Markers Of Renal Tubular Function Research Articles

Evaluation Effect of Tenofovir Alafenamide (TAF) in Long-Term Therapy for Chronic Hepatitis B: A Systematic Review

Background: Tenofovir alafenamide (TAF) is phosphonamidate prodrug of tenofir that inhibits hepatitis B virus and HIV type-1 reverse transcription. TAF more stable form in plasma than tenofovir disoproxil fumarate (TDF) as choice treatment before. TAF in long-term treatment also significantly reduced bone mineral density (BMD) and raised serum creatinine, as well as improved markers of renal tubular function. This study aims to review the long-term therapy of TAF effect in body weight gain, BMD, renal function, lipids profile, ALT normalization, and HBeAg loss.Method: The data was taken from Pubmed, ScienceDirect, and Cochrane Library. We found 363 articles from databases. The articles related to long-term therapy in chronic hepatitis-B and adjusted according to restriction criteria. Articles selection using PRISMA flowchart and quality test using GRADE method into eligible articles.Results: We selected articles that eligible for systematic review with different GRADE recommendation which were 4 high-grade articles, 1 low-grade, and 1 very low-grade article. TAF in long-term therapy showed an increase in BMD (p 0.001), body weight gain (p 0.001), decreased renal dysfunction (CrCl; p 0.0001 and GFR; p = 0.027), and normalized ALT (p = 0.016). However, lipids profile level increase that could increase risk of atherosclerosis and dyslipidemia. There was no significant in HBeAg loss.Conclusion: TAF therapy is favourable therapy in long-term therapy of chronic hepatitis B patients by smaller reduce of BMD, and significant body weight gain, reduce renal dysfunction, good improvement in lipid profile and improving ALT enzymes.

S1127 Safety and Efficacy of Switching to Tenofovir Alafenamide (TAF) in Virally Suppressed Chronic Hepatitis B (CHB) Patients With Renal Impairment: Week 48 Results From a Phase 2 Open-Label Study

Introduction: Switching to TAF, a novel tenofovir prodrug, has shown maintenance of viral suppression with stable or improved bone and renal safety at Week 24 in CHB patients with moderate to severe renal impairment (eGFR by Cockcroft-Gault [eGFRCG] < 60 mL/min) and ESRD patients on HD. We evaluated the safety and efficacy in these virally suppressed patients with renal impairment 1 year after switching to TAF in a Phase 2 study. Methods: CHB patients with renal impairment receiving TDF and/or other OAVs for ≥48 weeks and virally suppressed for ≥6 months with HBV DNA < 20 IU/mL at screening were enrolled into 2 cohorts: 1) moderate-severe renal impairment (eGFRCG 15 to < 60 mL/min) and 2) ESRD (eGFRCG < 15 mL/min) on chronic HD. All patients were switched to TAF 25 mg QD for 96 weeks (given post-HD on days of dialysis for ESRD patients). Safety assessments including changes in bone (hip and spine BMD) and renal (CrCl by Cockcroft-Gault [eGFRCG], serum creatinine) parameters, viral suppression, and biochemical responses were assessed in all patients at Week 48. Results: 93 patients (moderate-severe impairment 78; ESRD 15) were enrolled from 26 sites in 8 countries; 89% of patients remained on study at Week 48. At baseline, 74% were male, 77% Asian, 68% ≥60 y, 83% HBeAg-negative and median ALT was 17 U/L. Up to 25% overall (both cohorts) had osteoporosis at hip and/or spine, and a high proportion had comorbidities (60% HTN, 24% DM). Key efficacy/safety results at Week 48 are summarized in the Table. Efficacy (HBV DNA< 20 IU/mL) was maintained in nearly all patients on treatment at Week 48 and a high proportion had normal ALT levels. Five patients discontinued study drug early (withdrew consent) with last available HBV DNA < 20 U/mL; 1 patient had HBV DNA ≥20 IU/mL and 1 patient died. Relative to baseline levels, switching to TAF resulted in stable hip/spine BMD in moderate to severe renal impairment patients, with a slight decrease in hip BMD in ESRD patients. Slight improvements were observed in renal parameters including eGFRCG and markers of renal tubular function in moderate to severely impaired patients. TAF was well tolerated, with no Grade 3/4 or serious adverse events related to study drug. Conclusion: In renally-impaired CHB patients, including ESRD patients on HD, viral suppression was well maintained, and the bone and renal safety were stable or improved 48 weeks after switching to TAF.Table 1.: Study outcomes comparing EUS-guided liver biopsy and percutaneous liver biopsy.

