Course Of Nephropathy During Pregnancy

GFR rises by 40-80% in normal and uncomplicated diabetic pregnancy, as reflected by increasing CrCl and decreasing serum creatinine (Cr) [83,84]. The increase in GFR occurs in the first weeks of pregnancy [85] in advance of the expansion of plasma volume [86], and reaches an increment of 40-50% by the end of the first trimester [83]. The glomerular hyperfiltration and increase in renal plasma flow (RPF) is maximal at 26-30 weeks gestation [87], then RPF declines significantly by term pregnancy (but not to control levels) in subjects lying on their sides, while GFR by inulin clearance does not [84,88]. Therefore, filtration fraction (GFR/RPF) must increase in late normal pregnancy as osmotic pressure declines [84]. Since there is a slight decline in endogenous CrCl from 29 to 37 weeks (141 to 126 ml/min), it is possible there is reduced tubular secretion of Cr in late pregnancy, at the same time there is enhanced net tubular reabsorption of uric acid and slight decrease in uric acid clearance [88,89].

Studies in pregnant women and rat models indicate that increased GFR is due to elevated RPF and vasodilation of afferent and efferent arterioles without evidence of increased glomerular capillary pressure (Pgc) [86], with some contribution from both decreased afferent and efferent osmotic pressure and increased Kf [84,90]. Based on studies in chronically instrumented rats, it is unlikely that vasodilatory prostaglandins mediate the renal hemodynamic changes of pregnancy [86,91]. Nitric oxide is the prime candidate for causing glomerular vasodilation in pregnancy [92], as acute selective blockade of both iNO and nNO reduce the gestational levels of RPF and GFR without effect on systemic arterial pressure [93,94]. Extensive studies in various pregnant rat models of experimental nephropathy never showed increased Pgc [86], which is reassuring since hyperfiltration and hypertension in the glomerulus is considered a prerequisite for human DN.

With DN in pregnancy, the expected rise in CrCl is seen in only about one-third of patients, as summarized in table 2 [38,95,96]. In another one-third of DN patients, CrCl actually decreases, probably reflecting the underlying natural progression of nephropathy or accelerating hypertension. In a recent analysis, initial elevated Cr of 109-163 |M (1.0-1.5 mg/dL) was associated with a decline in CrCl during pregnancy in 12 women with DN, whereas in 9 patients with initial Cr >163 |M (1.5 mg/dL), CrCl remained stable but low at 41-65 ml/min [97]. When inverse serum Cr levels are used as an indicator of GFR, about one third of DN patients show a rise in Cr by the third trimester, related to reduced renal function at baseline and/or superimposed PET [98-102]. A rise in Cr was associated with "cross-over" from a hyperdynamic cardiac output to a vasoconstricted state in a preliminary report on a large number of pregnant women with DN [103]. Jovanovic found that prevention of hyperglycaemia and hypertension allowed a normal rise in CrCl during pregnancy in 8 diabetic women with sub-par values prior to conception [38]. On the other hand, Biesenbach et al observed that mean CrCl declined by 16% during the first two trimesters in 7 proteinuric diabetic women with subnormal CrCl prior to pregnancy (37-73 ml/min/1.73m2), in spite of intensified glycemic control and anthypertensive therapy during pregnancy [104]. These data illustrat the potential difficulty of pregnancy in DN patients with azotemia prior to pregnancy.

Table 2. Changes in creatinine clearance in 44 women with diabetic nephropathy with measurements in both first and third trimester of pregnancya

CrCl

First trimester

Third trimester

n (%)

Increased >25%

Stable

Decreased>15%

>90 ml/min

14 (32%)

3 (21%)

5 (36%)

6 (43%)

60-89 ml/min

20 (45.5%)

9 (45%)

6 (30%)

5 (25%)

<60 ml/min

10 (22.5%)

2 (20%)

6 (60%)

2 (20%)

Total

44 (100%)

14 (32%)

17 (39%)

13 (29%)

Data stratified by CrC1 in first trimester: normal, moderate reduction, and severe reduction. Data pooled from Kitzmiller et al [95], Jovanovic and Jovanovic [38], and Reece et al [96].

