Modest Salt Reduction Lowers Blood Pressure and Albumin Excretion in Impaired Glucose Tolerance and Type 2 Diabetes Mellitus: A Randomized Double-Blind Trial.

The role of salt restriction in patients with impaired glucose tolerance and diabetes mellitus is controversial, with a lack of well controlled, longer term, modest salt reduction trials in this group of patients, in spite of the marked increase in cardiovascular risk. We carried out a 12-week randomized double-blind, crossover trial of salt restriction with salt or placebo tablets, each for 6 weeks, in 46 individuals with diet-controlled type 2 diabetes mellitus or impaired glucose tolerance and untreated normal or high normal blood pressure (BP). From salt to placebo, 24-hour urinary sodium was reduced by 49±9 mmol (2.9 g salt). This reduction in salt intake led to fall in clinic BP from 136/81±2/1 mm Hg to 131/80±2/1 mm Hg, (systolic BP; P<0.01). Mean ambulatory 24-hour BP was reduced by 3/2±1/1 mm Hg (systolic BP, P<0.01 and diastolic BP, P<0.05), and albumin/creatinine ratio was reduced from 0.73 mg/mmol (0.5-1.5) to 0.64 mg/mmol (0.3-1.1; P<0.05). There was no significant change in fasting glucose, hemoglobin A1c, or insulin sensitivity. These results demonstrate that a modest reduction in salt intake, to approximately the amount recommended in public health guidelines, leads to significant and clinically relevant falls in BP in individuals who are early on in the progression of diabetes mellitus with normal or mildly raised BP. The reduction in urinary albumin excretion may carry additional benefits in reducing cardiovascular disease above the effects on BP.

Urinary catecholamines and the relationship with blood pressure and pharmacological therapy.

OBJECTIVES: Our aim was to assess the importance of the sympathetic nervous system as assessed by urinary catecholamine measurement in the aetiology of essential hypertension and the importance of antihypertensive therapy in the excretion of urinary catecholamines. METHODS: Twenty-four-hour urinary catecholamine measurement was performed in 1925 patients who were referred for treatment of hypertension and grouped according to the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure classification: of the 655 untreated patients, 59 were normotensive individuals (SBP < 140 and DBP < 90 mmHg), n = 219 stage 1 (SBP 140-159 or DBP 90-99 mmHg), n = 236 stage 2 (SBP 160-179 or DBP 100-109 mmHg) and n = 141 stage 3 (SBP ≥ 180 or DBP ≥ 110 mmHg). RESULTS: There was a statistically significant positive relationship between 24-h urinary norepinephrine excretion and the severity of hypertension, such that the higher the blood pressure the higher the urinary norepinephrine excretion (mean ±â€Šstandard error of mean): normotensive group, 221 ±â€Š13 nmol/24 h; stage 1, 254 ±â€Š8 nmol/24 h; stage 2, 263 ±â€Š7 nmol/24 h and stage 3, 296 ±â€Š12 nmol/24 h (P < 0.001). The above relationship remained highly significant when corrected for urinary creatinine, weight, age and sex. No differences were found with urinary epinephrine or dopamine excretion. Urinary norepinephrine excretion was increased in those patients taking single-drug therapy with either a long-acting dihydropyridine calcium antagonist or a ß-blocker. CONCLUSION: Our results demonstrate that in untreated hypertensive patients, urinary norepinephrine excretion is increased in proportion to the severity of blood pressure rise and also in patients taking a long-acting dihydropyridine calcium antagonist or a ß-blocker. Sympathetic overactivity may play a role in the aetiology and maintenance of essential hypertension.

Altering plasma sodium concentration rapidly changes blood pressure during haemodialysis.