Improvement of bone mineral density and markers of proximal renal tubular function in chronic hepatitis B patients switched from tenofovir disoproxil fumarate to tenofovir alafenamide.

Tenofovir alafenamide (TAF) is a novel prodrug that reduces tenofovir plasma levels by 90% compared to tenofovir disoproxil fumarate (TDF), resulting in decreased bone mineral density (BMD) loss and renal toxicity. We aimed to study changes in BMD and markers of renal function of chronic hepatitis B (CHB) patients previously treated with TDF who were switched to TAF in as early as 12weeks. This was a prospective single-arm open-label study of 75 CHB patients treated with TDF 300mg daily who were switched to TAF 25mg daily and followed for 24weeks. All patients had been treated with TDF for at least 12months and had HBV DNA <21IU/mL at the time of switch. BMD and markers of renal function were taken on the day of switch and repeated after 12 and 24weeks of TAF treatment. Hip and spine bone mineral density significantly increased from baseline to week 12 (+12.9% and +2.4%, respectively, P<0.01). There were significant decreases in urinary beta-2-microglobulin to creatinine and retinol-binding protein to creatinine ratios by week 12 (P<0.01 for both). Mean estimated glomerular filtration rate (GFR) did not change. Tubular reabsorption of phosphate was decreased at week 24 (P<0.05). In conclusion, CHB patients previously treated with TDF experienced significant improvement in bone density and some markers of renal tubular function and as early as 12weeks after switching to TAF. Bone density changes associated with TDF may not be entirely related to renal handling of phosphate.

Altered Underlying Renal Tubular Function in Patients With Chronic Hepatitis B Receiving Nucleos(t)ide Analogs in a Real-World Setting: The MENTE Study.

Cases of renal tubular dysfunction have been reported in patients with hepatitis B and in patients with human immunodeficiency virus who are undergoing tenofovir treatment. However, little is known about the impact on tubular function in patients with chronic hepatitis B (CHB) under long-term use of entecavir (ETV) and tenofovir disoproxil fumarate (TDF). We evaluated markers of renal tubular function and bone turnover in patients with CHB treated with ETV or TDF. A multicenter, cross-sectional study was performed on markers of renal tubular function and bone turnover in hepatitis B virus-monoinfected patients on long-term treatment with Entecavir or Tenofovir (the MENTE study). The analyzed parameters were: retinol-binding protein/creatinine, neutrophil gelatinase-associated lipocalin/creatinine, excretion of phosphates, uric acid excretion, glomerular filtrate, protein/creatinine, albumin/creatinine, serum creatinine, phosphate, CTX, P1NP, vitamin D, and parathormone. A total of 280 patients (ETV: 89, TDF: 69, control: 122) were included in this study. The TDF group was associated with altered levels of retinol-binding protein (RBP)/creatinine (TDF 25% vs. 7% ETV and control; P<0.001). Protein/creatinine, uric acid excretion, P1NP1, and parathormone were higher in the TDF group. The proportion of patients with serum phosphate <2.5 mg/dL was higher in both the ETV and the TDF groups compared with the control. The multivariate analysis showed that the use of TDF was independently associated with a higher risk of altered excretion of RBP/creatinine (4.4; interquartile range: 1.4 to 14; P=0.013). We found an independent association between TDF use and altered RBP excretion. This finding indicates subclinical tubular damage. Because tubular dysfunction can precede the decline of renal function, close monitoring of RBP levels in patients with CHB on nucleos(t)ide analog treatment must be performed for early detection of TDF-related renal toxicity. In this study, these differences in tubular function were not associated with concomitant changes in markers of bone turnover.

