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T W Meyer

Publications and source records attributed to T W Meyer.

At least 37 records · Page 2Linked to original sources

Clinical and pathological course of renal disease in non-insulin-dependent diabetes mellitus: the Pima Indian experience.

Non-insulin-dependent diabetes mellitus (NIDDM) and the renal disease attributable to it have been characterized extensively in the Pima Indians, a group of American Indians who form the Gila River Indian Community in Arizona. Both of these diseases are common in this community, and their onset and duration are known with greater certainty than in other populations because research examinations, which include oral glucose tolerance tests and measures of urinary protein excretion, have been performed frequently on most members of the population for the past 30 years. Studies of glomerular structure and hemodynamic function in diabetic Pima Indians indicate that glomerular hyperfiltration often develops at the onset of NIDDM and remains elevated until after overt nephropathy appears. Structurally, the glomeruli in subjects with microalbuminuria are not clearly distinguishable from those in subjects with normoalbuminuria, but macroalbuminuria is characterized by extensive glomerular sclerosis, mesangial expansion, and widening of epithelial cell foot processes that together lead to a rapid decline in the glomerular filtration rate. The decline in glomerular function in subjects with macroalbuminuria is due both to a loss of ultrafiltration surface area and to reduction in glomerular hydraulic permeability.

Albuminuria↗

Course of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus.

The course of renal disease attributable to non-insulin-dependent diabetes mellitus (NIDDM) has been characterized extensively in the Pima Indians of Arizona. Studies in this population indicate that the glomerular filtration rate often increases at the onset of NIDDM and remains elevated as long as normal urinary albumin excretion (< 30 mg albumin/g creatinine) or microalbuminuria (30-299 mg albumin/g creatinine) persist. After the development of macroalbuminuria (> or = 300 mg albumin/g creatinine), the glomerular filtration rate declines at least as rapidly as reported in subjects with insulin-dependent diabetes. Morphologic examination of kidney tissue reveals extensive glomerular sclerosis, mesangial expansion, and widening of epithelial cell foot processes and the glomerular basement membrane in the subjects with macroalbuminuria, but not in those with normo- or microalbuminuria. These findings suggest that substantial structural damage to the kidney occurs at or about the time that macroalbuminuria develops, and the decline in glomerular function in those with macroalbuminuria is due to a loss of ultrafiltration surface area and a reduction in glomerular hydraulic permeability.

Albuminuria↗

In vivo suppression of the renal Na+/Pi cotransporter by antisense oligonucleotides.

A 20-mer phosphorothioate oligonucleotide (AS1) was designed to hybridize to the message for the rat kidney sodium phosphate cotransporter NaPi-2 close to the translation initiation site. Single intravenous doses of this oligonucleotide were given to rats maintained on a low phosphorus diet to increase NaPi-2 expression. At 3 days after oligonucleotide infusion, rats receiving 2.5 micromol of AS1 exhibited a reduction in renal NaPi-2 to cyclophilin mRNA ratio by 40% +/- 17%, and rats receiving 7.5 micromol of AS1 exhibited a reduction in NaPi-2 to cyclophilin mRNA ratio by 46% +/- 21%. Reversed-sequence AS1 was without effect. The higher dose of 7.5 micromol of AS1 also reduced the rate of phosphate uptake into renal brush border membrane vesicles and the expression of NaPi-2 protein detected by Western blotting in these vesicles. Reversed sequence AS1 was again without effect on these parameters. These results suggest that systemically infused oligonucleotides can exert antisense effects in the renal proximal tubule.

Animals↗

Atubular glomeruli in patients with chronic allograft rejection.

