Serum relaxin levels and kidney function in late pregnancy with or without preeclampsia.

OBJECTIVE: Relaxin, a potent pregnancy-related hormone, has been proposed to be a major mediator of renal physiology in normal pregnancy. We wished to test relaxin levels in pregnancy and preeclampsia. METHODS: We performed precise physiologic measurements of kidney function in 38 normal peripartum women and 58 women with preeclampsia. We measured serum relaxin levels prior to delivery and over the first 4 postpartum weeks utilizing a modern, validated ELISA. Results were compared to those of 18 normal women of childbearing age. RESULTS: Relaxin levels were substantially elevated in women prior to delivery (364 ± 268 vs. 15 ± 16 pg/ml) and fell rapidly over the first postpartum week reaching normal non pregnant levels by Week 2 (32 ± 64 vs. 15 ± 16 pg/ml). No differences were seen between relaxin levels in normal pregnancy as compared to preeclampsia (364 ± 268 vs. 376 ± 241 pg/ml) despite substantial and persistent abnormalities in GFR (149 ± 33 vs. 89 ± 25 ml/min), albuminuria (14 vs. 687 mg/g) and mean arterial pressure (80 ± 8 vs. 111 ± 18). Furthermore no correlation could be established between physiologic measures (GFR, MAP, RBF, RVR) and relaxin levels (p > 0.3), either in the overall population or any of the subgroups. CONCLUSION: Relaxin is indeed significantly elevated in the serum of women during late pregnancy and the early puerperium. However, serum relaxin does not appear to influence BP, renal vascular resistance, renal blood flow or GFR in late pregnancy or in women with preeclampsia.

Course of preeclamptic glomerular injury after delivery.

We evaluated the early postpartum recovery of glomerular function over 4 wk in 57 women with preeclampsia. We used physiological techniques to measure glomerular filtration rate (GFR), renal plasma flow, and oncotic pressure (pi(A)) and computed a value for the two-kidney ultrafiltration coefficient (K(f)). Compared with healthy, postpartum controls, GFR was depressed by 40% on postpartum day 1, but by only 19% and 8% in the second and fourth postpartum weeks, respectively. Hypofiltration was attributable solely to depression, at corresponding postpartum times, of K(f) by 55%, 30%, and 18%, respectively. Improvement in glomerular filtration capacity was accompanied by recovery of hypertension to near-normal levels and significant improvement in albuminuria. We conclude that the functional manifestations of the glomerular endothelial injury of preeclampsia largely resolve within the first postpartum month.

Effect of L-arginine therapy on the glomerular injury of preeclampsia: a randomized controlled trial.

OBJECTIVE: To assess the benefit of l-arginine, the precursor to nitric oxide, on blood pressure and recovery of the glomerular lesion in preeclampsia. METHODS: Forty-five women with preeclampsia were randomized to receive either l-arginine or placebo until day 10 postpartum. Primary outcome measures including mean arterial pressure, glomerular filtration rate, and proteinuria were assessed on the third and 10th days postpartum by inulin clearance and albumin-to-creatinine ratio. Nitric oxide, cyclic guanosine 3'5' monophosphate, endothelin-1, and asymmetric-dimethyl-arginine and arginine levels were assayed before delivery and on the third and 10th days postpartum. Healthy gravid women provided control values. Assuming a standard deviation of 10 mm Hg, the study was powered to detect a 10-mm Hg difference in mean arterial pressure (alpha .05, beta .20) between the study groups. RESULTS: No significant differences existed between the groups with preeclampsia before randomization. Compared with the gravid control group, women with preeclampsia exhibited significantly increased serum levels of endothelin-1, cyclic guanosine 3'5' monophosphate, and asymmetric-dimethyl-arginine before delivery. Despite a significant increase in postpartum serum arginine levels due to treatment, no differences were found in the corresponding levels of nitric oxide, endothelin-1, cyclic guanosine 3'5' monophosphate, or asymmetric-dimethyl-arginine between the two groups with preeclampsia. Further, there were no significant differences in any of the primary outcome measures with both groups demonstrating similar levels in glomerular filtration rate and equivalent improvements in both blood pressure and proteinuria. CONCLUSION: Blood pressure and kidney function improve markedly in preeclampsia by the 10th day postpartum. Supplementation with l-arginine does not hasten this recovery. LEVEL OF EVIDENCE: I.