Office blood pressure is a predictor of aortic elastic properties and urinary protein excretion in subjects with white coat hypertension

BackgroundWhite coat hypertension (WCH) is related to target organ damage and increased cardiovascular risk. Arterial elastic properties and urinary protein excretion are determinants of cardiovascular performance and predictors of outcomes. We investigated whether office blood pressure (BP) is a better determinant of arterial and renal function than the ambulatory BP in WCH patients. MethodsWe studied 440 consecutive untreated non-diabetic patients with WCH (office BP >140/90mmHg, mean daytime ambulatory BP <135/85mmHg). Arterial function was evaluated with carotid–femoral pulse wave velocity (cfPWV), an index of aortic stiffness, and aortic augmentation index (AIx), a composite marker of aortic stiffness and wave reflections. In 24-hour urine, albumin excretion and albumin/creatinine ratio (ACR) were measured as markers of glomerular function and urinary α1-microglobulin was measured as a marker of renal tubular function. ResultsIn univariate analysis, office systolic BP correlated significantly with cfPWV (r=0.245, P<0.001), AIx (r=0.31, P<0.001), albumin (r=0.134, P=0.005), ACR (r=0.199, P<0.001) and α1-microglobulin (r=0.118, P=0.013). In contrast, mean ambulatory systolic BP did not correlate with arterial function or urinary proteins (all P>0.5). Hierarchical multilevel linear regression analysis showed that office systolic BP is an independent determinant of cfPWV (P=0.050), AIx (P=0.029), albumin (P=0.002) and ACR (P=0.001) and has a borderline association with α1-microglobulin (P=0.088). ConclusionsIn non-diabetic WCH individuals, office systolic BP is an independent predictor of aortic elastic properties and urinary protein excretion, whereas ambulatory BP is not. This finding suggests that office BP may be a marker of cardiovascular risk in subjects with WCH.

Clinical Importance of Hyper-Beta-2-Microglobulinuria in Patients With HIV-1 Infection on Tenofovir-Containing Antiretroviral Therapy

Clinical Importance of Hyper-Beta-2-Microglobulinuria in Patients With HIV-1 Infection on Tenofovir-Containing Antiretroviral Therapy

Initial evaluation of canine urinary cystatin C as a marker of renal tubular function

To evaluate the performance of a particle-enhanced turbidimetric assay for measuring canine urinary cystatin C and to investigate if the urinary cystatin C to creatinine ratio is higher in dogs with renal disease than in non-renal disease dogs. Urinary cystatin C was measured by particle-enhanced turbidimetric assay using an avian antihuman cystatin C antibody and the performance of this assay was evaluated. Clinical relevance was tested in 46 dogs that were divided into three groups: healthy dogs (n=14), non-renal disease dogs (n=17) and dogs with renal disease (n=15). The assay was linear (R(2)=0·99) and precise (mean intra- and inter-assay coefficients of variation were 2·3 and 2·9%, respectively). The recovery was 111·5% and the limit of blank was 0·02 mg/L. Urinary cystatin C and urinary cystatin C to creatinine ratio differed significantly (P<0·001) between the three cohorts of dogs. Measurement of cystatin C by particle-enhanced turbidimetric assay performed with high precision and linearity. This assay can be processed on automated clinical chemistry analysers making it widely available to commercial laboratories. Urinary cystatin C to creatinine ratio can differentiate dogs with renal disease from dogs without renal disease. These preliminary results suggest that urinary cystatin C to creatinine ratio is a promising marker for evaluating renal tubular function.

Neutrophil gelatinase-associated lipocalin as a marker of tubular damage appears to be unrelated to fractional excretion of sodium as a marker of tubular function in septic patients, with or without AKI

The utility of urinary biochemistry has recently been challenged [1], while there is emerging evidence that renal biomarkers may accurately quantify the risk of development of acute kidney injury (AKI) [2]. Neutrophil gelatinase-associated lipocalin (NGAL) is a marker of renal tubular damage [3]. Fractional excretion of sodium (FENa) is a marker of renal tubular function, and is a significantly cheaper investigation [4]. Insults damaging the tubules and resulting in AKI should both stimulate NGAL production and prevent resorption of sodium. Given the different pathological mechanisms underlying septic and nonseptic AKI, it is plausible that the relationship between these variables could be different in these two groups of patients [5].