Morphometric studies were performed in 15 patients with chronic renal allograft rejection. Biopsy cores were serially sectioned so that atubular glomeruli could be identified and volumes of individual glomeruli could be measured. Control tissue was obtained from 9 cadaver donors and 8 living donors. Serial sectioning revealed that atubular glomeruli were as common as sclerotic glomeruli in chronic rejection. The prevalence of atubular glomeruli averaged 18 +/- 15% (mean +/- SD) in recipients with chronic rejection, 2 +/- 2% in cadaver donors, and 1 +/- 3% in living donors (P<0.05, recipients vs. donor groups). In comparison, the prevalence of sclerotic glomeruli averaged 19 +/- 13%, 4 +/- 7%, and 7 +/- 10% in the three groups (P<0.05 recipients vs. donor groups). Atubular glomeruli exhibited reduced mean volume (3.1 +/- 0.9 x 10(6)micron(3) vs. 4.5 +/- 1.5 x lO(6)micron(3), atubular vs. open glomeruli in recipients, P < 0.05) but could not be distinguished from open glomeruli by their appearance on single sections. Recipients with chronic rejection exhibited tubular atrophy and interstitial fibrosis with an increase in the interstitial volume fraction to 51 +/- 14% as compared with 29 +/- 6% in cadaver donors and 17 +/- 2% in living donors (P<0.05 recipients vs. donor groups). Similar interstitial expansion was observed in recipients with a high prevalence of atubular glomeruli, recipients with a high prevalence of sclerotic glomeruli, and also in four recipients in whom the predominant form of glomerular injury was transplant glomerulopathy. These results suggest that mechanisms responsible for development of atubular glomeruli are among the processes that contribute to loss of graft function in patients with chronic rejection.

Adult↗

Antisense and the kidney.

Antisense oligonucleotides are being used as gene-therapeutic agents. This short overview focuses on the in vivo kinetics and on potential in vivo applications for research purposes as well as therapeutic applications. The most promising experimental results have been obtained with oligonucleotides targeted against genes involved in cell proliferation, such as c-myc, c-myb, Kras, and cdc-2. High parenteral doses of such oligonucleotides have limited growth of experimental tumors, and local application of such oligonucleotides has limited neointimal proliferation in injured arteries. Therapeutic use of antisense in the kidney seems more distant. Because proximal tubule cells take up circulating oligonucleotides, transient suppression of proximal tubule message expression may be obtained following parenteral oligonucleotide administration. More sophisticated delivery systems, however, will be required to achieve antisense efficacy over longer periods and in other compartments of the kidney.

Animals↗

Renal uptake of an 18-mer phosphorothioate oligonucleotide.

Renal uptake of a 35S labeled 18-mer phosphorothioate oligodeoxynucleotide (molecular wt approximately 6,000) was evaluated following intravenous infusion into rats. The kidneys contained 21 +/- 3% of the infused dose at five hours after infusion and 3 +/- 1% of the infused dose at four days after infusion. The concentration of oligonucleotide was greater in the kidney than in the liver, spleen, or plasma at both intervals. Urine excretion of oligonucleotide label averaged 17 +/- 1%, 35 +/- 5%, and 64 +/- 3% of the infused dose at five hours, one day, and four days after infusion. Electrophoresis (PAGE) showed that oligonucleotide was retained in the kidney was the intact 18-mer at both five hours and four days after infusion, while full size oligonucleotide was not found in the urine at either interval. Light microscopic autoradiography showed that oligonucleotide uptake was most prominent in the early proximal tubule. Electron microscopic autoradiography indicated that oligonucleotide was not confined to the brush border or endocytic-lysosomal pathway. Micropuncture studies showed that the tubule fluid to plasma concentration ratios of oligonucleotide label averaged 7 +/- 3% in Bowman's space and 6 +/- 2% in the distal tubule. Despite restriction of filtration by plasma protein binding, as indicated by the low Bowman's space to plasma concentration ratio, the calculated tubular reabsorption rate for oligonucleotide was sufficient to account for the large amount of oligonucleotide found in the kidney after intravenous infusion. These results indicate that the proximal tubule plays a prominent role in the disposition of intravenously infused oligonucleotide, and raise the possibility that oligonucleotides could exert antisense effects in this nephron segment.

Animals↗

Morphometric analysis of effects of angiotensin II on glomerular structure in rats.