BACKGROUND: Plasma sodium is increased following each meal containing salt. There is an increasing interest in the effects of plasma sodium concentration, and it has been suggested that it may have direct effects on blood pressure (BP) and possibly influences endothelial function. Experimental increases of plasma sodium concentration rapidly raise BP even when extracellular volume falls. METHODS: Ten patients with end-stage renal failure established on haemodialysis were studied during the first 2 h of dialysis without fluid removal during this period. They were randomized to receive haemodialysis with (i) dialysate sodium concentration prescribed to 135 mmol/L and (ii) 145 mmol/L in random order in a prospective, single-blinded crossover study. BP measurements and blood samples were taken every 30 min. RESULTS: Pre-dialysis sitting BP was 137/76 ± 7/3 mmHg. Lower dialysate sodium concentration (135 mmol/L) reduced plasma sodium concentration [139.49 ± 0.67 to 135.94 ± 0.52 mmol/L (P < 0.001)], whereas plasma sodium concentration was not altered by higher dialysate sodium (145 mmol/L) (140.17 ± 0.66 mmol/L at baseline to 140.72 ± 0.43 mmol/L at 120 min). Systolic BP was lower with dialysate sodium concentration 135 mmol/L [area under the curve (AUC) 15823.50 ± 777.15 (mmHg)min] compared with 145 mmol/L [AUC 17018.20 ± 1102.17 (mmHg)min], mean difference 1194.70 ± 488.41 (mmHg)min, P < 0.05. There was a significant positive relationship between change in plasma sodium concentration and change in systolic BP. This direct relationship suggests that a fall of 1 mmol/L in plasma sodium concentration would be associated with a 1.7 mmHg reduction in systolic BP (P < 0.05). CONCLUSIONS: The potential mechanism for the increase in BP seen with salt intake may be through small but significant changes in plasma sodium concentration.

Dietary salt influences postprandial plasma sodium concentration and systolic blood pressure.

The plasma sodium concentration has a direct effect on blood pressure in addition to its effects on extracellular volume regulated through changes in the endothelium. The mechanism for elevated blood pressure seen with habitually increased salt intake is unclear, especially the effect of salt in a single meal on plasma sodium concentration and blood pressure. To resolve this we compared the effect of soup with or without 6 g of salt (an amount similar to that in a single meal) on the plasma sodium concentration and blood pressure in 10 normotensive volunteers using a randomized, crossover design. The plasma sodium concentration was significantly increased by 3.13±0.75 mmol/l with salted compared with unsalted soup. Blood pressure increased in volunteers ingesting soup with added salt, and there was a significant positive correlation between plasma sodium concentration and systolic blood pressure. A 1-mmol/l increase in plasma sodium was associated with a 1.91-mm Hg increase in systolic blood pressure by linear regression. Thus, changes in plasma sodium concentration occur each time a meal containing salt is consumed. A potential mechanism for the changes in blood pressure seen with salt intake may be through its effects on plasma sodium concentration.

Effect of modest salt reduction on skin capillary rarefaction in white, black, and Asian individuals with mild hypertension.

Microvascular rarefaction occurs in hypertension. We carried out a 12-week randomized double-blind crossover trial to determine the effect of a modest reduction in salt intake on capillary rarefaction in 71 whites, 69 blacks, and 29 Asians with untreated mildly raised blood pressure. Both basal and maximal (during venous congestion) skin capillary density were measured by capillaroscopy at the dorsum and the side of the fingers. In addition, we used orthogonal polarization spectral imaging to measure skin capillary density at the dorsum of the fingers and the hand web. With a reduction in salt intake from 9.7 to 6.5 g/day, there was an increase in capillary density (capillaries per millimeter squared) from 101+/-21 to 106+/-23 (basal) and 108+/-22 to 115+/-22 (maximal) at the dorsum, and 101+/-25 to 107+/-26 (basal) and 110+/-26 to 116+/-26 (maximal) at the side of the fingers (P<0.001 for all). Orthogonal polarization spectral imaging also showed a significant increase in capillary density both at the dorsum of the fingers and the web. Subgroup analysis showed that most of the changes were significant in all of the ethnic groups. Furthermore, there was a significant relationship between the change in 24-hour urinary sodium and the change in capillary density at the side of the fingers. These results demonstrate that a modest reduction in salt intake, as currently recommended, improves both functional and structural capillary rarefactions that occur in hypertension, and a larger reduction in salt intake would have a greater effect. The increase in capillary density may possibly carry additional beneficial effects on target organs.

Effects of potassium chloride and potassium bicarbonate on endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives.