The dynamics of glomerular filtration in the puerperium.

We evaluated the glomerular filtration rate (GFR) during the second postpartum week in 22 healthy women who had completed an uncomplicated pregnancy. We used physiological techniques to measure GFR, renal plasma flow, and oncotic pressure and computed a value for the two-kidney ultrafiltration coefficient (K(f)). We compared these findings with those in pregnant women previously studied on the first postpartum day as well as nongravid women of reproductive age. Healthy female transplant donors of reproductive age permitted the morphometric analysis of glomeruli and computation of the single-nephron K(f). The aforementioned physiological and morphometric measurements were utilized to estimate transcapillary hydraulic pressure (Delta P) from a mathematical model of glomerular ultrafiltration. We conclude that postpartum day 1 is associated with marked glomerular hyperfiltration (+41%). A theoretical analysis of GFR determinants suggests that depression of glomerular capillary oncotic pressure, the force opposing the formation of filtrate, is the predominant determinant of early elevation of postpartum GFR. A reversal of the gestational hypervolemia and hemodilution, still evident on postpartum day 1, eventuates by postpartum week 2. An elevation of oncotic pressure in the plasma that flows axially along the glomerular capillaries to supernormal levels ensues; however, GFR remains modestly elevated (+20%) above nongravid levels. An analysis of filtration dynamics at this time suggests that a significant increase in Delta P by up to 16%, an approximately 50% increase in K(f), or a combination of smaller increments in both must be invoked to account for the persistent hyperfiltration.

Determinants of GFR depression in early membranous nephropathy.

We evaluated the glomerular filtration rate (GFR) in 34 subjects with membranous nephropathy (MN) of new onset. We used physiological techniques to measure GFR, renal plasma flow, and oncotic pressure and computed a value for the two-kidney ultrafiltration coefficient (K(f)). A morphometric analysis of glomeruli in the diagnostic biopsy permitted computation of the single-nephron ultrafiltration coefficient (SNK(f)). MN subjects were divided into two groups: moderate or severe, according to whether GFR was depressed by less or more than 50%. SNK(f) was subnormal but similar in moderate and severe MN. In contrast, two-kidney K(f) was significantly more depressed in severe than in moderate MN. We estimated the total number of functioning glomeruli (N(g)) by dividing two-kidney K(f) by SNK(f). Whereas mean N(g) was similar in controls and moderate MN (1.5 and 1.4-1.7 x 10(6), respectively), it was significantly lower in severe MN (0.5 x 10(6)). This degree of glomerulopenia was not reflected in the rate of global sclerosis. We conclude that a combination of depressed SNK(f) (due to foot process broadening) and profound glomerulopenia accounts for GFR depression of >50% early in the course of MN. The cause of the glomerulopenia remains to be elucidated.

Glomerular permselectivity in early stages of overt diabetic nephropathy.