Micropuncture and morphometric studies related the effects of angiotensin II (ANG II) on glomerular function and structure. Compared with control animals, rats receiving an intrarenal infusion of ANG II at 40 ng.kg-1.min-1 exhibited a marked reduction in the glomerular ultrafiltration coefficient (Kf) (0.84 +/- 0.13 vs. 1.43 +/- 0.05 microliters.s-1.mmHg-1, ANG II vs. control), which caused a decrease in glomerular filtration rate (GFR) (1.04 +/- 0.11 vs. 1.27 +/- 0.11 ml/min) despite an increase in glomerular transcapillary hydraulic pressure difference (46 +/- 1 vs. 40 +/- 1 mmHg). Morphometric studies showed that these hemodynamic changes were not associated with any reduction in glomerular volume (1.27 +/- 0.05 vs. 1.31 +/- 0.07 x 10(6) microns3, ANG II vs. control), glomerular capillary volume (4.25 +/- 0.36 vs. 4.41 +/- 0.33 x 10(5) microns3), or glomerular peripheral capillary surface area (2.24 +/- 0.11 vs. 2.29 +/- 0.30 x 10(5) microns2). Higher-power electron micrographs showed that ANG II also did not alter mean foot process width (478 +/- 14 vs. 491 +/- 18 nm, ANG II vs. control), reduce the total filtration slit length overlying the peripheral capillary wall (7.0 +/- 0.6 vs. 6.6 +/- 0.5 x 10(5) microns), or reduce the average width of individual filtration slits (45 +/- 2 vs. 43 +/- 2 nm). ANG II infusion thus caused a 40% reduction in the value of Kf without causing detectable changes in epithelial cell or filtration slit structure.

Angiotensin II↗

Tubulointerstitial injury and impaired renal function after recovery from acute puromycin nephrosis.

Renal function was assessed at 2 and 8 wk after infusion of puromycin into the left renal artery of Munich Wistar rats. At 2 wk, albumin excretion averaged 90 +/- 12 micrograms/min in the left kidney and 4 +/- 1 microgram/min in the right kidney. Unilateral nephrosis was accompanied by reduction in the glomerular filtration rate (GFR) (left, 0.71 +/- 0.04; right, 1.31 +/- 0.02 ml/min) and by impaired excretion of sodium (FENa; left, 0.025 +/- 0.004; right, 0.064 +/- 0.006%). Reductions in GFR and FENa in the nephrotic kidney were not reversed by acute angiotensin II receptor blockade with losartan. At 8 wk, albumin excretion averaged 6 +/- 1 in the left kidney and 8 +/- 1 microgram/min in the right kidney. Recovery from nephrosis was accompanied by persistent reduction in GFR (left, 1.05 +/- 0.05; right, 1.41 +/- 0.05 ml/min) and impairment of sodium excretion in the previously nephrotic left kidney (left, 0.031 +/- 0.004; right, 0.051 +/- 0.004%). Losartan again did not return GFR and FENa toward normal. The reductions in GFR and FENa in the previously nephrotic left kidney were associated with structural changes, including intratubular casts, an increased fractional volume of the interstitium (left, 25 +/- 1; right, 15 +/- 1%), decreased fractional volume of tubules (left, 66 +/- 2; right, 77 +/- 1%), and glomerular collapse (left, 15 +/- 2; right, 1 +/- 1%). These findings suggest that tubulointerstitial injury can cause persistent reduction in GFR and impairment of sodium excretion after recovery from acute nephrosis.

Acute Disease↗

Endothelial cell injury initiates glomerular sclerosis in the rat remnant kidney.

The development of progressive glomerulosclerosis in the renal ablation model has been ascribed to a number of humoral and hemodynamic events, including the peptide growth factor, transforming growth factor-beta 1 (TGF-beta 1). An important role has also been attributed to angiotensin II (AII), which, in addition to its hemodynamic effects, can stimulate transcription of TGF-beta 1. We postulated that increased glomerular production of AII, resulting from enhanced intrinsic angiotensinogen expression, stimulates local TGF-beta 1 synthesis, activating glomerular matrix protein synthesis, and leads to sclerosis. Using in situ reverse transcription, the glomerular cell sites of alpha-1 (IV) collagen, fibronectin, laminin B1, angiotensinogen, and TGF-beta 1 mRNA synthesis were determined at sequential periods following renal ablation. The early hypertrophic phase was associated with global, but transient, increases in the mRNA for alpha-1 (IV) collagen. No changes were noted for fibronectin, TGF-beta 1, and angiotensinogen mRNAs. At 24 d after ablation, at which time sclerosis is not evident, endothelial cells, particularly in the dilated capillaries at the vascular pole, expressed angiotensinogen and TGF-beta 1 mRNAs, as well as fibronectin and laminin B1 RNA transcripts. By 74 d after ablation angiotensinogen and TGF-beta 1 mRNAs were widely distributed among endothelial and mesangial cells, and were particularly prominent in regions of evolving sclerosis. These same regions were also notable for enhanced expression of matrix protein mRNAs, particularly fibronectin. All receptor blockade inhibited angiotensinogen, TGF-beta 1, fibronectin, and laminin B1 mRNA expression by the endothelium. We conclude that, as a result of hemodynamic changes, injured or activated endothelium synthesizes angiotensinogen, triggering a cascade of TGF-beta 1 and matrix protein gene expression with resultant development of the segmental glomerular sclerotic lesion.