Cadmium-induced renal tubular dysfunction in a group of welders

Occupational exposure to welding fumes has been associated with several diseases including metal fume fever, lung cancer, welder's pneumoconiosis and manganism. However, there are few reports on cadmium-induced renal tubular dysfunction in welders. To evaluate the body burden of cadmium and cadmium-induced proteinuria in a group of Chinese welders. Cadmium concentrations in the breathing zone and in urine were measured by atomic absorption spectrometry. β(2)-microglobulin (β(2)-MG) in urine as a marker of renal tubular function was measured using an ELISA kit. All urinary parameters were adjusted by urinary creatinine (Cr). A total of 103 welders participated. The concentration of airborne cadmium in the welders' breathing zones ranged from 5 to 86 μg/m(3), and 17% of samples exceeded the threshold limit value. Six welders' urinary cadmium levels exceeded the Chinese recommended reference value. Urinary β(2)-MG levels increased significantly with increasing urinary cadmium levels and in two welders, the values were close to the level for chronic cadmium poisoning in China. Environmental and urinary cadmium levels were raised in this group of welders and were associated with raised markers of renal tubular dysfunction. The exact source of the cadmium warrants further assessment.

Comparison of urinary neutrophil glucosaminidase-associated lipocalin, cystatin C, and α1-microglobulin for early detection of acute renal injury after cardiac surgery

Acute renal injury is a frequent complication after cardiac surgery that necessitates additional treatment and increases mortality. To apply measures for optimizing renal function in a well-directed and effective way, it is most important to detect acute kidney injury at an early stage. The present study compares three markers of renal tubular function for detection of acute renal injury according to the acute kidney injury (Acute Kidney Injury Network (AKIN)) criteria. Urinary concentration of the tubular markers neutrophil glucosaminidase-associated lipocalin (NGAL), α1-microglobulin (α1MG), and cystatin C (CysC) were measured in 50 patients after elective cardiac surgery. Samples were taken once preoperatively and postoperatively every 12 h for up to 5 days. Based on the highest recorded postoperative AKIN score, patients were divided into two groups (AKIN 0 and AKIN 1-3). Statistical analysis was done for marker concentrations at three time points: preoperative, after admission to the intensive care unit (ICU), and at the highest postoperative AKIN level. In addition, all concentrations of marker proteins were multiplied by the ratio of creatinine concentrations in serum and urine; these products were also analyzed statistically. In this way, we were able to eliminate the influence of varying degrees of diuresis on marker concentrations. As early as at admission to the ICU, all marker proteins showed significantly higher concentrations compared with preoperative values. However, differences in concentrations between the groups AKIN 0 and AKIN 1-3 were only statistically significant for NGAL. Using receiver operating characteristic (ROC) analysis, we found that only NGAL concentrations were suitable for detecting acute kidney injury with adequate sensitivity and specificity (area under the curve (AUC)=0.773). Levels of α1MG yielded a comparable accuracy when urinary concentrations were multiplied by the serum/urine creatinine ratio (AUC=0.712). An increase in urinary NGAL is an early sign of acute kidney injury after cardiac surgery. After multiplication by the serum/urine creatinine ratio, urinary α1MG is also suitable for detection of acute kidney injury at an early stage.

Alterations in the biochemical markers of renal function after sevoflurane anaesthesia

This study has been carried out to see whether renal function is acutely altered in patients undergoing sevoflurane anaesthesia. For this purpose, the urinary levels of markers of renal tubular function, namely leucine amino peptidase (LAP), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and beta-2 microglobulin (beta-2M), and urinary albumin as a predictor of renal glomerular function were measured before and after sevoflurane anaesthesia. This study was comprised of 20 patients (11 males and nine females) aged 18-55, who underwent various elective surgical procedures under general anaesthesia. Urine samples of all patients were collected before and 1, 2 and 8 h after the anaesthesia. The levels of LAP, GGT, beta-2M, and albumin were then expressed as factored by urinary creatinine. In all patients, the anaesthesia was maintained with sevoflurane (2% end-tidal) at a high flow-rate (6 L/min). Urinary beta-2M and LAP levels after anaesthesia were unchanged (P > 0.05). While urinary GGT and ALP levels were found elevated in the first hour, LDH levels were higher in the second hour (P < 0.05). They returned to normal levels in the later periods after the anaesthesia. Urinary albumin excretion (UAE) was significantly elevated in the second hour after the anaesthesia (P < 0.001). Although UAE was decreased in the eighth hour after the anaesthesia, it still remained higher than the pre-anaesthesia level (P < 0.001). These results suggest that a 2% end-tidal concentration of sevoflurane at a high flow-rate (6 L/min) acutely alters renal glomerular function but does not have a significant acute effect on biochemical markers of renal tubular damage.