BACKGROUND: Impairment of glomerular size selectivity has been demonstrated by the dextran-sieving technique in nephropathic diabetics with heavy, but not mild proteinuria. The purpose of the present study was to determine whether such a barrier defect could be demonstrated with mild proteinuria by substituting Ficoll 70, a polysucrose, for dextran as a probe of the filtration barrier. METHODS: Differential solute clearances were performed in 12 individuals with early diabetic nephropathy on two occasions: after 60 days of treatment with losartan 50 mg daily or a placebo. An uncharged preparation of nonreabsorbable Ficoll 70 was infused along with inulin. Fractional clearance (theta) of Ficoll of discrete size was determined after separating molecules in urine and plasma in narrow 2 A fractions over a 20 to 60 A radius interval by size exclusion high-performance liquid chromatography (HPLC). A hydrodynamic theory of hindered ficoll transport through water-filled pores was used to characterize the pore size distribution of the glomerular barrier. RESULTS: The theta for Ficoll molecules with radii> 50 A was selectively enhanced in placebo-treated diabetic nephropathy versus corresponding theta in healthy control subjects (N = 12). Computations revealed a lower distribution of glomerular pores that was unaltered in nephropathic diabetics. However, an upper distribution of large, shunt-like pores was more prominent, exceeding healthy controls by one order of magnitude in diabetic nephropathy (P = 0.01). A trend to lower theta for Ficoll in the 56 to 60 A radius range during losartan therapy is computed to have lowered the fraction of shunted filtrate by 26 to 44%, depending on whether glomerular pressure declined. The corresponding reduction in theta for endogenous albumin, IgG, and IgG4 was by 19 to 23% (P < 0.05). CONCLUSION: Our findings suggest that shunt-like defects, partially reversible by angiotensin II blockade, are present early in the course of diabetic nephropathy. We estimate that such defects can account for immunoglobulinuria in this disorder. Additional impairment of either charge- or shape-selectivity must be invoked to explain the observed level of albuminuria, however.

Evolution of incipient nephropathy in type 2 diabetes mellitus.

BACKGROUND: We examined the course of glomerular injury in 12 Pima Indians with long-standing (>8 years) type 2 diabetes mellitus, normal serum creatinine, and microalbuminuria. They were compared with a group of 10 Pima Indians in Arizona with new-onset (<5 years) type 2 diabetes, normal renal function, and normoalbuminuria (<30 mg albumin/g creatinine on random urine specimens). METHODS: A combination of physiological and morphological techniques was used to evaluate glomerular function and structure serially on two occasions separated by a 48-month interval. Clearances of iothalamate and p-aminohippuric acid were used to determine glomerular filtration rate (GFR) and renal plasma flow, respectively. Afferent oncotic pressure was determined by membrane osmometry. The single nephron ultrafiltration coefficient (Kf) was determined by morphometric analysis of glomeruli and mathematical modeling. RESULTS: The urinary albumin-to-creatinine ratio (median + range) increased from 84 (28 to 415) to 260 (31 to 2232) mg/g between the two examinations (P = 0.01), and 6 of 12 patients advanced from incipient (ratio = 30 to 299 mg/g) to overt nephropathy (>/=300 mg/g). A 17% decline in GFR between the two examinations from 186 +/- 41 to 155 +/- 50 mL/min (mean +/- SD; P = 0.06) was accompanied by a 17% decline in renal plasma flow (P = 0.003) and a 6% increase in plasma oncotic pressure (P = 0.02). Computed glomerular hydraulic permeability was depressed by 13% below control values at both examinations, a result of a widened basement membrane and a reduction in frequency of epithelial filtration slits. The filtration surface area declined significantly, however, from 6.96 +/- 2.53 to 5.51 +/- 1.62 x 105 mm2 (P = 0.01), a change that was accompanied by a significant decline in the number of mesangial cells (P = 0.001), endothelial cells (P = 0.038), and podocytes (P = 0.0005). These changes lowered single nephron Kf by 20% from 16.5 +/- 6.0 to 13.2 +/- 3.6 nL/(minutes + mm Hg) between the two examinations (P = 0.02). Multiple linear regression analysis revealed that among the determinants of GFR, only the change in single nephron Kf was related to the corresponding change in GFR. CONCLUSION: We conclude that a reduction in Kf is the major determinant of a decline in GFR from an elevated toward a normal range as nephropathy in type 2 diabetes advances from an incipient to an overt stage.

Changing glomerular filtration with progression from impaired glucose tolerance to Type II diabetes mellitus.