Angiotensin II↗

The effect of hyperglycemia on glomerular function in obese Zucker rats.

Studies were carried out in two groups of obese male Zucker rats with hereditary insulin resistance. Group 1 rats were made hyperglycemic by reducing beta-cell reserve with streptozotocin. Group 2 rats served as controls. Group 1 rats exhibited hyperglycemia (blood glucose concentration, 263 +/- 14 mg/dl) whereas insulin levels remained greater than those observed in lean rats (plasma insulin concentrations: group 1,508 +/- 89 mU/ml; lean rats, 91 +/- 23 mU/ml). In group 2 rats more marked hyperinsulinemia (plasma insulin concentration, 1096 +/- 234 mU/ml) maintained normoglycemia (blood glucose concentration, 75 +/- 4 mg/dl). Studies at 5 weeks showed that hyperglycemic group 1 rats exhibited increases in kidney weight (group 1, 2.78 +/- 0.11 gm; group 2, 2.16 +/- 0.07 gm; p < 0.05) and glomerular filtration rate (GFR) (group 1, 1.83 +/- 0.08 ml/min; group 2, 1.55 +/- 0.10 ml/min; p < 0.05). Micropuncture revealed that the increase in GFR in hyperglycemic rats was attributable to increases in the single-nephron plasma flow rate (group 1, 225 +/- 16 nl/min; group 2, 172 +/- 14 nl/min; p < 0.05) and the glomerular ultrafiltration coefficient (group 1, 2.49 +/- 0.17 nl/min/mm Hg; group 2, 2.02 +/- 0.14 nl/min/mm Hg; p < 0.05), which were not accompanied by an increase in glomerular transcapillary hydraulic pressure (group 1, 49 +/- 1 mm Hg; group 2, 48 +/- 1 mm Hg). Morphologic studies revealed that the increase in GFR in group 1 was associated with an increase in glomerular volume (group 1, 3.46 +/- 0.15 x 10(6) m3; group 2, 2.99 +/- 0.14 x 10(6) m3; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

The effect of acute angiotensin II blockade on renal function in rats with reduced renal mass.

The effect of acute Ang II blockade on renal function in rats with reduced nephron number was assessed in micropuncture studies. The Ang II receptor blocker, losartan, was administered at a dose of 10 mg i.v. at two intervals following five-sixths renal ablation. At eight weeks following ablation, Ang II blockade (Ang IIX) increased sodium excretion [UNa V, Ang IIX 2.2 +/- 0.4 microEq/min; time control (TC) 1.0 +/- 0.3 microEq/min; P < 0.05] but did not reduce mean arterial pressure (AP, Ang IIX 142 +/- 6 mm Hg; TC 151 +/- 6 mmHg), glomerular transcapillary pressure (delta P, Ang IIX 50 +/- 1 mm Hg; TC 50 +/- 1 mm Hg), or urine albumin excretion (UAlb V: Ang IIX 149 +/- 18 micrograms/min; TC 168 +/- 20 micrograms/min). Similarly, at two weeks following ablation, Ang II blockade increased UNa V (Ang IIX 2.8 +/- 0.4 microEq/min; TC 0.5 +/- 0.2 microEq/min; P < 0.05) without reducing AP (Ang IIX 132 +/- 6 mm Hg; TC 140 +/- 7 mm Hg), delta P (Ang IIX 50 +/- 3 mm Hg; TC 48 +/- 2 mm Hg), or UAlb V (Ang IIX 32 +/- 3 micrograms/min; TC 36 +/- 10 micrograms/min). These findings indicate that within the remant kidney, Ang II promotes sodium retention but does not have an acutely reversible effect on glomerular pressure or permselectivity.