Markers of cadmium exposure in workers in a cadmium pigment factory after changes in the exposure conditions

The objective of this study was to assess changes in concentrations of cadmium in the blood (Cd-B), cadmium in the urine (Cd-U), beta2-microglobulin in the serum (beta2-mG-S) and beta2-microglobulin in the urine (beta2-mG-U) of workers at a cadmium (Cd) pigment factory in Japan in which exposure conditions improved. We evaluated reversibility of these markers in continuously employed workers in relation to changes in exposure levels resulting from improvements in the workplace and the reduced production of Cd. Our study involved both environmental and biological monitoring. Data were collected for four years. We measured the Cd concentration in the air of each work area, using the time-weighted average (TWA). Cd-B and Cd-U were measured in workers as direct indices of Cd exposure. beta2-mG-S and beta2-mG-U were measured as markers of renal tubular function. Exposure levels were high in all work areas, according to the criteria set by the American Conference of Governmental Industrial Hygienists (ACGIH). Workers' Cd-B and Cd-U concentrations reflected high levels of exposure. Correlation was found between these direct indices and beta2-mG-S concentrations. Since the second year, ambient Cd concentrations decreased and reacted markers have been improved. Our results suggest that Cd-B, Cd-U, beta2-mG-S and beta2-mG-U are appropriate markers for monitoring both the level of Cd exposure and the tubular function of workers. Reversibility of urinary low molecular weight protein was observed in the workers over the four years.

Proximal tubular reabsorption of growth hormone and sodium/fluid in normo- and microalbuminuric insulin-dependent diabetes mellitus.

Proximal tubular dysfunction may be implicated in the pathogenesis of diabetic nephropathy. An investigation of proximal tubular function was carried out by assessing proximal tubular sodium-reabsorption and low molecular weight protein excretion in a group of patients with type 1 diabetes mellitus. Normoalbuminuric [group A, n = 6, albumin excretion rate (AER) mean (range) 4 (0-10) micrograms/min], and microalbuminuric [group B, n = 6, AER 88 (35-198) micrograms/min] patients with type 1 diabetes were compared with matched controls. Simultaneous lithium and growth hormone (GH) clearance and urinary beta 2-microglobulin excretion were assessed. Fasting plasma glucose at the start of the study was [median (range)] 13 (10.2-15.1), 9.3 (5.9-15) and 4.1 (4.0-5.0) mmol/l in groups A, B and controls, respectively, with a mean coefficient of variation during the study of 3.9% (group A) and 5.2% (group B). There was no significant difference in plasma glucose levels between patients in groups A and B. Urinary GH excretion was raised in the patients with microalbuminuria (group B; P < 0.05), although there was no difference in serum GH clearance rate between the patient groups and controls. Urinary GH correlated with B 2-microglobulin in the diabetic subjects (r = 0.665, P < 0.05) and with the degree of microalbuminuria in group B patients (r = 1, P < 0.01). Urinary GH was also greater than 10 microU, the median value observed in the controls, in 5 of 6 (83%) patients in group A. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) measured by constant infusion of 51Cr-ethylene diamine tetra-acetic acid (EDTA) and I125-para-amino hippuric acid (PAH), respectively, showed relative hyperfiltration in the normoalbumiruric group compared with controls (P < 0.05) and group B (P < 0.05). Absolute proximal reabsorption of sodium and of water (APRNa and APRH2O) was significantly higher in group A patients (P < 0.05). Although GFR was significantly higher in group A patients, no differences were found in fractional proximal reabsorption of sodium and water (FPRNa+H2O) or end proximal delivery between the patient groups and controls. Therefore, the measurement of protein reabsorptive capacity provides a more sensitive marker of renal tubular impairment in type 1 diabetes than sodium/fluid reabsorptive capacity. In patients with microalbuminuria, both glomerular and tubular damage may coexist. Our results stress the usefulness of markers of renal tubular function in monitoring the course of diabetic nephropathy. This study also shows that assessment of GH clearance has promise as a marker of renal tubular protein reabsorptive capacity.