To determine the effects of potassium supplementation on endothelial function, cardiovascular risk factors, and bone turnover and to compare potassium chloride with potassium bicarbonate, we carried out a 12-week randomized, double-blind, placebo-controlled crossover trial in 42 individuals with untreated mildly raised blood pressure. Urinary potassium was 77+/-16, 122+/-25, and 125+/-27 mmol/24 hours after 4 weeks on placebo, potassium chloride, and potassium bicarbonate, respectively. There were no significant differences in office blood pressure among the 3 treatment periods, and only 24-hour and daytime systolic blood pressures were slightly lower with potassium chloride. Compared with placebo, both potassium chloride and potassium bicarbonate significantly improved endothelial function as measured by brachial artery flow-mediated dilatation, increased arterial compliance as assessed by carotid-femoral pulse wave velocity, decreased left ventricular mass, and improved left ventricular diastolic function. There was no significant difference between the 2 potassium salts in these measurements. The study also showed that potassium chloride reduced 24-hour urinary albumin and albumin:creatinine ratio, and potassium bicarbonate decreased 24-hour urinary calcium, calcium:creatinine ratio, and plasma C-terminal cross-linking telopeptide of type 1 collagen significantly. These results demonstrated that an increase in potassium intake had beneficial effects on the cardiovascular system, and potassium bicarbonate may improve bone health. Importantly, these effects were found in individuals who already had a relatively low-salt and high-potassium intake.

Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives.

A reduction in salt intake lowers blood pressure. However, most previous trials were in whites with few in blacks and Asians. Salt reduction may also reduce other cardiovascular risk factors (eg, urinary albumin excretion, arterial stiffness). However, few well-controlled trials have studied these effects. We carried out a randomized double-blind crossover trial of salt restriction with slow sodium or placebo, each for 6 weeks, in 71 whites, 69 blacks, and 29 Asians with untreated mildly raised blood pressure. From slow sodium to placebo, urinary sodium was reduced from 165+/-58 (+/-SD) to 110+/-49 mmol/24 hours (9.7 to 6.5 g/d salt). With this reduction in salt intake, there was a significant decrease in blood pressure from 146+/-13/91+/-8 to 141+/-12/88+/-9 mm Hg (P<0.001), urinary albumin from 10.2 (IQR: 6.8 to 18.9) to 9.1 (6.6 to 14.0) mg/24 hours (P<0.001), albumin/creatinine ratio from 0.81 (0.47 to 1.43) to 0.66 (0.44 to 1.22) mg/mmol (P<0.001), and carotid-femoral pulse wave velocity from 11.5+/-2.3 to 11.1+/-1.9 m/s (P<0.01). Subgroup analysis showed that the reductions in blood pressure and urinary albumin/creatinine ratio were significant in all groups, and the decrease in pulse wave velocity was significant in blacks only. These results demonstrate that a modest reduction in salt intake, approximately the amount of the current public health recommendations, causes significant falls in blood pressure in all 3 ethnic groups. Furthermore, it reduces urinary albumin and improves large artery compliance. Although both could be attributable to the falls in blood pressure, they may carry additional benefits on reducing cardiovascular disease above that obtained from the blood pressure falls alone.

The effect of sodium and angiotensin-converting enzyme inhibition on the classic circulating renin-angiotensin system in autosomal-dominant polycystic kidney disease patients.

BACKGROUND: It has been suggested that inappropriate stimulation of the renin-angiotensin system (RAS) is responsible for the increase in blood pressure that occurs in autosomal-dominant polycystic kidney disease (ADPKD) before the development of renal failure. However, the interpretation of previous studies in ADPKD patients is confounded by inadequate matching with control populations for blood pressure and renal function, or failure to control the sodium intake of participants. METHODS: A double-blind, placebo-controlled study of two different sodium intakes (350 and 50 mmol/day for 5 days) in a group of 11 hypertensive ADPKD patients and eight matched control subjects with essential hypertension. In addition, blood pressure and hormonal responses were measured after the administration of the angiotensin-converting enzyme inhibitor enalapril for 3 days. RESULTS: Blood pressure and hormonal responses of the RAS after a reduction in sodium intake and after the administration of enalapril were identical in ADPKD patients and controls. CONCLUSIONS: Activation of the classic circulating RAS is no greater in hypertensive ADPKD patients than in individuals with essential hypertension.

Modest salt reduction reduces blood pressure and urine protein excretion in black hypertensives: a randomized control trial.