Data stratified by CrC1 in first trimester: normal, moderate reduction, and severe reduction. Data pooled from Kitzmiller et al [95], Jovanovic and Jovanovic [38], and Reece et al [96].

In streptozotocin (STZ)-treated pregnant rats with acute hyperglycemia from the onset of pregnancy, the diabetes leads to enhanced RPF and GFR dependent on increased renal synthesis of NO [105]. Increased NO production and changes in renal hemodynamics in pregnant rats are dependent on differential expression of renal NO synthase isoforms, with eNOS down-regulated and iNOS and nNOS upregulated [106]. STZ given at day 8 of pregnant rats produced hypertension, proteinuria , and reduced fetal size [107]. It is of interest that chronic nonselective inhibition of NO synthase in the pregnant rat reduces GFR accompanied by proteinuria and hypertension [108].

Data are few on use of serum cystatin C as a reciprocal indicator of GFR [24] during pregnancy. The mean serum concentration of cystatin C was found to be paradoxically higher for pregnant than healthy non-pregnant women, in spite of increased GFR, while mean serum creatinine levels were lower in normal pregnancy [26]. Since the serum level of a substance is inversely related to its clearance, reciprocals of cystatin C concentrations were correlated (r 0.76) with a reference method for GFR during pregnancy; perhaps there is increased production of cycstatin C during gestation [26]. Maternal cystatin C levels did not correlate with neonatal concentrations [109], nor with fetal or placental weight, although the highest serum levels were found in twin gestations [26]. Women with PET had higher serum levels of cystatin C and lower GFR (113 vs 153 ml/min) than healthy pregnant women [26], and the group in Sweden believes serum cystatin C to be a better marker for PET than serum urate [110]. I am not aware of published measurements in pregnant diabetic women with albuminuria.

An increase in kidney volume can be measured by ultrasound in pregnancies in normal controls [111] and in insulin-dependent diabetic women [112]. In the latter group the expansion occurs in spite of strict glycaemic control, and the increase correlates with CrCl but not with albuminuria or BP levels. Renal expansion is less in pregnant women withDN, but renal volume did not decline as expected 4 months postpartum in this group in one study [112]. Interestingly, development of persistent microalbuminuria was most likely in the group of diabetic women with normoalbuminuria and relatively small renal volumes in early pregnancy.

The urinary excretion of albumin (UAE) increases only slightly innormal pregnancy [84,113-117], while total urinary protein excretion (TPE) increases by 40-200 %, albeit to <300 mg/24hrs (table 3) [118,119]. Albumin represents a small fraction of TPE. The increase in TPE is presumably due to increased GFR and limited tubular reabsorption [18,119]. Low molecular weight proteins like ^2-microglobulin, retinol binding protein, and immunoglobulin light chains are freely filtered by the glomerulus and increased load to the proximal tubules in pregnancy must exceed reabsorptive capacity as there is increased urinary excretion [113,117]. This may be similar to the proximal tubular dysfunction seen in non-pregnant type 1 and type 2 diabetic patients + microalbuminuria [120]. Glomerular permselectivity for the heart-shaped albumin [121] (radius 3.6 nm) remains relatively intact in normal pregnancy [122], or else specific tubular albumin uptake is stable or enhanced. I know of no studies of urinary albumin fragments (as a marker of tubular processing of albumin) [123] in pregnancy.

Table 3. Albuminuria and proteinuria before, during and after normal and type 1 diabetic pregnancies without clinical nephropathy.