Urinary growth hormone measurements as a marker of renal tubular function in diabetes mellitus

Urinary growth hormone (UGH) excretion was assessed in 44 adult subjects (10 control, 21 insulin dependent diabetics (Group I), 13 diabetics in poor glycaemic control (Group II)). UGH was markedly elevated in the diabetic population. The UGH excretion in (1) control subjects ranged from undetectable levels to 0.7 μU/h, mean 0.4, (2) Group I 73–422 μU/h, mean 250 and (3) Group II 10–5,283 μU/h, mean 705. There was a significant correlation between UGH excretion and albumin excretion rate (AER) ( r = 0.38, p < 0.05) in the subjects studied although only 50% of patients had an AER of >20 μg/min. A stronger correlation was observed between β2-microglobulin and UGH excretion ( r = 0.7, p < 0.01). There was no significant change in the 6-h serum GH levels following treatment in the patients in Group II. However a 23–79% decline in UGH excretion was observed following improvement of glycaemic control, although UGH levels failed to revert to normal. We conclude that the major factor responsible for increased UGH excretion in DM appears to be reduced tubular reabsorption of the hormone. This test may therefore prove useful as an additional marker for screening for diabetic nephropathy and may help in the understanding of the contribution of renal tubular abnormalities to the nephropathic process.

Estimation of renal tubular secretion in man, in health and disease, using endogenous N-1-methylnicotinamide.

We have been investigating the possibility of using the renal clearance of endogenous N-1-methylnicotinamide (NMN) as a marker of renal tubular function. Sixty-three subjects (11 healthy volunteers and 52 patients with renal impairment) were used for this study. The subjects were divided into three groups according to their creatinine clearance: group 1, over 80 ml/min; group 2, between 30 and 80 ml/min, and group 3, less than 30 ml/min. The correlation between NMN and creatinine clearance was compared for each group. A good correlation (r = 0.84) was found for groups 1 and 3 (r = 0.76), whereas for group 2, a poor correlation was found (r = 0.43). For subjects with mild renal impairment (group 2), there was clear evidence of glomerulo-tubular imbalance manifest by a larger variability in NMN clearance than creatinine clearance and an essentially non-parallel decline in these two parameters for this group. When all subjects were grouped together, the relationship between the clearance of NMN and of creatinine was best described by a 3-term polynomial equation (r = 0.93). NMN clearance is a potentially useful non-invasive marker of renal tubular function in man and provides additional information to that provided by the measurement of creatinine clearance alone. This substance should be more fully evaluated as a potential diagnostic aid.

Renal effects of trimethoprim in ciclosporin- and azathioprine-treated kidney-allografted patients.

Sixteen stable renal transplant patients on chronic ciclosporin (CS, n = 8) or azathioprine (AZA, n = 8) treatment were given trimethoprim (TMP) 160 mg twice a day for 7 days. This TMP dose did not affect glomerular filtration, as 99mTc-DTPA clearance was unchanged in both groups. TMP did, however, increase serum creatinine and reduce creatinine clearance in all patients. This effect was most pronounced in CS-treated patients. We conclude that even at the moderate dosage, as employed presently, TMP blocks tubular secretion of creatinine. This route for creatinine excretion is quite important as the clearance ratio between creatinine and DTPA averaged 1.21 in CS-treated patients and 1.05 in AZA-treated patients before TMP treatment. During TMP the ratio was reduced to 0.95 and 0.99, respectively, suggesting a complete cessation of tubular creatinine secretion by TMP. TMP did not, however, significantly affect other markers of renal tubular function.

Retinol binding protein as a small molecular weight marker of renal tubular function in diabetes mellitus.

A radioimmunoassay has been developed for the measurement in urine of retinol-binding protein (alpha 2-microglobulin) and used as an index of renal tubular function in adult Type 1 (insulin-dependent) diabetics and to define reference ranges in non-diabetic controls. There was a significantly greater excretion (P less than 0.001) of retinol-binding protein in the diabetic group compared to the controls in both overnight and daytime samples. There was a weak positive correlation with albumin excretion (r = 0.33; P less than 0.01) but no correlation with HbA1, duration of diabetes or arterial blood pressure. The results indicate that retinol-binding protein excretion may be increased in diabetic subjects without increased albumin excretion. The possibility therefore exists that renal tubular damage may occur early in diabetic nephropathy without apparent glomerular dysfunction.