.85), alpha 1-microglobulin (r = -0.74) and Scr (r = -0.78). In patients with mildly impaired renal function (defined as Ccr 71-90 ml/min), a significant increase in cystatin-C level was observed in 24% of patients, whereas elevated beta 2-microglobulin and Scr were seen in 8% and elevated alpha 1-microglobulin was seen in 17%. In patients with normal renal function (defined as Ccr > or = 100 ml/min), increased cystatin-C level was observed in 7% of patients, whereas beta 2-microglobulin was seen in 2%, Scr in 2% and alpha 1-microglobulin in 11%. These data suggest that cystatin-C is a better marker of glomerular filtration than beta 2-microglobulin, alpha 1-microglobulin and Scr. Moreover cystatin-C measurement offers improved clinical sensitivity as a screening test for early renal damage.