High blood pressure and proteinuria are the major risk factors for cardiovascular and renal disease. In black individuals, there is an increased risk of hypertension, stroke, heart failure, and kidney disease. There are no controlled studies of the effects of reducing salt intake on blood pressure and urine protein excretion in black individuals. Therefore, the aim of our study was to determine the effects of modest salt restriction on blood pressure and urine protein excretion in nondiabetic black hypertensive subjects. The study was randomized, double blind, and placebo controlled. After run-in periods on their usual diet and on reduced salt, participants continued to restrict their salt intake and then received either slow sodium tablets, designed to bring their salt intake back to normal, or placebo tablets for 4 weeks in a randomized, double-blind, crossover study. In the 40 who completed the study, urinary sodium excretion fell on slow sodium to placebo from 169+/-73 to 89+/-52 mmol per 24 hours (P<0.001; approximately 10 to 5 g salt per day). Blood pressure fell from 159/101+/-13/8 to 151/98+/-13/8 mm Hg (P<0.01). Protein excretion fell from 93+/-48 mg to 75+/-30 mg per 24 hours (P<0.008). Thus, reducing salt intake from approximately 10 to 5 g per day reduced blood pressure and urine protein excretion in black hypertensives. In light of these findings, we would recommend that all black individuals with raised blood pressure reduce their salt intake to < or =5 g per day.

Modest salt reduction lowers blood pressure in isolated systolic hypertension and combined hypertension.

Many randomized trials have shown that a reduction in salt intake lowers blood pressure in hypertensive individuals. However, few have looked at the effects according to hypertension category. A recent analysis of the third and fourth National Health and Nutrition Examination Survey suggests that salt intake may not be related to blood pressure in isolated systolic or combined hypertension. To look at this further, we reanalyzed the data of our previous salt reduction trials. Hypertensive individuals were studied in randomized double-blind crossover studies: 1 month of usual salt intake compared with 1 month of reduced salt intake. In isolated systolic hypertension (n=24), blood pressure was reduced from 166+/-19/86+/-7 to 156+/-20/85+/-7 mm Hg (systolic P<0.001; diastolic P=0.459) with a reduction in urinary sodium from 175+/-51 to 87+/-38 mmol per 24-hour period (10.3 to 5.1 g per day of salt). In combined hypertension (n=88), blood pressure was reduced from 161+/-16/100+/-9 to 154+/-17/96+/-9 mm Hg (P<0.001) with a reduction urinary sodium from 176+/-65 to 98+/-51 mmol per 24-hour period (10.4 to 5.8 g per day of salt). These results demonstrate that salt reduction has a significant effect on blood pressure in isolated systolic and combined hypertension. The fall in systolic observed in isolated systolic hypertension would be predicted to reduce stroke by approximately one third, ischemic heart disease by one quarter, and heart failure by one quarter in the population between 60 and 80 years of age, in whom isolated systolic hypertension is the predominate form of hypertension and carries the highest risk. These results provide strong support for universal salt reduction in all hypertensives.

Effect of short-term supplementation of potassium chloride and potassium citrate on blood pressure in hypertensives.

Randomized trials have shown that increasing potassium intake lowers blood pressure. However, most previous trials used potassium chloride, whereas potassium in fruits and vegetables is not a chloride salt. It is unclear whether a nonchloride salt of potassium has a greater or lesser effect on blood pressure compared with potassium chloride. We performed a randomized crossover trial comparing potassium chloride with potassium citrate (96 mmol/d, each for 1 week) in 14 hypertensive individuals. At baseline, blood pressure was 151+/-16/93+/-7 mm Hg with a 24-hour urinary potassium of 81+/-24 mmol. During the randomized crossover part of the study, blood pressure was 140+/-12/88+/-7 mm Hg with potassium chloride (24-hour urinary potassium: 164+/-36 mmol) and 138+/-12/88+/-6 mm Hg with potassium citrate (24-hour urinary potassium: 160+/-33 mmol). These blood pressures were significantly lower compared with that at baseline; however, there was no significant difference in blood pressure between potassium chloride and potassium citrate, mean difference (95% confidence interval): 1.6 (-2.3 to 5.6) mm Hg for systolic and 0.6 (-2.4 to 3.7) mm Hg for diastolic. Our results, in conjunction with the evidence from many previous trials that potassium chloride has a significant blood pressure-lowering effect, suggest that potassium citrate has a similar effect on blood pressure as potassium chloride. These results support other evidence for an increase in potassium intake and indicate that potassium does not need to be given in the form of chloride to lower blood pressure. Increasing the consumption of foods high in potassium is likely to have the same effect on blood pressure as potassium chloride.