Before

3rd trimester

4*-6**mo PP

11 nl controls *

UAE (mg/d)

9

12

13

TPE (mg/d)

117*

262

174

7 normoalb type 1**

UAE

12

71

13

TPE

73

4

7

microalb type 1**

UAE

80

478

114

TPE

233

2350

239

* Roberts et al 1996 [122] UAE, urinary albumin excretion

** Biesenbach, Zasgornik 1989 [130] TPE, total protein excretion

* Roberts et al 1996 [122] UAE, urinary albumin excretion

** Biesenbach, Zasgornik 1989 [130] TPE, total protein excretion

Glomerular permeability involves charge-, shape-, and size-selectivity for the filtered macromolecules [124], although the concept of charge-selectivity has become controversial [125]. Sieving studies with dextran particles of 3.5-6.0 nm radius are most consistent with an isoporous + shunt model of glomerular ultrafiltration in normal pregnant women, with a decrease in small pores of 3.04.9 nm [84,90]. This model assumes that the glomerular wall "is perforated by a series of restrictive pores of identical radius and has a parallel shunt pathway that fails to restrict the passage of large molecules" [90]. There are technical problems with dextran sieving due to changes in conformation during passage, and studies using the more rigid spherical Ficoll particles [126] are needed for normal and proteinuric pregnancies. The current general model of the structural determinants of glomerular permeability emphasizes the cellular layers (fenestrated endothelium, epithelial {podocyte} filtration slits) rather than the glomerular basement membrane (GBM) as determining the size selectivity for macromolecules [127]. The central size-selective filtration barriers are the slit diaphragms bridging the podocyte foot processes on the epithelial side of the GBM [128].

In diabetic women without microalbuminuria in early pregnancy (<30 mg/24 hrs), UAE increases slightly in the second trimester and sometimes greatly in the third trimester, while urinary TPE can rise to >300 mg/24hrs [129-131]. Of course, some cases of this proteinuria may be explained by mild PET, which always muddles the view of changes in renal function in pregnant diabetic women. The glomerulo-tubular functional/structural determinants of this diabetes-associated progression in albuminuria in pregnancy have not been adequately studied. Assuming analogous processes to those in non-pregnant women may be misleading. In the setting of the DCCT, only 10 of 180 type 1 diabetic women in either treatment group developed microalbuminuria (>40mg/24hr) during pregnancy [53]. With microalbuminuria before pregnancy in diabetic women, the increase in UAE and TPE during gestation is even greater (table 3) [132-134]. Most investigators have observed that diabetic microalbuminuria in early pregnancy predicts a risk of superimposed PET of 35-60% compared to 6-14 % in diabetic women without microalbuminuria [132, 133,135-137]. Similar findings are reported for non-diabetic pregnant women with microalbuminuria measured in mid-pregnancy [138-141], suggesting that this is a marker for a subtle generalized vascular disorder, related to insulin resistance or inflammation [142-147].

The gestational changes in total proteinuria mean that most clinical studies of DN in pregnancy have probably included women with undetected microalbuminuria prior to conception who happened to progress to mild macroproteinuria (400-600 mg total protein/24hrs) in early pregnancy, and thus were inappropriately selected as patients with mild DN. With definite clinical diabetic nephropathy diagnosed prior to pregnancy, albuminuria and total proteinuria often increase dramatically during gestation, even without associated hypertension, frequently exceeding 10 g/24 hours in the third trimester. Though some of this increase may reflect the underlying progression of nephropathy, protein excretion usually subsides after delivery, but not necessarily to preconception levels [95,96, 104,148]. It is unknown whether the heavy proteinuria is due to effacement of the podocyte foot processes and changes in the slit diaphragms with overload to the tubules, and the mechanisms of postpartum repair are also unclear. There is concern that temporary heavy overload proteinuria in pregnancy exceeding maximal proximal tubular reabsorption could contribute to later tubulo-interstitial fibrosis via upregulation of vasoactive and inflammatory genes [149]. Follow-up studies of women with DN are discussed in the next section.