Glomerular filtration rate (iothalamate clearance) was measured serially for 48 months in 26 Pima Indians with impaired glucose tolerance and 27 with normal glucose tolerance. At baseline, the mean glomerular filtration rate (SEM) was 133+/-8 ml/min in subjects with impaired glucose tolerance and 123+/-5 ml/min in those with normal glucose tolerance (p = 0.12). In the 12 subjects with impaired glucose tolerance who progressed to Type II (non-insulin-dependent) diabetes during follow-up, mean glomerular filtration rate increased by 30% (p = 0.011). Among the remaining 14 subjects with impaired glucose tolerance, 12 reverted to normoglycaemia. The glomerular filtration rate both at baseline and after 48 months in this subgroup exceeded the values of subjects with normal glucose tolerance by 20 % (p = 0.008) and 14% (p=0.013), respectively. A pronounced rise in the glomerular filtration rate occurs at the onset of Type II diabetes but a trend to hyperfiltration is also present in those with impaired glucose tolerance.

Molecular configuration and glomerular size selectivity in healthy and nephrotic humans.

We studied eight healthy volunteers and eight nephrotic subjects to compare the glomerular sieving coefficients (theta) of dextran, a linear polymer of glucopyranose, with those of Ficoll, a spherical polysucrose. Over a molecular radius (rs) interval of 20-70 A, theta for a given Ficoll was uniformly lower than corresponding theta for a dextran of equivalent rs. For each macromolecular species, the theta of molecules with rs > 50 A was selectively enhanced in nephrotic vs. healthy subjects. Analysis of either dextran or Ficoll sieving curves with pore theory revealed the glomerular barrier to have a bimodal pore size distribution: a lower mode of restrictive pores with a lognormal distribution of radii and an upper mode of large shuntlike pores. Nephrotics differed from controls in that the lower mode was broadened and shifted to pores of smaller mean size, but the prominence of shuntlike pores was enhanced by an order of magnitude. Both the mean radius of restrictive pores and the magnitude of the shunt pathway were substantially smaller when estimated from Ficoll than dextran sieving. We interpret the more realistic values for pore parameters derived from Ficoll than dextran sieving to indicate 1) that the normal glomerular barrier prevents albuminuria by virtue of a combination of both charge- and size-selective properties and 2) that a combined impairment of both barrier charge selectivity and size selectively are required to account for the observed level and composition of proteinuria in our nephrotic subjects.

Modeling of progressive glomerular injury in humans with lupus nephritis.

We studied glomerular function longitudinally for 36-120 mo in 21 patients undergoing treatment for diffuse, proliferative lupus nephritis. We determined glomerular filtration rate (GFR) and glomerular oncotic pressure (IIGC) and computed the two-kidney ultrafiltration coefficient (Kf) at 6- to 12-mo intervals. The relationships and cross talk among the three variables over time were then analyzed by eigenfunction regression and canonical correlations. We also performed a morphometric analysis of serial biopsies and computed single-nephron Kf in patent glomeruli at baseline and after 36-94 mo of follow-up. Patients were divisible into progressors (n = 12) or nonprogressors (n = 9) according to the presence or absence, respectively, of an irrevocable decline in GFR over time. Examination of longitudinal variables revealed GFR to be strongly related to Kf in all patients and inversely related to IIGC in progressors. By serial morphometric analysis we observed a threefold increase in the prevalence of global sclerosis in progressors but unchanged prevalence in nonprogressors. Whereas single-nephron Kf of remnant glomeruli increased to supernormal levels in nonprogressors, the absence of this compensatory phenomenon in progressors permitted GFR and Kf to decline in parallel with the declining number of functional glomeruli.

Progression of overt nephropathy in non-insulin-dependent diabetes.