Albuminuria↗

Forty-five year follow-up after uninephrectomy.

This study examined the consequences of nephrectomy in United States Army personnel who lost a kidney due to trauma during World War II (WWII). Records of 62 servicemen who underwent nephrectomy at an average age of 25 years were obtained. Mortality was compared with that of WWII servicemen of the same age. Medical records of 28 deceased subjects were reviewed for evidence of kidney disease. Medical histories were obtained and blood pressure and kidney function were assessed in 28 living subjects. Two subjects could not be located, and four subjects declined to participate. Mortality at 45 years was not increased in nephrectomized subjects. Kidney disease present in six of 28 deceased subjects was attributable to causes other than prior nephrectomy. Glomerular sclerosis was not increased in 10 subjects who had autopsy examinations. The prevalence of hypertension was not increased in living subjects. Five of 28 living subjects had abnormal renal function manifested by proteinuria greater than 250 mg/day in four cases (range: 377 to 535 mg/day) and serum creatinine levels greater than 1.5 mg/dl in three cases (range: 1.7 to 1.9 mg/dl). Conditions other than nephrectomy could have contributed to impairment of renal function in each of these subjects. These findings suggest that uninephrectomy in young adults has few major adverse consequences over 45 years.

Adult↗

Effects of angiotensin II receptor blockade on remnant glomerular permselectivity.

This study examined the mechanisms by which angiotensin II (Ang II) receptor blockade improves glomerular barrier function in rats with reduced nephron number. Proteinuria was measured at four weeks after 5/6 renal ablation, and rats were then divided into a group which received the Ang II receptor blocker MK954 and a group which received no treatment. Studies performed one week later showed that Ang II receptor blockade reduced proteinuria without altering GFR in renal ablated rats. Micropuncture studies showed that Ang II blockade reduced both mean arterial pressure (142 +/- 7 mm Hg, ablation without treatment; 105 +/- 2 mm Hg, ablation with treatment) and glomerular transcapillary pressure (54 +/- 3 mm Hg, ablation without treatment; 43 +/- 1 mm Hg, ablation with treatment). Dextran sieving studies showed that untreated rats developed a size-selective defect characterized by increased transglomerular passage of neutral dextrans with radii 54 to 76 A and a charge-selective defect characterized by an increased transglomerular passage of anionic dextran sulfate with a radius of approximately 18 A. Ang II blockade reduced fractional clearance values for large neutral dextrans near to values observed in normal rats but had no effect on the fractional clearance of dextran sulfate (0.68 +/- 0.11, ablation without treatment; 0.66 +/- 0.08, ablation with treatment; 0.46 +/- 0.05, normal rats). These findings indicate that reducing Ang II activity improves size-selectivity without affecting charge-selectivity in injured remnant glomeruli.

Angiotensin II↗

The effects of blood pressure reduction on cyclosporine nephrotoxicity in the rat.

The effects of blood pressure reduction on cyclosporine nephrotoxicity were studied over 12 months in four groups of rats. Group 1 received no drugs and served as controls. Groups 2, 3, and 4 received cyclosporine (CyA), approximately 9 mg/kg.day, in their food. In addition, Group 3 received enalapril and Group 4 received minoxidil, hydrochlorothiazide, and reserpine. Time-averaged monthly systolic blood pressure was equal in Groups 1 and 2 (136 +/- 1 and 135 +/- 1 mm Hg, respectively). Antihypertensive agents reduced average systolic blood pressure in Groups 3 and 4 (116 +/- 1 and 117 +/- 1 mm Hg, respectively). Morphometric studies showed that 12 months of CyA treatment caused interstitial fibrosis with an increase in the fractional volume of cortical interstitium (VvInt: Group 2, 20 +/- 1%; Group 1, 11 +/- 1%) and a reduction in mean glomerular volume (VG. Group 2, (2.00 +/- 0.06) x 10(6) mu 3; Group 1, (2.48 +/- 0.06) x 10(6) mu 3). These structural changes were accompanied by a significant reduction in GFR (Group 2, 2.27 +/- 0.10 mL/min; Group 1, 2.76 +/- 0.10 mL/min). Cotreatment with enalapril reduced interstitial fibrosis (VvInt, 14 +/- 1%) and maintained VG (2.23 +/- 0.08 x 10(6) mu 3) and GFR (2.56 +/- 0.08 mL/min) at near-normal values in Group 3. In contrast, the combination antihypertensive regimen increased the extent of interstitial fibrosis (VvInt, 24 +/- 1%) and further lowered VG (1.72 +/- 0.05 x 10(6) mu 3) and GFR (1.72 +/- 0.05 mL/min) in Group 4. These results show that sustained treatment with a moderate dose of CyA causes interstitial fibrosis and impairs renal function in rats. The administration of enalapril, but not minoxidil, reserpine, and hydrochlorothiazide, limits renal injury in this model.