Prior to pregnancy the subtle rise in daytime blood pressure (BP) observed in most diabetic women and adolescents with persistent microalbuminuria [150152] has been considered secondary [153] or perhaps compensatory [154] to early renovascular pathology [155-157]. On the other hand, several studies of ambulatory BP monitoring suggest that subtly higher daytime or nocturnal systolic pressure precedes or predicts the development of microalbuminuria in type 1 and type2 diabetic women [158-163]. It is important to note that 24-hr ambulatory BP monitoring of non-diabetic controls showed that females have significantly lower daytime and nightime systolic and diastolic levels than males, but that this gender differential is minimized with type 1 diabetes for unknown reasons [164]. Diabetic microalbuminuria is associated with (1) enhanced BP responsiveness to norepinephrine and angiotensin II infusion and sodium intake [165-167], (2) increased Na+/Li+ countertransport activity

[168], and (3) an increased peripheral transcapillary escape rate of albumin

[169], suggesting linkage of renal and vascular pathogenic processes. These studies and many others raise the question of genetic susceptibility to hypertension and nephropathy [170] which is perhaps linked to PET [171].

During pregnancy ambulatory BP monitoring of non-diabetic women has been used to predict hypertensive complications in the third trimester with fairly low sensitivity and specificity [172,173]. In type 1 diabetic pregnant women, mid-pregnancy cutoffs of >105 nighttime systolic [174] or >122 daytime systolic [136] provided the best sensitivity-specificity for third trimester hypertension. However, a careful study in Denmark showed that UAE 30-299 mg/24hr was a better predictor of PET in type 1 diabetes than diurnal BP (patients with treated hypertension were excluded) [135]. In a study of early pregnancy TPE in American diabetic women (mixed type 1 and type 2), 27% of 45 women with microproteinuria (190-499 mg/24hr) were treated for chronic hypertension compared to 39% in 62 patients with 500 mg/24hr and only 6% in 204 women with TPE <190 mg/24hr [133]. Patients with both early pregnancy microproteinuria and chronic hypertension had the highest frequency (~50%) of superimposed PET.

In a New Zealand study of pooled groups of 100 each of type 1 and 2 diabetes, significant factors predicting the development of hypertension in pregnancy included nulliparity (RR 1.5), smoking (RR 0.39), duration diabetes >10 years (RR 1.87), earliest HbA1c >9.0 (RR 1.9), retinopathy (RR 1.8), earliest UAE 30-300 mg/24hr (RR 1.8), earliest systolic BP 116-129 mmHg or higher (RR 2.1), and earliest diastolic BP >80 mmHg (RR 2.5) [175]. Many of these parameters are interelated. Primary PET was more common in type 1 (19%) than in type 2 (7%) diabetes, while the latter cases had more chronic hypertension and micro- and macroalbuminuria. Similar predictors of hypertensive disorders in pregnant women with type 1 diabetes were identified in large Swedish and North American multicenter studies [176-178]. Initial hypertension in women with DN is a strong predictor of "cross-over" from a hyperdynamic hemodynamic state with increased cardiac output to vasoconstriction associated with PET and decline in renal function [103]. A combined family history for hypertension and type 2 diabetes is a strong predictor of risk of hypertension [171], perhaps related to insulin resistance as a risk factor for PET [179-180]. Prediction of risks for development of PET and understanding of its pathogenesis [181-183] is important to find means of preventing this syndrome [184], which is a major cause of maternal-fetal mortality and morbidity. Trials of supplementation of fish oil, calcium, magnesium, and zinc, and use of low-dose aspirin have generally been disappointing [185-186]. Trials of antihypertensive drugs for prevention of PET have been inadequately powered and choice of agents limited by concerns for fetal injury [185]. Supplementation with antioxidant vitamins in pregnant women at high risk holds some promise [187]. Undoubtedly studies will be designed to test the hypothesis (see below) that normalization of circulating free vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) levels will halt progression of PET [188], which would certainly improve the outcome of DN in pregnancy if the pathogenesis is the same as in "pure" PET.