The detection of overt albuminuria (> 300 mg/g creatinine) in the absence of azotemia was used to diagnose early nephropathy in 34 Pima Indians with NIDDM of 16 +/- 1 years duration. Differential solute clearances were performed serially to define the course of the glomerular injury over 48 months. At baseline, the GFR (107 +/- 5 ml/min), filtration fraction and sieving coefficients of relatively permeant dextrans (< 52 A) were all depressed below corresponding values in 20 normoalbuminuric Pima Indians with a similar duration of NIDDM. Over the ensuing 48 months the GFR (-34%) and filtration fraction (-13%) in the nephropathic patients declined further. The sieving coefficients of large, nearly impermeant dextrans (> 56 A radius) increased selectively and fractional clearances of albumin and IgG increased correspondingly by > 10-fold. Analysis of the findings with pore theory revealed: (1) a progressive decline in pore density and the ultrafiltration coefficient (Kf); and (2) broadening of glomerular pore-size distribution that resulted in greater prominence of large pores (> 70 A radius). We conclude that increasing loss of intrinsic ultrafiltration capacity is the predominant cause of the early and progressive decline in GFR that follows the development of nephropathy in NIDDM. We speculate that progressive impairment of barrier size-selectivity contributes to but does not fully account for the increasingly heavy proteinuria that is observed early in the course of this disorder.

Effects of acute acid-base disturbances on K+ delivery to the juxtamedullary end-descending limb.

Effects of acute-base disturbances on fractional delivery of potassium to the juxtamedullary end-descending limb were examined by micropuncture in the rat to test the hypothesis that potassium is reabsorbed from the collecting duct and is secreted in juxtamedullary pars recta or descending limb in the renal medulla. In metabolic acidosis, fractional potassium delivery was only slightly reduced compared with control values and was a function of potassium excretion, as the hypothesis predicts. Fractional potassium delivery was sharply reduced both in respiratory acidosis and metabolic alkalosis and was no longer a function of potassium excretion. Although seemingly inconsistent with the recycling hypothesis, the latter finding may be reconciled by the following observations. In respiratory acidosis, vasa recta blood flow nearly doubled, which would lead to vascular washout of interstitial potassium. In metabolic alkalosis, flow rate in the pars recta or descending limb was reduced by 28%, which would limit transepithelial potassium addition. The results indicate complex effects of acid-base disturbances on fractional potassium delivery to the end-descending limb, which can be unified by postulated changes in transepithelial potassium concentration differences across the juxtamedullary pars recta or descending limb. An unexpected observation emerged--fractional delivery of water to the end-descending limb declined as a function of plasma bicarbonate concentration when all groups were combined.

Effects of acute acid-base disturbances on renal tubule reabsorption of magnesium in the rat.

The effects of acute metabolic and respiratory acidosis and acute metabolic alkalosis on magnesium excretion and on fractional magnesium delivery to the end-accessible proximal tubule of the superficial nephron and the end-descending limb of the juxtamedullary nephron were examined by micropuncture in anesthetized thyroparathyroid-intact rats. Compared with normal control rats, acute metabolic acidosis (HCl infusion) did not produce any significant change. Acute respiratory acidosis (15% CO2 in inspired air) significantly increased the absolute but not the fractional excretion of magnesium and did not alter fractional delivery of magnesium to the end-accessible superficial proximal tubule or juxtamedullary end-descending limb. Acute metabolic alkalosis (NaHCO3 infusion) significantly reduced absolute and fractional magnesium excretion and fractional magnesium delivery to the end-descending limb of the juxtamedullary nephron but did not affect fractional magnesium delivery to the end-accessible proximal tubule of the superficial nephron. Tubule fluid-to-ultrafilterable magnesium ratio was a function of tubule fluid-to-plasma inulin ratio in the end-descending limb when all groups were combined. These results suggest that although acute metabolic or respiratory acidosis has no significant effect, acute metabolic alkalosis enhances magnesium reabsorption in the juxtamedullary proximal nephron--possibly in the pars recta.