Plasma sodium: ignored and underestimated.

Salt intake is a major regulator of blood pressure. There is evidence that those who develop high blood pressure have an underlying defect in the ability of the kidney to excrete salt. It has been suggested that this results in a greater tendency to retain sodium and an increased compensatory response that is responsible for the rise in blood pressure. There is also evidence suggesting that small increases in plasma sodium may directly affect blood pressure, independent of the associated expansion in extracellular volume. We reanalyzed 3 types of studies of changing salt intake. (1) An acute and large reduction in salt intake from 350 mmol/d to 10 to 20 mmol/d for 5 days in hypertensives and normotensives was associated with a fall in plasma sodium of approximately 3 mmol/L (P<0.001). (2) Progressive increases in salt intake from 10 to 250 mmol/d by a daily amount of 50 mmol in normotensives caused increases in plasma sodium (P<0.001). (3) Longer-term modest reduction in salt intake in hypertensives was studied in double-blind randomized crossover studies; 1 month of usual salt intake ( approximately 170 mmol/d) compared with reduced salt intake ( approximately 100 mmol/d). There was a decrease in plasma sodium of 0.4+/-0.2 mmol/L (P<0.05), which was weakly but significantly correlated with the fall in systolic blood pressure (r=0.18; P<0.05). These studies demonstrate that an increase or a decrease in salt intake causes changes in plasma sodium. Small changes in plasma sodium alter extracellular volume, which may influence blood pressure. Changes in plasma sodium may also affect blood pressure directly.

Molecular variants of the sodium/hydrogen exchanger type 3 gene and essential hypertension.

OBJECTIVES: The objectives of this study were to identify polymorphic variants within the gene coding for the sodium/hydrogen exchanger type 3 (NHE3) and to examine their relationship with hypertension and biochemical indices of sodium balance. DESIGN AND METHODS: Case-control comparisons on a total of 691 subjects of which 399 (68% with essential hypertension) were of African or Afro-Caribbean origin (blacks) and 292 (50% with essential hypertension) were of Caucasian origin (whites). RESULTS: Eight exons of the C terminus of the NHE3 gene were screened systematically. A total of six variants were identified: (G1579A, G1709A, G1867A, C1945T, A2041G and C2405T). Further analyses in relation to essential hypertension and phenotypic characteristics were confined to the more frequent A2041G and the C2405T polymorphisms. The genotype frequencies of the A2041G polymorphism were significantly different between the whites and blacks, with the A allele being more frequent in the white population (0.43 for the whites and 0.14 for the blacks, respectively; P < 0.001). In contrast, there was no significant difference in the C2405T polymorphism between whites and blacks (C allele frequency: 0.86 for the whites and 0.88 for the blacks, respectively). In both the white and the black groups, there were no significant associations between these variants and essential hypertension (P > 0.05) or with serum electrolytes, creatinine or plasma renin activity (PRA) (ANOVA P > 0.05). CONCLUSIONS: These results suggest a high degree of structural conservation of the NHE3 gene; however, the lack of association between these polymorphisms and blood pressure status does not necessarily eliminate the participation of this important sodium/hydrogen exchanger in the pathophysiology of essential hypertension, as we cannot exclude the existence of functionally important genetic variants in other sequences within the NEH3 gene.

Contrasting associations between aldosterone synthase gene polymorphisms and essential hypertension in blacks and in whites.