Maternal characteristics identified in early pregnancy in 225 cases of clinical DN reported in 1981-1996 include ~50% frequencies of proliferative retinopathy, anemia, and hypertension. Reduced CrCl (<80 ml/min) was recorded in 45% of cases and 15% of the total had serum creatinine (Cr) >134uM (table 4) [38,95,96,98,100,101,148,189-192]. Low-level proteinuria (<1 gm total protein/24 hrs before 20 weeks gestation) was detected in many of the women, so these cases are suspected not to be "true" DN, therefore the frequencies of anemia, hypertension, PDR, and impaired glomerular filtration probably should be higher. Of 146 diabetic women with >1 gm total protein/24 hrs in early pregnancy, 57 had impaired renal function at that stage of gestation (Cr>134 uM or CrCl <80 ml/min), and 37% showed a further decline of >15% during later pregnancy. Three series of pregnant women with DN reported since 1996 show similar proportions of these maternal complications [102, 104,193]. Pregnancy is probably contraindicated in patients with DN if the Cr is above 206 ^M or CrCl is below 50 ml/min before or in early pregnancy, because of the high rate of maternal and fetal complications, until renal transplantation can be performed 2 years prior to conception.

Table 4. Course of renal parameters during and after pregnancy in women with diabetic nephropathy. Data pooled from references 95,96,100,101,148,190,191,192

Hypertension

Ur Prot > 5 gm/d

Decr CrC1 Incr Cr

Renal Failure

Death

Early preg

42%

9%

34%

0

0

Late preg

71%

26%

26%

0

0

Follow-up

60%

17%

43%

23%**

5.6%

Maternal anemia results from both decreased erythropoietin production by damaged kidneys and the physiologic hemodilution of pregnancy. The degree of anemia is related to the severity of nephropathy as reflected in lower creatinine clearance and is not usually associated with abnormal iron studies [95]. Exogenous erythropoietin can be used to treat anemia unresponsive to iron and folate replacement [194-197]. Asymptomatic bacteriuria is more common in diabetic than non-diabetic women, leading to a greater risk of UTI [198-201], but there is controversy over screening and treatment outside of pregnancy [202,203]. During pregnancy screening and preventive treatment of women with hypertension or DN is justified due to the deleterious effects of pyelonephritis [95]. Although paradoxically PET in the third trimester may be less common in non-diabetic women who smoke cigarettes [175,177,204], smoking should be strongly discouraged in diabetic women due to impaired fetal oxygenation in mid-pregnancy and hazardous effects on progression of DN [206-209].

Diabetic nephropathy can progress to end-stage renal disease (ESRD) during pregnancy, although this is unusual. Of 195 women followed after pregnancy and summarized in table 4, none progressed to end-stage disease during pregnancy. There is experience with both hemodialysis and continuous ambulatory peritoneal dialysis in pregnancy, but analyzed cases include few diabetic women [210-216]. In about one-fourth of reported cases of dialysis in pregnancy the patients conceived prior to starting dialysis - they either were close to needing dialysis prior to the unplanned gestation or had a rapid decline in renal function during pregnancy [213]. In this group termination of pregnancy rarely rescues the kidneys [217,218], and "unless transplant is a certainty, the pregnancy may be the woman's last chance to have a child" [213]. In women using dialysis prior to conception treatment of anemia with erythropoietin and/or blood transfusion is usually required [195]. In a US national registry survey of pregnancy in dialysis patients with ESRD of various causes (36.6% primary glomerular diseases, 26.3% lupus or other vasculitis, 7.4% diabetes, 6.6% interstitial diseases, 14.2% other) , BP was normal in only 21%, and severe hypertension (BP >170/110) was noted at some time during pregnancy or postpartum in 48% [213]. There were 5 episodes of peritonitis in 59 pregnancies in women treated with peritoneal dialysis; there were 245 pregnancies in women using hemodialysis, and 2 maternal deaths in the entire group, which is "lower than the average for dialysis patients of child-bearing age as a whole" [213]. Therefore the risk of death for a dialysis patient who becomes pregnant is not increased by the pregnancy, but "the severity of the illness in the women with hypertensive crisis is evidence that pregnancy is a dangerous undertaking for a pregnant patient" [213].

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