Animals↗

Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass.

The effects of angiotensin II (AII) blockade were compared with the effects of angiotensin converting enzyme inhibition in rats with reduced nephron number. Rats were subjected to five-sixths renal ablation and divided into four groups with similar values for blood pressure and serum creatinine after 2 wk. Group 1 then served as untreated controls, while group 2 received the AII receptor antagonist MK954 (which has previously been designated DuP753), group 3 received the converting enzyme inhibitor enalapril, and group 4 received a combination of reserpine, hydralazine, and hydrochlorothiazide. Micropuncture and morphologic studies were performed 10 wk later. Converting enzyme inhibition, AII receptor blockade, and the combination regimen were equally effective in reversing systemic hypertension (time-averaged systolic blood pressure: group 1, 185 +/- 5 mmHg; group 2, 125 +/- 2 mmHg; group 3, 127 +/- 2 mmHg; group 4, 117 +/- 4 mmHg). Micropuncture studies showed that glomerular transcapillary pressure was reduced significantly by converting enzyme inhibition and by AII blockade but not by the combination regimen (delta P: group 1, 49 +/- 1 mmHg; group 2, 42 +/- 1 mmHg; group 3, 40 +/- 2 mmHg, group 4, 47 +/- 1 mmHg). Reduction of systemic blood pressure was associated with the development of markedly less proteinuria and segmental glomerular sclerosis in rats receiving enalapril and MK954 but not in rats receiving the combination regimen (prevalence of glomerular sclerotic lesions: group 1, 41 +/- 4%; group 2, 9 +/- 1%; group 3, 9 +/- 1%; group 4, 33 +/- 6%). These results indicate that the effects of converting enzyme inhibition on remnant glomerular function and structure depend on reduction in AII activity and are not attributable simply to normalization of systemic blood pressure.

Angiotensin II↗

Glomerular hypertrophy accelerates hypertensive glomerular injury in rats.

Micropuncture and morphological studies were performed in four groups of rats that received subcutaneous infusions of saline or angiotensin II (ANG II) for 8 wk. Group 1 rats received saline; group 2 rats were subjected to uninephrectomy and then received saline; group 3 rats received ANG II (100 ng/min); and group 4 rats were subjected to uninephrectomy and then received ANG II (50 ng/min). In comparison with group 1 rats, group 2 rats exhibited no increase in mean arterial pressure (MAP) (group 2, 102 +/- 6 mmHg; group 1, 104 +/- 10 mmHg) or glomerular capillary pressure (PGC) (group 2, 56 +/- 3 mmHg; group 1, 55 +/- 4 mmHg). In the absence of glomerular hypertension, an increase in glomerular volume (VG) was not associated with glomerular sclerosis in group 2 rats. In contrast to group 2 rats, group 3 rats exhibited increases in MAP (161 +/- 13 mmHg) and PGC (70 +/- 7 mmHg) without any increase in VG. Glomerular hypertension was associated with development of increased albuminuria and glomerular sclerosis in group 3. Group 4 rats exhibited increases in MAP (157 +/- 18 mmHg), PGC (69 +/- 6 mmHg), and VG. These rats also developed glomerular sclerosis and significantly more albuminuria than would have been expected from simple combination of effects of uninephrectomy and ANG II infusion. Additional morphological studies were performed in two groups of rats that received ANG II for 12 wk. Over this period, uninephrectomized group 6 rats infused with ANG II (50 ng/min) developed markedly greater albuminuria and glomerular sclerosis than intact group 5 rats infused with ANG II (100 ng/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Albuminuria↗