BACKGROUND: Genetic variability in the gene for aldosterone synthase--a key enzyme in the production of aldosterone--can affect sodium homeostasis and thereby blood pressure. The possibility of impaired aldosterone production for the development of hypertension is of particular relevance in black Afro-Caribbeans exposed to a high dietary sodium intake. OBJECTIVES: To compare the frequency of three variants (-344C/T, intron 2 conversion, and the K173R polymorphism) of the aldosterone synthase gene in blacks and whites, and to determine any association of the variants with hypertension. DESIGN AND METHODS: We made case-control comparisons of the three gene variants in relation to ethnic background and to essential hypertension in 193 white (51% hypertensive) and 245 black individuals (59% hypertensive) living in south London. RESULTS: The frequency of each of the variants was significantly different between the two ethnic groups. The T and the K alleles were more frequent in the black participants (79 compared with 50% for the -344T allele and 81 compared with 50% for K173 allele), whereas the frequency of the intron 2 conversion allele was much lower in that group (8 compared with 38%). None of these variants was associated with essential hypertension in the black participants. In contrast, in the white participants there was a significant and graded association between the intron 2 conversion allele and essential hypertension (odds ratio 1.86, 95% confidence interval 1.16 to 2.98; = 0.01). Moreover, among the white population, the presence of homozygosity both of the T allele and of the intron 2 conversion alleles was associated with a much greater frequency of hypertension (71 compared with 43%; chi(2) = 0.03). CONCLUSIONS: The contrasting associations between these variants and essential hypertension do not necessarily exclude the possibility that other, as yet undefined, variants of the aldosterone synthase gene could be linked with hypertension in black people. Nonetheless, the strong association between the intron 2 conversion allele and essential hypertension in the white population reinforces the view that the increased blood pressure may be due, at least in part, to abnormal expression of enzymes involved in the metabolism of adrenal mineralocorticoids.

Amiloride, a specific drug for hypertension in black people with T594M variant?

The T594M polymorphism of the epithelial sodium channel is found in approximately 5% of people of African origin and is significantly associated with high blood pressure. Although the T594M polymorphism could increase renal sodium absorption through affected channels, it is not known whether this polymorphism causes hypertension. Amiloride specifically inhibits overactive sodium channels and effectively controls blood pressure in Liddle's syndrome, in which hypertension is caused by separate epithelial sodium channel mutations. The aim of this study was to determine whether amiloride was effective in lowering blood pressure in individuals with the T594M polymorphism. In an open, controlled study, 14 black hypertensive individuals with the T594M polymorphism were withdrawn from their usual medication and treated with amiloride. On entry to the study, individuals taking a mean of 2 drugs had blood pressure of 142/89+/-3/3 mm Hg. Amiloride alone (10 mg BID) controlled blood pressure effectively to the same level (140/91+/-4/2 mm Hg). When amiloride was withdrawn for 2 weeks, there was a large increase in blood pressure of 17/8+/-4/2 mm Hg (systolic, P<0.05; diastolic, P<0.01). On restarting amiloride, blood pressure was again controlled to 140/88+/-6/2 mm Hg. These results demonstrate that 10 mg BID amiloride is effective in controlling blood pressure in hypertensive individuals of African origin who have the T594M polymorphism. Our study supports the concept that the T594M polymorphism contributes to the elevation of blood pressure and suggests that consideration should be given to the use of amiloride in affected individuals.

Urinary protein and essential hypertension in black and in white people.

The objectives of this work were to examine the association between urinary protein and blood pressure and to compare the pattern of urinary protein excretion with essential hypertension in people of European origin (whites) and in people of African or African-Caribbean origin (blacks) living in southwest London, United Kingdom. In the groups as a whole, there were no significant differences in total urinary protein excretion between blacks and whites (geometric means [95% CI]: 94.0 [85.9 to 102.9] mg/24h for the blacks [n=151] and 102.1 [96.1 to 108.4] mg/24h for the whites [n= 219]). There were also no significant differences between blacks and whites in urinary albumin (6.5 [4.9 to 8.5] mg/24h for the blacks [n=97] and 7.1 [5.6 to 9.0] mg/24h for the whites [n=123]). In both groups, those with essential hypertension displayed a significantly raised urinary protein excretion (1.21-fold higher for the blacks and 1.19-fold higher for the whites) and albumin excretion (1.69-fold higher for the blacks and 2.40-fold higher for the whites). Urinary transferrin excretion measured in a subgroup of 67 subjects was also raised in those with essential hypertension (3.22-fold higher in the blacks and 2.76-fold higher in the whites). Examination of urinary proteins by SDS-PAGE did not identify any pattern consistent with a reduction in renal tubular protein reabsorption in those with essential hypertension. These results suggest that the increase in protein excretion in essential hypertension could be due, at least in part, to an increase in glomerular protein ultrafiltration.